| 2021 | Acceptance and completion of rifapentine-based TB preventive therapy (3HP) among people living with HIV (PLHIV) in Kampala, Uganda-patient and health worker perspectives. | Implement Sci Commun | A 12-dose, once-weekly regimen of Isoniazid and rifapentine (3HP) is effective in preventing tuberculosis (TB) among people living with HIV (PLHIV). We sought to identify potential barriers to and facilitators of acceptance and completion of 3HP treatment from the perspective of people living with HIV (PLHIV) and health workers in a routine HIV care setting in Kampala, Uganda.We conducted semi-structured interviews with 25 PLHIV and 10 health workers at an HIV/AIDS clinic in Kampala, Uganda. For both groups, we explored their understanding and interpretations of TB and TB preventive therapy (TPT), and perceptions about social and contextual factors that might influence the willingness of PLHIV to initiate and complete 3HP. We analyzed the data using an inductive thematic approach and aligned the emergent themes to the Behavior Change Wheel framework to identify sources of behavior and targeted behavior change interventions.Facilitators of acceptance and completion of 3HP treatment among PLHIV were fear of contracting TB, awareness of being at risk of getting TB, willingness to take TPT, trust in health workers, and the perceived benefits of directly observed therapy (DOT) and self-administered therapy (SAT) 3HP delivery strategies. Barriers included inadequate understanding of TPT, fear of potential side effects, concerns about the effectiveness of 3HP, and the perceived challenges of DOT or SAT. Among health workers, perceived facilitators included knowledge that TB is a common cause of mortality for PLHIV, fear of getting TB, and trust in the health workers by PLHIV, the advantages of once-weekly 3HP dosing, and the benefits of DOT and SAT 3HP delivery strategies. Health worker-reported barriers for PLHIV included inadequate understanding of TB and benefits of TPT, TB-associated stigma, potential side effects pill burden, and challenges of DOT and SAT 3HP delivery strategies. Lack of experience in the use of digital technology to monitor patient care was identified as a health worker-specific barrier. Identified intervention functions to address the facilitators or barriers included education, persuasion, environmental restructuring, enablement, and training.Using a formative qualitative and comprehensive theoretical approach, we identified key barriers, facilitators, and appropriate interventions, including patient education, enhancing trust, and patient-centered treatment support that could be used to optimize the delivery of 3HP to PLHIV in our setting. These interventions are likely generalizable to other clinical interventions in similar populations in sub-Saharan Africa and other TB high-burden settings. |
| 2021 | High rate of completion for weekly rifapentine plus isoniazid treatment in Chinese children with latent tuberculosis infection-A single center study. | PLoS One | Three months of weekly rifapentine plus Isoniazid (3HP) is a short course regimen for latent tuberculosis infection treatment with satisfied safety and efficacy. However, research on its use in children is limited. In this study, we evaluated the completion rate and safety of the 3HP regimen among children in China. Participants aged 1-14 years receiving 3HP for TB prevention at Shanghai Public Health Clinical Center were followed from December 2019 to November 2020 to evaluate the safety and completion rate of the treatment. Thirty-one children were eligible for inclusion, but five were excluded from the analysis (three were treated with a lower than recommended dose, and two were lost to follow-up). Of the 26 children included in the analysis, the treatment completion rate was 100%. Adverse drug reactions (ADRs) were reported in 38.5% (10/26) of the patients. The most common ADRs were gastrointestinal symptoms (19.2%,5/26), and all ADRs were rated as Grade 1. The 3HP regimen has a high completion rate, and it seems well tolerated in our study population. However, further randomized controlled clinical trial with larger sample size are warranted. |
| 2021 | An observational study on prevalence of latent tuberculosis infection and outcome of 3HP treatment in patients under hemodialysis in Taiwan. | J Formos Med Assoc | Identification and treatment for latent tuberculosis infection (LTBI) are of great epidemiological importance of controlling tuberculosis (TB) worldwide. Identification in high-risk population on dialysis and treatment with 12-week weekly rifapentine plus Isoniazid (3HP) help improve prevention outcomes effectively.We conducted a single-center, nonrandomized follow-up study on end-stage renal disease patients on hemodialysis. The interferon-gamma release assay (IGRA) was used for the diagnosis of LTBI. Participants were treated with 3HP, and treatment responses were recorded and analyzed.A total of 123 of the 641 patients showed positive IGRA results. The male sex, age >60 years, low serum albumin level (<4.0 g/dL), and hypercalcemia (serum calcium level > 10.2 mg/dL) were associated with IGRA positivity. Seventy-five patients were treated with 3HP, with a completion rate of 66.67%. The male sex, albumin level >4.0 g/dL, and absence of adverse drug reaction were associated with increased completion rates. Adverse drug reactions included dizziness, fatigue, nausea and vomiting, fever, and hypertension.Risk factors for LTBI in dialysis patients were identified to prioritize LTBI screening and initiate early treatment. The completion rate in dialysis patients were approximately 2 of 3 patients with mild adverse drug reaction, leading to discontinuation of the treatment. |
| 2021 | Cost-effectiveness analysis of 3 months of weekly rifapentine and isoniazid compared to isoniazid monotherapy in a Canadian arctic setting. | BMJ Open | To assess the cost effectiveness of once weekly rifapentine and Isoniazid for 12 weeks (3HP) to the current standard care for latent tuberculosis (TB) infection (LTBI) in Iqaluit, Nunavut.A cost-effectiveness analysis using a Markov model reflecting local practices for LTBI treatment.A remote Canadian arctic community with a high incidence of TB.Hypothetical patients with LTBI.The cost effectiveness of 3HP was compared with the existing standard of care in the study region which consists of 9 months of twice weekly Isoniazid (9H) given by directly observed therapy.Effectiveness was measured in quality-adjusted life years (QALYs) with model parameters were derived from historical programmatic data, a local implementation study of 3HP and published literature. Costs from the perspective of the Nunavut healthcare system were measured in 2019 US dollars and were obtained primarily from local, empirically collected data. Secondary health outcomes included estimated TB cases and TB deaths averted using 3HP versus 9H. One way and probabilistic sensitivity analyses were performed.The 3HP regimen was dominant over 9H: costs were lower (US$628 vs US$924/person) and health outcomes slightly improved (20.14 vs 20.13 QALYs/person). In comparison to 9H, 3HP treatment resulted in fewer TB cases (27.89 vs 30.16/1000 persons) and TB deaths (2.29 vs 2.48/1000 persons). 3HP completion, initiation and risk of fatal adverse events were the primary drivers of cost effectiveness.In a remote Canadian arctic setting, using 3HP instead of 9H for LTBI treatment may result in cost savings and similar or improved health outcomes. |
| 2021 | Adverse events associated with weekly short course isoniazid and rifapentine therapy in pediatric patients with latent tuberculosis: A chart and literature review. | Pediatr Pulmonol | Effective yet safe treatment of latent tuberculosis is important for preventing the spread of tuberculosis and the progression to active disease in pediatric patients. As of 2017, the short course combination regimen of weekly Isoniazid and rifapentine (3HP) administered by directly observed therapy (DOT) has replaced 9 months of Isoniazid as the standard of treatment for latent tuberculosis in pediatric patients. The literature, limited in size, has established the 3HP regimen's superior safety and adherence.We completed a retrospective chart review (n = 22) of pediatric patients at our institution receiving the 3HP regimen via DOT between 2017 and 2019. Frequencies of selected outcomes were compared to previously published data collected in a literature review.In this retrospective chart review, pediatric patients ages 2-20 years receiving 3HP with DOT for latent tuberculosis experienced frequent adverse events, more severe adverse events such as anaphylaxis, and higher treatment discontinuation than that which has been previously reported in the literature. Of note, our cohort's race/ethnicity differed from the cohorts described in the literature.Our data suggests that the short course combination regimen for pediatric latent tuberculosis patients may have a higher adverse event rate than previously established. Although this sample size is small, this study urges further investigation of more diverse cohorts to better establish the 3HP regimen's safety and tolerability. |
| 2021 | Four-Month Rifapentine Regimens with or without Moxifloxacin for Tuberculosis. | N Engl J Med | Rifapentine-based regimens have potent antimycobacterial activity that may allow for a shorter course in patients with drug-susceptible pulmonary tuberculosis.In an open-label, phase 3, randomized, controlled trial involving persons with newly diagnosed pulmonary tuberculosis from 13 countries, we compared two 4-month rifapentine-based regimens with a standard 6-month regimen consisting of rifampin, Isoniazid, pyrazinamide, and ethambutol (control) using a noninferiority margin of 6.6 percentage points. In one 4-month regimen, rifampin was replaced with rifapentine; in the other, rifampin was replaced with rifapentine and ethambutol with moxifloxacin. The primary efficacy outcome was survival free of tuberculosis at 12 months.Among 2516 participants who had undergone randomization, 2343 had a culture positive for that was not resistant to Isoniazid, rifampin, or fluoroquinolones (microbiologically eligible population; 768 in the control group, 791 in the rifapentine-moxifloxacin group, and 784 in the rifapentine group), of whom 194 were coinfected with human immunodeficiency virus and 1703 had cavitation on chest radiography. A total of 2234 participants could be assessed for the primary outcome (assessable population; 726 in the control group, 756 in the rifapentine-moxifloxacin group, and 752 in the rifapentine group). Rifapentine with moxifloxacin was noninferior to the control in the microbiologically eligible population (15.5% vs. 14.6% had an unfavorable outcome; difference, 1.0 percentage point; 95% confidence interval [CI], -2.6 to 4.5) and in the assessable population (11.6% vs. 9.6%; difference, 2.0 percentage points; 95% CI, -1.1 to 5.1). Noninferiority was shown in the secondary and sensitivity analyses. Rifapentine without moxifloxacin was not shown to be noninferior to the control in either population (17.7% vs. 14.6% with an unfavorable outcome in the microbiologically eligible population; difference, 3.0 percentage points [95% CI, -0.6 to 6.6]; and 14.2% vs. 9.6% in the assessable population; difference, 4.4 percentage points [95% CI, 1.2 to 7.7]). Adverse events of grade 3 or higher occurred during the on-treatment period in 19.3% of participants in the control group, 18.8% in the rifapentine-moxifloxacin group, and 14.3% in the rifapentine group.The efficacy of a 4-month rifapentine-based regimen containing moxifloxacin was noninferior to the standard 6-month regimen in the treatment of tuberculosis. (Funded by the Centers for Disease Control and Prevention and others; Study 31/A5349 ClinicalTrials.gov number, NCT02410772.). |
| 2021 | Safety and feasibility of 1 month of daily rifapentine plus isoniazid to prevent tuberculosis in children and adolescents: a prospective cohort study. | Lancet Child Adolesc Health | Shorter regimens for tuberculosis prevention can improve completion rates and protection against developing active tuberculosis disease after tuberculosis exposure. We aimed to assess the safety and feasibility of 1 month of daily Isoniazid and rifapentine (1HP) in children and adolescents in a low-resource setting in south Asia with low prevalence of HIV.This prospective cohort study was done in eight tuberculosis facilities in Karachi, Pakistan. Eligible participants were aged 2-19 years and were household contacts of patients with drug-susceptible tuberculosis infection. After clinical, radiological, and laboratory evaluation to rule out tuberculosis disease, participants were prescribed 1HP as a preventive regimen. Isoniazid was administered as 100 mg or 300 mg oral tablets and rifapentine was administered as 150 mg oral tablets. Dosing was according to participant bodyweight. The primary endpoints were the cumulative probability of a household contact completing all stages of the preventive care cascade, assessed in all eligible participants, and the proportion of household contacts completing 1HP, assessed among all those who initiated the regimen. Safety was assessed in all household contacts who initiated the 1HP regimen.Between Dec 21, 2019, and March 20, 2020, 1395 household contacts of 253 patients with tuberculosis were identified, including 678 household contacts who were eligible to participate. 628 (93%) completed evaluation, of whom ten (2%) had active tuberculosis disease. Of the 618 individuals eligible for tuberculosis prevention, 408 (66%) initiated 1HP, 385 (94%) of whom completed the regimen. The median duration of 1HP was 31 days (IQR 30-32) in those who completed the regimen. The cumulative probability of completing all steps of the tuberculosis prevention cascade was 58%. A girl aged 11 years developed tuberculosis disease within 6 months of completing 1HP. A boy aged 14 years developed a burning sensation during 1HP therapy and discontinued the regimen. No other adverse events were observed.1HP can be safely and feasibly implemented as tuberculosis prevention in children and adolescents in programmatic settings.The Global Fund to Fight AIDS, Tuberculosis and Malaria. |
| 2021 | Determinants of Drug-Induced Hepatotoxicity Among Patients with Human Immunodeficiency Virus Taking a High Dose of Rifapentine Plus Isoniazid Drugs at the All Africa Leprosy Tuberculosis Rehabilitation and Training Center in Addis Ababa, Ethiopia. | HIV AIDS (Auckl) | The drugs for the treatment of latent Tuberculosis are potentially hepatotoxic and can lead to drug-induced hepatotoxicity. The current study aimed at identifying the determinants of anti-tuberculosis drug-induced hepatotoxicity among patients living with Human Immunodeficiency Virus taking Isoniazid and rifapentine at All Africa Leprosy Tuberculosis Rehabilitation and Training Center in Addis Ababa, Ethiopia.An unmatched case-control study was conducted from March, 21, to April 21, 2020, at All Africa Leprosy Tuberculosis Rehabilitation and Training Center. A total of 65 cases and 130 controls were interviewed. Data were collected using a data extraction tool from clinical reporting forms, follow-up charts, and patients' logbooks. Binary and multiple logistic regressions were conducted to check the association between independent and dependent variables. Adjusted odds ratios and the corresponding 95% confidence intervals were estimated to assess the strength of association. P-values <0.05 were used to declare statistical significance.The prevalence of anti-TB drug-induced hepatotoxicity was 8%. Body mass index <18.5 Kg/m2 (AOR = 5.8 [95% CI: 2.2-8.9]), low CD4 count (AOR = 4.9 [95% CI: 1.6-15.8]), and the presence of comorbid illnesses (AOR = 3.9 [95% CI: 1.7-8.9]) were identified as independent predictors of drugs-induced hepatotoxicity among Human Immunodeficiency Virus positive patients taking Isoniazid and rifapentine.The prevalence of anti-TB drug-induced hepatotoxicity was higher compared to standard references. BMI<18 kg/m2, low CD4 count, and comorbid illness were positively associated with anti-tuberculosis drug-induced hepatotoxicity among patients with HIV. |
| 2021 | Completion Rate and Safety of Programmatic Screening and Treatment for Latent Tuberculosis Infection in Elderly Patients with Poorly Controlled Diabetic Mellitus: A Prospective Multicenter Study. | Clin Infect Dis | Poor control of diabetes mellitus (DM) increases active tuberculosis (TB) risk. Understanding risk factors for latent TB infection (LTBI) in this population and intervention completion rates is crucial for policy making.Under a collaborative multidisciplinary team consisting of public health professionals, endocrinologists, and pulmonologists, patients aged >45 years with poorly controlled DM (pDM), defined as having a glycated hemoglobin level of ≥9% within the preceding year, were enrolled by endocrinologists from 2 hospitals; these patients underwent LTBI screening by using QuantiFERON (QFT). Once-weekly Isoniazid and rifapentine for 12 weeks (3HP) or daily Isoniazid for 9 months (9H) was administered by pulmonologists. QFT-positivity predictors were evaluated using logistic regression. Completion rates and safety were also investigated.Among 980 patients with pDM (age: 64.2 ± 9.7 years), 261 (26.6%) were QFT-positive. Age, DM duration, chronic kidney disease stage ≥3, and dipeptidyl peptidase-4 inhibitor use, not using metformin, were associated with QFT-positivity. Preventive therapy (3HP: 138; 9H: 62) was administered in 200 (76.6%) QFT-positive patients. The completion rates of 3HP and 9H were 84.1% and 79.0%, respectively (p=0.494). Nine (6.5%) and zero patients in the 3HP and 9H groups, respectively, developed systemic drug reactions (p=0.059); 78.3% and 45.2% had ≥1 adverse drug reactions (p<0.001); and post-treatment QFT conversion rates were 32% and 20%, respectively (p=0.228).LTBI prevalence exceeds 25% in elderly patients with pDM. Under care from a collaborative multidisciplinary team, the completion rate of preventive therapy, regardless of regimen could approach, or even exceed 80% in this population. |
| 2021 | Patient choice improves self-efficacy and intention to complete tuberculosis preventive therapy in a routine HIV program setting in Uganda. | PLoS One | A 12-dose weekly regimen of rifapentine plus Isoniazid (3HP) is recommended for the prevention of active tuberculosis (TB); however, it is unclear whether 3HP should be provided by directly observed therapy (DOT) or self-administered therapy (SAT). In addition, the introduction of patient informed choice between delivery modalities may have a positive impact on factors leading to treatment completion. The authors randomized 252 participants with HIV to a hypothetical scenario of providing preventive therapy by either DOT or an informed choice between DOT and SAT. Out of 104 participants who were randomized to a choice between DOT and SAT, 103 chose therapy by SAT. Participants rated their level of confidence and intention to complete therapy. Compared to those assigned to the DOT scenario, patients assigned to the choice scenario expressed greater confidence and intention to complete preventive therapy. Convenience and travel required to complete 3HP therapy were important factors in deciding between delivery modalities. Those assigned to DOT identified more barriers to completing therapy than those given a choice. Empowering patients to make informed decisions about how they receive TB preventive therapy may improve completion rates. |
| 2021 | Biomarker-guided tuberculosis preventive therapy (CORTIS): a randomised controlled trial. | Lancet Infect Dis | Targeted preventive therapy for individuals at highest risk of incident tuberculosis might impact the epidemic by interrupting transmission. We tested performance of a transcriptomic signature of tuberculosis (RISK11) and efficacy of signature-guided preventive therapy in parallel, using a hybrid three-group study design.Adult volunteers aged 18-59 years were recruited at five geographically distinct communities in South Africa. Whole blood was sampled for RISK11 by quantitative RT-PCR assay from eligible volunteers without HIV, recent previous tuberculosis (ie, <3 years before screening), or comorbidities at screening. RISK11-positive participants were block randomised (1:2; block size 15) to once-weekly, directly-observed, open-label Isoniazid and rifapentine for 12 weeks (ie, RISK11 positive and 3HP positive), or no treatment (ie, RISK11 positive and 3HP negative). A subset of eligible RISK11-negative volunteers were randomly assigned to no treatment (ie, RISK11 negative and 3HP negative). Diagnostic discrimination of prevalent tuberculosis was tested in all participants at baseline. Thereafter, prognostic discrimination of incident tuberculosis was tested in the untreated RISK11-positive versus RISK11-negative groups, and treatment efficacy in the 3HP-treated versus untreated RISK11-positive groups, during active surveillance through 15 months. The primary endpoint was microbiologically confirmed pulmonary tuberculosis. The primary outcome measures were risk ratio [RR] for tuberculosis of RISK11-positive to RISK11-negative participants, and treatment efficacy. This trial is registered with ClinicalTrials.gov, NCT02735590.20 207 volunteers were screened, and 2923 participants were enrolled, including RISK11-positive participants randomly assigned to 3HP (n=375) or no 3HP (n=764), and 1784 RISK11-negative participants. Cumulative probability of prevalent or incident tuberculosis disease was 0·066 (95% CI 0·049 to 0·084) in RISK11-positive (3HP negative) participants and 0·018 (0·011 to 0·025) in RISK11-negative participants (RR 3·69, 95% CI 2·25-6·05) over 15 months. Tuberculosis prevalence was 47 (4·1%) of 1139 versus 14 (0·78%) of 1984 in RISK11-positive compared with RISK11-negative participants, respectively (diagnostic RR 5·13, 95% CI 2·93 to 9·43). Tuberculosis incidence over 15 months was 2·09 (95% CI 0·97 to 3·19) vs 0·80 (0·30 to 1·30) per 100 person years in RISK11-positive (3HP-negative) participants compared with RISK11-negative participants (cumulative incidence ratio 2·6, 95% CI 1·2 to 5·9). Serious adverse events related to 3HP included one hospitalisation for seizures (unintentional Isoniazid overdose) and one death of unknown cause (possibly temporally related). Tuberculosis incidence over 15 months was 1·94 (95% CI 0·35 to 3·50) versus 2·09 (95% CI 0·97 to 3·19) per 100 person-years in 3HP-treated RISK11-positive participants compared with untreated RISK11-positive participants (efficacy 7·0%, 95% CI -145 to 65).The RISK11 signature discriminated between individuals with prevalent tuberculosis, or progression to incident tuberculosis, and individuals who remained healthy, but provision of 3HP to signature-positive individuals after exclusion of baseline disease did not reduce progression to tuberculosis over 15 months.Bill and Melinda Gates Foundation, South African Medical Research Council. |
| 2021 | Tele-TB: Using TeleMedicine to Increase Access to Directly Observed Therapy for Latent Tuberculosis Infection. | Mil Med | Treatment of latent tuberculosis infection (LTBI) decreases risk of progression to active tuberculosis. Traditional treatment regimens required either daily Isoniazid for 9 months, with historically poor compliance, or 12-week directly observed therapy (DOT) with Isoniazid and rifapentine, with improved compliance but additional challenges of coordinating weekly clinic visits, further complicated if patients must travel a great distance for care.Our referral area is complicated by congested traffic often resulting in one-way commutes, which can exceed 2 hours. These travel times would be prohibitive for conducting weekly in-clinic DOT. In an effort to improve access to DOT, we implemented TeleMedicine LTBI DOT (vDOT) within a military pediatric infectious diseases clinic. Patients aged 24 months or older diagnosed with LTBI were referred for possible enrollment into our vDOT clinic. All patients without contraindications for receiving Isoniazid and/or rifapentine were offered LTBI treatment via weekly vDOT or daily treatment with Isoniazid or rifampin. The first visit for vDOT patients was performed in person to discuss treatment options, demonstrate use of TeleMedicine software, and ensure the patient was able to take the medications. Baseline information about patients and travel time to our facility was determined.To date, 16 patients have completed LTBI therapy using vDOT. Average one-way travel time to our facility for patients was 51 minutes. Actual time spent in most vDOT encounters was less than 10 minutes. Appointments were arranged to take place outside usual school and work hours so patients could complete vDOT with minimal interruptions to daily life, resulting in 100% treatment compliance and completion.Conducting LTBI DOT using TeleMedicine is a viable and time-saving measure that still allows for high levels of patient compliance and treatment completion while minimizing interruptions to academic and work schedules. |
| 2021 | An open label, randomised controlled trial of rifapentine versus rifampicin based short course regimens for the treatment of latent tuberculosis in England: the HALT LTBI pilot study. | BMC Infect Dis | Ending the global tuberculosis (TB) epidemic requires a focus on treating individuals with latent TB infection (LTBI) to prevent future cases. Promising trials of shorter regimens have shown them to be effective as preventative TB treatment, however there is a paucity of data on self-administered treatment completion rates. This pilot trial assessed treatment completion, adherence, safety and the feasibility of treating LTBI in the UK using a weekly rifapentine and Isoniazid regimen versus daily rifampicin and Isoniazid, both self-administered for 12 weeks.An open label, randomised, multi-site pilot trial was conducted in London, UK, between March 2015 and January 2017. Adults between 16 and 65 years with LTBI at two TB clinics who were eligible for and agreed to preventative therapy were consented and randomised 1:1 to receive either a weekly combination of rifapentine/Isoniazid ('intervention') or a daily combination of rifampicin/Isoniazid ('standard'), with both regimens taken for twelve weeks; treatment was self-administered in both arms. The primary outcome, completion of treatment, was self-reported, defined as taking more than 90% of prescribed doses and corroborated by pill counts and urine testing. Adverse events were recorded.Fifty-two patients were successfully enrolled. In the intervention arm 21 of 27 patients completed treatment (77.8, 95% confidence interval [CI] 57.7-91.4), compared with 19 of 25 (76.0%, CI 54.9-90.6) in the standard of care arm. There was a similar adverse effect profile between the two arms.In this pilot trial, treatment completion was comparable between the weekly rifapentine/Isoniazid and the daily rifampicin/Isoniazid regimens. Additionally, the adverse event profile was similar between the two arms. We conclude that it is safe and feasible to undertake a fully powered trial to determine whether self-administered weekly treatment is superior/non-inferior compared to current treatment.The trial was funded by the NIHR, UK and registered with ISRCTN ( 26/02/2013-No.04379941 ). |
| 2021 | Toward patient-centered tuberculosis preventive treatment: preferences for regimens and formulations in Lima, Peru. | BMC Public Health | To ensure patient-centered tuberculosis preventive treatment, it is important to consider factors that make it easier for patients to complete treatment. However, there is little published literature about patient preferences for different preventive treatment regimen options, particularly from countries with high tuberculosis burdens.We conducted a qualitative research study using a framework analysis approach to understand tuberculosis preventive treatment preferences among household contacts. We conducted three focus group discussions with 16 members of families affected by tuberculosis in Lima, Peru. Participants were asked to vote for preferred preventive treatment regimens and discuss the reasons behind their choices. Coding followed a deductive approach based on prior research, with data-driven codes added.In total, 7 (44%) participants voted for 3 months Isoniazid and rifapentine, 4 (25%) chose 3 months Isoniazid and rifampicin, 3 (19%) chose 4 months rifampicin, and 2 (13%) chose 6 months Isoniazid. Preferences for shorter regimens over 6 months of Isoniazid were driven by concerns over "getting tired" or "getting bored" of taking medications, the difficulty of remembering to take medications, side effects, and interference with daily life. For some, weekly dosing was perceived as being easier to remember and less disruptive, leading to a preference for 3 months Isoniazid and rifapentine, which is dosed weekly. However, among caregivers, having a child-friendly formulation was more important than regimen duration. Caregivers reported difficulty in administering pills to children, and preferred treatments available as syrup or dispersible formulations.There is demand for shorter regimens and child-friendly formulations for tuberculosis preventive treatment in high-burden settings. Individual preferences differ, suggesting that patient-centered care would best be supported by having multiple shorter regimens available. |
| 2021 | Integrated TB and HIV care for Mozambican children: temporal trends, site-level determinants of performance, and recommendations for improved TB preventive treatment. | AIDS Res Ther | Pediatric tuberculosis (TB), human immunodeficiency virus (HIV), and TB-HIV co-infection are health problems with evidence-based diagnostic and treatment algorithms that can reduce morbidity and mortality. Implementation and operational barriers affect adherence to guidelines in many resource-constrained settings, negatively affecting patient outcomes. This study aimed to assess performance in the pediatric HIV and TB care cascades in Mozambique.A retrospective analysis of routine PEPFAR site-level HIV and TB data from 2012 to 2016 was performed. Patients 0-14 years of age were included. Descriptive statistics were used to report trends in TB and HIV indicators. Linear regression was done to assess associations of site-level variables with performance in the pediatric TB and HIV care cascades using 2016 data.Routine HIV testing and cotrimoxazole initiation for co-infected children in the TB program were nearly optimal at 99% and 96% in 2016, respectively. Antiretroviral therapy (ART) initiation was lower at 87%, but steadily improved from 2012 to 2016. From the HIV program, TB screening at the last consultation rose steadily over the study period, reaching 82% in 2016. The percentage of newly enrolled children who received either TB treatment or Isoniazid preventive treatment (IPT) also steadily improved in all provinces, but in 2016 was only at 42% nationally. Larger volume sites were significantly more likely to complete the pediatric HIV and TB care cascades in 2016 (p value range 0.05 to < 0.001).Mozambique has made significant strides in improving the pediatric care cascades for children with TB and HIV, but there were missed opportunities for TB diagnosis and prevention, with IPT utilization being particularly problematic. Strengthened TB/HIV programming that continues to focus on pediatric ART scale-up while improving delivery of TB preventive therapy, either with IPT or newer rifapentine-based regimens for age-eligible children, is needed. |
| 2021 | Completion and Adverse Drug Events of Latent Tuberculosis Infection Treatment in Patients Receiving Dialysis: Predictors and Impacts of Different Regimens in a Prospective Cohort Study. | Antimicrob Agents Chemother | Although patients with end-stage renal disease receiving maintenance hemodialysis are at high risk for tuberculosis, the optimal treatment regimen for latent tuberculosis infection (LTBI) in this group has scarcely been studied for predictors of completion rate and adverse drug events (ADE). We prospectively enrolled dialysis patients for LTBI intervention from three medical centers in Taiwan. LTBI treatments were 3 months of weekly rifapentine plus Isoniazid (3HP) and 9 months of daily Isoniazid (9H). Completion rate, ADE, and reasons for treatment termination were recorded. Factors associated with treatment termination and ADE were analyzed using multivariate logistic regression. In all, 91 treatment courses (41 9H and 50 3HP) were surveyed. The completion rates were 61% for 9H and 82% for 3HP ( = 0.046). Use of 9H and development of ADE with a grade of ≥2 (≥grade 2 ADE) were associated with treatment termination. Hypersensitivity occurred in 29.2% of subjects in the 3HP group and 10.8% in the 9H group ( = 0.035) and independently correlated with 3HP regimen, diabetes mellitus (DM), and peritoneal dialysis (PD). Similarly, the independent predictors of ≥grade 2 ADE were use of 3HP regimen, presence of DM, and use of PD, whereas ≥grade 3 ADE were associated with eosinophil counts of >700/mm after 2 weeks of LTBI treatment even after adjustment for age and gender. In conclusion, for patients on dialysis, 3HP showed a higher rate of completion but also a higher rate of ≥grade 2 ADE than 9H. In addition, DM and PD were risk factors for ≥grade 2 ADE. Eosinophilia after 2-week treatment might be an alert for severe ADE. |
| 2020 | Cost of delivering 12-dose isoniazid and rifapentine versus 6 months of isoniazid for tuberculosis infection in a high-burden setting. | Clin Infect Dis | Successful delivery and completion of tuberculosis preventive treatment delivery is necessary for tuberculosis elimination. Shorter preventive treatment regimens currently have higher medication costs, but patients spend less time in care and are more likely to complete treatment. It is unknown how economic costs of successful delivery differ between longer and shorter regimens in high-tuberculosis-burden settings.We developed survey instruments to collect costs from program and patient sources, considering costs incurred from when household contacts first entered the health system. We compared the cost per completed course of preventive treatment with either 6 months of daily Isoniazid (6H) or 3 months of weekly Isoniazid and rifapentine (3HP), delivered by the Indus tuberculosis program in Karachi, Pakistan, between October 2016 and February 2018.During this period, 459 individuals initiated 6H, and 643 initiated 3HP; 39% and 61% completed treatment, respectively. Considering costs to both the program and care recipients, the cost per completed course was 394 USD for 6H and 333 USD for 3HP. Using a new 2020 price for rifapentine reduced the cost per completed course of 3HP to 290 USD. Under varying assumptions about drug prices and costs incurred by care recipients, the cost per completed course was lower for 3HP in all scenarios, and the largest cost drivers were the salaries of clinical staff.In a high-burden setting, the cost of successful delivery of 3HP was lower than that of 6H, driven by higher completion. |
| 2021 | Nevirapine pharmacokinetics in HIV-infected persons receiving rifapentine and isoniazid for TB prevention. | J Antimicrob Chemother | The use of rifamycin antibiotics for TB prevention carries a risk of detrimental drug-drug interactions with concomitantly used ART.To evaluate the interaction of the antiretroviral drug nevirapine in combination with 4 weeks of daily rifapentine and Isoniazid for TB prevention in people living with HIV.Participants were individuals enrolled in the BRIEF-TB study receiving nevirapine and randomized to the rifapentine/Isoniazid arm of the study. Participants provided sparse pharmacokinetic (PK) sampling at baseline and weeks 2 and 4 for trough nevirapine determination. Nevirapine apparent oral clearance (CL/F) was estimated and the geometric mean ratio (GMR) of CL/F prior to and during rifapentine/Isoniazid was calculated.Seventy-eight participants had evaluable PK data: 61 (78%) female, 51 (65%) black non-Hispanic and median (range) age of 40 (13-66) years. Median (IQR) nevirapine trough concentrations were: week 0, 7322 (5266-9302) ng/mL; week 2, 5537 (3552-8462) ng/mL; and week 4, 5388 (3516-8243) ng/mL. Sixty out of 78 participants (77%) had nevirapine concentrations ≥3000 ng/mL at both week 2 and 4. Median (IQR) nevirapine CL/F values were: week 0 pre-rifapentine/Isoniazid, 2.03 (1.58-2.58) L/h; and during rifapentine/Isoniazid, 2.62 (1.81-3.42) L/h. The GMR (90% CI) for nevirapine CL/F was 1.30 (1.26-1.33).The CL/F of nevirapine significantly increased with concomitant rifapentine/Isoniazid. The decrease in nevirapine trough concentrations during rifapentine/Isoniazid therapy suggests induction of nevirapine metabolism, consistent with known rifapentine effects. The magnitude of this drug-drug interaction suggests daily rifapentine/Isoniazid for TB prevention should not be co-administered with nevirapine-containing ART. |
| 2020 | Impact of age on outcome of rifapentine-based weekly therapy for latent tuberculosis infection. | Clin Infect Dis | Weekly rifapentine and Isoniazid (3HP) is gaining popularity for latent tuberculosis infection treatment because of its short course and high completion rate. Prior to widespread use, comprehensive 3HP treatment assessment covering an all-age population is essential.Participants receiving ≥1 3HP dose from September 2014 to December 2019 were stratified into elderly (≥65 years), middle-aged (35-65 years), and younger (≤35 years) groups. This study investigated the impact of age on treatment outcome, particularly systemic drug reaction (SDR) and 3HP discontinuation.Overall, 134 (23.1%) of 579 participants were elderly. The completion rate was 83.1% in overall and was highest and lowest in the younger group (94.5%) and elderly (73.9%) groups, respectively. However, the 3HP discontinuation rate was not significantly different among the three groups in multivariate logistic regression analysis. In total, 362 (62.5%) participants experienced ≥1 adverse drug reactions (ADRs), of which 38 (10.5%) and 98 (27.1%) required temporary and permanent treatment interruption, respectively. The SDR risk was 11.2% in overall and 17.1% in the middle-aged group, 3.04-fold higher than that in the elderly group (p=0.025). This finding was consistently observed in different clinical settings. Hypertensive event accompanied with flu-like symptoms occurred in 11.2% of elderly participants, and accounted for 50% of grade ≥3 ADRs.With proper medical support and programmatic follow-up, the 3HP completion rate is higher than 70% even in elderly participants. In middle-aged and elderly individuals, 3HP should be employed with caution because of risk of SDR and hypertensive event, respectively. |
| 2020 | Cost-effectiveness of one month of daily isoniazid and rifapentine versus three months of weekly isoniazid and rifapentine for prevention of tuberculosis among people receiving antiretroviral therapy in Uganda. | J Int AIDS Soc | Preventive therapy is essential for reducing tuberculosis (TB) burden among people living with HIV (PLWH) in high-burden settings. Short-course preventive therapy regimens, such as three-month weekly rifapentine and Isoniazid (3HP) and one-month daily rifapentine and Isoniazid (1HP), may help facilitate uptake of preventive therapy for latently infected patients, but the comparative cost-effectiveness of these regimens under different conditions is uncertain.We used a Markov state-transition model to estimate the incremental costs and effectiveness of 1HP versus 3HP in a simulated cohort of patients attending an HIV clinic in Uganda, as an example of a low-income, high-burden setting in which TB preventive therapy might be prescribed to PLWH. Our primary outcome was the incremental cost-effectiveness ratio, expressed as 2019 US dollars per disability-adjusted life year (DALY) averted. We estimated cost-effectiveness under different conditions of treatment completion and efficacy of 1HP versus 3HP, latent TB prevalence and rifapentine price.Assuming equivalent clinical outcomes using 1HP and 3HP and a rifapentine price of $0.21 per 150 mg, 1HP would cost an additional $4.66 per patient treated. Assuming equivalent efficacy but 20% higher completion with 1HP versus 3HP, 1HP would cost $1,221 per DALY averted relative to 3HP. This could be reduced to $18 per DALY averted if 1HP had 5% greater efficacy than 3HP and the price of rifapentine were 50% lower. At a rifapentine price of $0.06 per 150 mg, 1HP would become cost-neutral relative to 3HP.1HP has the potential to be cost-effective under many realistic circumstances. Cost-effectiveness depends on rifapentine price, relative completion and efficacy, prevalence of latent TB and local willingness-to-pay. |
| 2021 | Pharmacogenetic interactions of rifapentine plus isoniazid with efavirenz or nevirapine. | Pharmacogenet Genomics | The effect of rifapentine plus Isoniazid on efavirenz pharmacokinetics was characterized in AIDS Clinical Trials Group protocol A5279 (NCT01404312). The present analyses characterize pharmacogenetic interactions between these drugs, and with nevirapine.A subset of HIV-positive individuals receiving efavirenz- or nevirapine-containing antiretroviral therapy in A5279 underwent pharmacokinetic evaluations at baseline, and again weeks 2 and 4 after initiating daily rifapentine plus Isoniazid. Associations with polymorphisms relevant to efavirenz, nevirapine, Isoniazid, and rifapentine pharmacokinetics were assessed.Of 128 participants, 101 were evaluable for associations with rifapentine and its active 25-desacetyl metabolite, 87 with efavirenz, and 38 with nevirapine. In multivariable analyses, NAT2 slow acetylators had greater week 4 plasma concentrations of rifapentine (P = 2.6 × 10) and 25-desacetyl rifapentine (P = 7.0 × 10) among all participants, and in efavirenz and nevirapine subgroups. NAT2 slow acetylators also had greater plasma efavirenz and nevirapine concentration increases from baseline to week 4, and greater decreases from baseline in clearance. CYP2B6 poor metabolizers had greater efavirenz concentrations at all weeks and greater nevirapine concentrations at baseline. None of 47 additional polymorphisms in 11 genes were significantly associated with pharmacokinetics.Among HIV-positive individuals receiving efavirenz or nevirapine, and who then initiated rifapentine plus Isoniazid in A5279, NAT2 slow acetylators had greater rifapentine and 25-desacetyl rifapentine concentrations, and greater increases from baseline in plasma efavirenz and nevirapine concentrations. These associations are likely mediated by greater Isoniazid exposure in NAT2 slow acetylators. |
| 2020 | Protocol for the 3HP Options Trial: a hybrid type 3 implementation-effectiveness randomized trial of delivery strategies for short-course tuberculosis preventive therapy among people living with HIV in Uganda. | Implement Sci | Recently, a 3-month (12-dose) regimen of weekly Isoniazid and rifapentine (3HP) was recommended by the World Health Organization for the prevention of tuberculosis (TB) among people living with HIV (PLHIV) on common antiretroviral therapy regimens. The best approach to delivering 3HP to PLHIV remains uncertain.We developed a three-armed randomized trial assessing optimized strategies for delivering 3HP to PLHIV. The trial will be conducted at the Mulago Immune Suppression Syndrome (i.e., HIV/AIDS) clinic in Kampala, Uganda. We plan to recruit 1656 PLHIV, randomized 1:1 to each of the three arms (552 per arm). Using a hybrid type 3 effectiveness-implementation design, this pragmatic trial aims to (1) compare the acceptance and completion of 3HP among PLHIV under three delivery strategies: directly observed therapy (DOT), self-administered therapy (SAT), and informed patient choice of either DOT or SAT (with the assistance of a decision aid); (2) to identify processes and contextual factors that influence the acceptance and completion of 3HP under each delivery strategy; and (3) to estimate the costs and compare the cost-effectiveness of three strategies for delivering 3HP. The three delivery strategies were each optimized to address key barriers to 3HP completion using a theory-informed approach. We hypothesize that high levels of treatment acceptance and completion can be achieved among PLHIV in sub-Saharan Africa and that offering PLHIV an informed choice between the optimized DOT and SAT delivery strategies will result in greater acceptance and completion of 3HP. The design and planned evaluation of the delivery strategies were guided by the use of implementation science conceptual frameworks.3HP-one of the most promising interventions for TB prevention-will not be scaled up unless it can be delivered in a patient-centered fashion. We highlight shared decision-making as a key element of our trial design and theorize that offering PLHIV an informed choice between optimized delivery strategies will facilitate the highest levels of treatment acceptance and completion.ClinicalTrials.gov: NCT03934931 ; Registered 2 May 2019. |
| Ramadan and Culturally Competent Care: Strengthening Tuberculosis Protections for Recently Resettled Muslim Refugees. | J Public Health Manag Pract | To improve latent tuberculosis infection treatment completion rates, Tarrant County Public Health began providing after-dusk home delivery of a 12-dose latent tuberculosis infection regimen of weekly rifapentine plus Isoniazid administered via directly observed preventive therapy during Ramadan, a month of prayer and daytime fasting observed by Muslims. In unadjusted difference-in-difference logistic regression analyses (n = 148), Muslim patients had lower treatment completion rates than non-Muslim patients during Ramadan prior to program implementation (68.8% vs 95.4%), whereas rates were comparable postimplementation (95.7% vs 96.4%; difference-in-difference P = .011). Similar results were found after adjusting for age and gender (pre: 71.4% vs 94.8%; post: 95.5% vs 96.3%; P = .032). These findings provide evidence of the need for and effectiveness of programmatic innovations tailored to the varying cultural norms of the widely diverse populations served by public health authorities and suggest that culturally competent clinical care may advance population health goals. |
| 2020 | Comparison of a Novel Regimen of Rifapentine, Tedizolid, and Minocycline with Standard Regimens for Treatment of Pulmonary Mycobacterium kansasii. | Antimicrob Agents Chemother | The combination of Isoniazid, rifampin, and ethambutol is recommended by the American Thoracic Society (ATS) for treatment of pulmonary , while the British Thoracic Society (BTS) recommends clarithromycin, rifampin and ethambutol. Unfortunately, therapy duration for both regimens lasts for years. In this study, we administered tedizolid, minocycline, clarithromycin, and rifapentine as monotherapy as well as novel combinations in the intracellular hollow-fiber model system of (HFS-) in a 28-day study. The ATS and BTS regimens were used as comparators. Repetitive sampling was used to validate the intended intrapulmonary pharmacokinetics of each drug and to monitor changes in burden. As monotherapy, tedizolid at an observed area under the concentration-time curve from 0 to 24 h (AUC)/MIC of 5.85 and minocycline at an AUC/MIC of 5.77 failed to kill the bacteria below day 0 (stasis), clarithromycin at an AUC/MIC of 2.4 held the bacterial burden at stasis, but rifapentine at an AUC/MIC of 140 killed 2 log CFU/ml below stasis. The BTS regimen kill slope was -0.083 ± 0.035 CFU/ml/day, which was significantly superior to the ATS regimen slope of -0.038 ± 0.038 CFU/ml/day. The rifapentine-tedizolid-minocycline combination kill slope was -0.119 ± 0.031 CFU/ml/day, superior to that of the ATS regimen and comparable to that of the BTS regimen. In conclusion, the BTS regimen and the novel rifapentine-tedizolid-minocycline regimen showed better kill of intracellular bacteria in the HFS- However, the efficacy of the new combination regimen remains to be tested in clinical settings. |
| 2020 | Rapid and simultaneous determination of ten anti-tuberculosis drugs in human plasma by UPLC-MS/MS with applications in therapeutic drug monitoring. | J Chromatogr B Analyt Technol Biomed Life Sci | Tuberculosis remains a global challenge, particularly with a growing number of resistant cases, which may become an obstacle to eliminating this disease. Standardized short-course therapy composed of first-line anti-tuberculosis drugs Isoniazid (INH), rifampicin (RIF), ethambutol (EMB), and pyrazinamide (PZA) is playing vital roles for curbing the rapid spread of tuberculosis. However, some patients have poor responses to standardized short-course therapy. As the number of drug-resistant tuberculosis increase, some other anti-tuberculous drugs are needed to achieve better treatment outcomes. In this study, we established a UPLC-MS/MS method for simultaneous detection of ten anti-tuberculosis drugs in human plasma including INH, EMB, PZA, RIF, rifampin, rifapentine as well as four second-line antituberculosis drugs, i.e. ethionamide, protionamide, thiosemicarbazone and clofazimine. This study contains almost all the commonly used anti-tuberculosis drugs. The plasma samples were treated with acetonitrile to precipitate proteins, and doped with the isotope internal standard. A Shiseido CAPCELL RAK-ADME (2.1 mm × 50 mm, 3 μm) column was used for chromatographic separation, and acetonitrile-water (containing 0.1% formic acid) was the mobile phase. The separation used gradient elution with a flow rate of 0.4 mL/min. The column temperature was 40 °C, and the sample volume was 1 μL. The electrospray ionization source (ESI) and the positive ion multiple reaction monitoring (MRM) mode were used for the detection. The analysis time was as short as 7 min. The results show a good linear relationship under optimized conditions in the range of 5.00-7.50 × 10, 1.00-1.50 × 10, 5.00-5.00 × 10, 5.00-7.50 × 10, 1.00-3.00 × 10, 1.00 × 10-1.00 × 10, 1.00-3.00 × 10, 1.00-3.00 × 10, 2.00-4.00 × 10, and 1.00 × 10-2.00 × 10 ng/mL for INH, EMB PZA, RIF, rifabutin, rifapentine, ethionamide, protionamide, thiosemicarbazone, and clofazimine, respectively, with a linear correlation coefficient of R > 0.99. Finally, 34 patients with pulmonary TB were tested for therapeutic drug monitoring. The results showed that the presented method have significant advances in sensitivity, separation efficiency and simplicity. |
| 2020 | Model-Based Cost-Effectiveness of State-level Latent Tuberculosis Interventions in California, Florida, New York and Texas. | Clin Infect Dis | Targeted testing and treatment (TTT) for latent tuberculosis infection (LTBI) is a recommended strategy to accelerate TB reductions and further tuberculosis elimination in the United States (US). Evidence on cost-effectiveness of TTT for key populations can help advance this goal.We used a model of TB transmission to estimate the numbers of individuals who could be tested by interferon-γ release assay (IGRA) and treated for LTBI with three months of self-administered rifapentine and Isoniazid (3HP) under various TTT scenarios. Specifically, we considered rapidly scaling up TTT among people who are non-US-born, diabetic, HIV-positive, homeless or incarcerated in California, Florida, New York, and Texas - states where more than half of US TB cases occur. We projected costs (from the healthcare system perspective, in 2018 dollars), thirty-year reductions in TB incidence, and incremental cost effectiveness (cost per quality-adjusted life year [QALY] gained) for TTT in each modeled population.The projected cost effectiveness of TTT differed substantially by state and population, while the health impact (number of TB cases averted) was consistently greatest among the non-US-born. TTT was most cost-effective among persons living with HIV (from $2,828/QALY gained in Florida to $11,265/QALY gained in New York) and least cost-effective among people with diabetes (from $223,041/QALY gained in California to $817,753 /QALY in New York).The modeled cost-effectiveness of TTT for LTBI varies across states but was consistently greatest among people living with HIV, moderate among people who are non-US-born, incarcerated, or homeless, and least cost-effective among people living with diabetes. |
| 2021 | Efficacy and safety of weekly rifapentine and isoniazid for tuberculosis prevention in Chinese silicosis patients: a randomized controlled trial. | Clin Microbiol Infect | The aim was to evaluate the efficacy, safety and completion rate of 3-month, once-weekly rifapentine and Isoniazid for tuberculosis (TB) prevention among Chinese silicosis patients.Male silicosis patients without human immunodeficiency virus infection, aged 18 years to 65 years, with or without latent TB infection, were randomized 1:1 to receive rifapentine/Isoniazid under direct observation (3RPT/INH group) or were untreated (observation group). Active TB incidence was compared between the two groups with 37 months of follow-up. Safety profile and complete rates were evaluated.A total of 1227 adults with silicosis were screened; 513 eligible participants were enrolled and assigned to 3RPT/INH (n = 254) vs. observation (n = 259). Twenty-eight participants were diagnosed with active TB, and 9 and 19 in the 3RPT/INH group and observation groups, respectively. In the intention-to-treat analysis, the cumulative active TB rate was 3.5% (9/254) in the 3RPT/INH group and 7.3% (19/259) in the observation group (log rank p 0.055). On per protocol analysis, the cumulative active TB rates were 0.7% (1/139) and 7.3% (19/259), respectively (log rank p 0.01). Owing to an unexpected high frequency of adverse events (70.4%) and Grade 3 or 4 AEs (7.9%), the completion rate of the 3RPT/INH regimen was 54.7% (139/254). Twenty-six (10.8%) participants had flu-like systemic drug reactions; five (2.1%) experienced hepatotoxicity.Weekly rifapentine/Isoniazid prophylaxis prevented active TB among Chinese people with silicosis when taken, irrespective of LTBI screening; efficacy was reduced by lack of compliance. The regimen must be used with caution because of the high rates of adverse effects.ClinicalTrials.gov number: NCT02430259. |
| 2020 | Isoniazid Preventive Therapy in Contacts of Multidrug-Resistant Tuberculosis. | Am J Respir Crit Care Med | The World Health Organization recommends the use of Isoniazid (INH) alone or in combination with rifapentine to treat latent tuberculosis infections. The recent rise of drug-resistant tuberculosis has complicated the choice of treatment regimen for latent tuberculosis infection. To evaluate the effects of INH preventive therapy on the contacts of patients with multidrug-resistant tuberculosis. In a prospective cohort study conducted between September 2009 and August 2012, we identified 4,500 index patients with tuberculosis and 14,044 tuberculosis-exposed household contacts who we followed for 1 year for the occurrence of incident tuberculosis disease. Although Peruvian national guidelines specify that INH preventive therapy should be provided to contacts aged 19 years old or younger, only half this group received INH preventive therapy. Among 4,216 contacts under 19 years of age, 2,106 contacts (50%) initiated INH preventive therapy at enrollment. The protective effect of INH was more extreme in contacts exposed to drug-sensitive tuberculosis (adjusted hazard ratio, 0.30; 95% confidence interval, 0.18-0.48) and to multidrug-resistant tuberculosis (adjusted hazard ratio, 0.19; 95% confidence interval, 0.05-0.66) compared with those exposed to mono-INH-resistant tuberculosis (adjusted hazard ratio, 0.80; 95% confidence interval, 0.23-2.80). In the second independent study, tuberculosis occurred in none of the 76 household contacts who received INH preventive therapy compared with 3% (8 of 273) of those who did not. Household contacts who received INH preventive therapy had a lower incidence of tuberculosis disease even when they had been exposed to an index patient with multidrug-resistant tuberculosis. INH may have a role in the management of latent multidrug-resistant tuberculosis infection. |
| 2020 | Safety and treatment completion of latent tuberculosis infection treatment in the elderly population-A prospective observational study in Taiwan. | Int J Infect Dis | The detection and treatment of latent tuberculosis infection (LTBI) is a key step in eliminating tuberculosis (TB), but information on safety and on treatment interruption in elderly LTBI patients remains limited.This multicenter prospective observational study included individuals with LTBI who underwent preventive therapy. Incidents of systemic adverse reactions (SARs) and treatment interruption rates in an elderly group (≥60 years old) and a young group (<60 years old) were analyzed.A total of 406 LTBI patients, comprising 167 elderly and 239 young patients, were included in the analyses. The incidence of SARs was similar in the elderly group (18%) and the young group (15.1%). Being middle-aged (35-59 years), body mass index <23 kg/m, a regimen of 3 months of once-weekly rifapentine plus Isoniazid, and end-stage renal disease were independent factors associated with SARs. The treatment interruption rate was similar between the elderly group (21.6%) and the young group (15.9%). LTBI patients aged ≥80 years with SARs had the highest risk of treatment interruption.The occurrence of SARs was similar in the elderly (≥60 years old) and young (<60 years old) LTBI patients receiving preventive therapy. Extremely old (≥80 years old) LTBI patients had a higher treatment interruption rate, especially when they had SARs. |
| 2020 | Does Isoniazid Preventive Therapy Provide Better Treatment Outcomes in HIV-Infected Individuals in Northern Ethiopia? A Retrospective Cohort Study. | AIDS Res Treat | Early antiretroviral therapy (ART), Isoniazid preventive therapy (IPT), and Isoniazid-rifapentine (3HP) are effective strategies for preventing tuberculosis (TB) among people living with HIV (PLHIV). The study aimed to determine the effect of IPT on the TB incidence, follow-up CD4 T cells, and all-cause mortality rate. . Eligible patients on ART ( = 1, 863) were categorized into one-to-two ratios of exposed groups to IPT ( = 621) and nonexposed groups to IPT ( = 1, 242). Exposed groups entered the cohort at their first prescription of IPT, and unexposed groups entered into the study at the first prescription of ART and then followed until the occurrence of the outcome or date of administrative censoring (June 30, 2017). The outcome endpoints were TB incidence, follow-up CD4 T cells, and all-cause mortality rate.The follow-up CD4 T cells for the exposed and nonexposed groups were 405.74 and 366.95 cells/mm (World Health Organization (WHO), 2017), respectively, a statistically significant finding ( = -3.770, < 0.0001; Cohen's = 0.186). Nine percent of the exposed patients (620 incidence of TB per 100,000 person-years (PYs)) and 21.9% of the nonexposed patients (3160 incidence of TB per 100,000 PYs) developed TB. Mortality rate (per 100,000 PYs) was 440 for the exposed and 1490 for the unexposed patients. Statistically significant determinants of the all-cause mortality were unscheduled follow-up (AHR = 1.601; 95% CI: 1.154-2.222) and unable to work properly (AHR = 2.324; 95% CI: 1.643-3.288).This study demonstrates the effect of IPT in reducing incidence of TB and all-cause mortality rate and improving follow-up CD4 T cells. Promoting IPT use can help to achieve the TB eradicating national agenda in Ethiopia. |
| 2020 | Twice-Daily Doravirine Overcomes the Interaction Effect from Once-Weekly Rifapentine and Isoniazid in Healthy Volunteers. | Clin Transl Sci | Doravirine (DOR) is a non-nucleoside reverse transcriptase inhibitor indicated for the treatment of HIV-1. Its use in combination with rifapentine (RPT), an antituberculosis (TB) antibiotic, may reduce the exposure of DOR compromising viral suppression in those living with HIV-1 co-infected with TB. We conducted a prospective, phase I, open label, two-period, fixed sequence, drug interaction study to evaluate the effect of once-weekly RPT and Isoniazid (INH) on the pharmacokinetics (PKs) of DOR in healthy volunteers. DOR 100 mg was administered alone twice-daily for 4 days in period 1. In period 2, once-weekly RPT + INH were co-administered with multiple doses of DOR 100 mg twice-daily for study days 7, 14, and 21. Plasma was obtained for DOR PKs when given alone and co-administered with RPT + INH. Eleven healthy volunteers enrolled and completed the study. The geometric mean ratios and 90% confidence intervals for DOR area under the concentration-time curve from zero to 12 hours (AUC ) and C in the presence of RPT + INH compared with DOR alone were 0.71 (0.60-0.85) and 0.69 (0.54-0.89), respectively. Although exposures were moderately reduced in the presence of RPT + INH, trough DOR values were within the concentration range associated with virological suppression. These results demonstrate that a modest decrease in DOR exposure would unlikely be clinically relevant in a virally suppressed patient co-administered once-weekly RPT + INH. |
| 2020 | The implementation of rifapentine and isoniazid (3HP) in two remote Arctic communities with a predominantly Inuit population, the Taima TB 3HP study. | Int J Circumpolar Health | : The incidence of TB among Inuit is the highest in Canada. A significantly shorter latent TB infection (LTBI) treatment with rifapentine and Isoniazid once weekly for 12 weeks (3HP) is now available in limited settings in Canada.: A prospective open-label 2-year observational postmarketing study was conducted introducing 3HP for the first time in Canada in Iqaluit followed by a program rollout in Qikiqtarjuaq, Nunavut.: A total of 247 people were offered 3HP, 102 in the Iqaluit postmarketing study and 145 in the Qikiqtarjuaq program roll out. Although statistical significance was not reached, more people who started treatment completed treatment in the 3HP group (Iqaluit, 60/73 (82.2%) and Qikiqtarjuaq, 89/115 (77.4%)) than in the historical control 9INHgroup (306/420 = 72.9%) (p = 0.2). Most of the adverse events in 3HP treated patients were associated with mild discomfort but no disruption of normal daily activity. Not drinking alcohol was associated with increased 3HP completion (OR 13.33, 95% CI, 2.27-78.20) as was not taking concomitant medications (OR 7.19, 95% CI, 1.47-35.30).: The present study supports the feasibility and safety profile of 3HP for the treatment of LTBI in Nunavut. |
| 2020 | How are high burden countries implementing policies and tools for latent tuberculosis infection? A survey of current practices and barriers. | Health Sci Rep | Despite the World Health Organization (WHO)'s updated guidelines on tuberculosis (TB) preventive treatment, the scale-up of TB preventive therapy remains low in many high-burden countries (HBCs). We conducted a survey to better understand the current status of policy implementation and barriers for scale-up.Survey questions pertained to HBCs' current latent TB infection (LTBI) screening and treatment strategies, and the availability of LTBI tests and newer treatments (eg, Isoniazid/rifapentine [3HP]). The 19-question survey was piloted and sent out via email in June 2019 as a protected Microsoft Word document to contacts [National TB Program (NTP) staff, researchers, and health officials] in the 30 TB HBCs. Responses were accepted until February 2020.Thirty-seven completed surveys from 24 HBCs were received. Respondents from five countries (Brazil, Lesotho, Mozambique, Russia, Zambia) reported having LTBI guidelines that are fully implemented. Among respondents who indicated their country currently has no LTBI guideline implementation (Angola, China, DRC, India, Indonesia, Kenya, Myanmar), the most often cited barrier to implementation was the prioritization of active TB over LTBI management (n = 5, Angola, China, DRC, India, Kenya). Of the 16 countries in which respondents reported using purified protein derivative (PPD), 9 reported having experienced a PPD shortage within the past year (from time of survey). Respondents from six countries reported currently using Interferon-gamma Release Assays (IGRAs) in their NTP, and 13 cited high cost as a barrier to IGRA use. Lastly, rifapentine was stated not be available in 8 HBCs.This survey indicates limited implementation of WHO LTBI guidelines in HBCs and provides some insight into barriers to implementation, including shortage of products (eg, PPD), high costs (eg, IGRAs), and lack of regulatory approval of newer treatments (eg, rifapentine). Thus, we should work towards price reductions for LTBI tests and treatments, and the development of tests that can be more easily implemented at peripheral healthcare levels. |
| 2020 | Risk-benefit analysis of tuberculosis infection testing for household contact management in high-burden countries: a mathematical modelling study. | Lancet Glob Health | Preventive therapy for tuberculosis reduces the risk of disease in people who have been infected but who are not sick. Countries with a high burden of tuberculosis that are expanding preventive therapy use must decide how tuberculosis infection testing should be used for risk stratification among household contacts of patients with tuberculosis.We modelled the risks of tuberculosis disease and severe adverse events, comparing the following two preventive therapy strategies: preventive therapy for all household contacts, or preventive therapy for only household contacts with a positive tuberculin skin test (TST) result. We used data from clinical trials and literature on tuberculosis natural history to model outcomes, assuming different preventive therapy regimens, ages, and TST positivity prevalence.Assuming 25% prevalence of TST positivity among 1000 household contacts aged 0-17 years, a treat-all approach with Isoniazid and rifapentine compared with a treat-TST-only approach led to 13 fewer incident tuberculosis cases (IQR -5 to -18) and four additional severe adverse events (2 to 6). With rifampicin, the difference was 11 fewer incident tuberculosis cases (-3 to -17) and two additional severe adverse events (1 to 3). For adults, a treat-all approach led to fewer incident tuberculosis cases, and additional adverse events increased with age. Assuming 25% prevalence of TST positivity among adult contacts, a treat-all approach would lead to around two fewer tuberculosis cases per 1000 contacts for all regimens; the number of additional severe adverse events ranged from seven (IQR 5 to 8) for 18 to 34-year-olds treated with rifampicin to 63 (50 to 74) for people older than 64 years treated with Isoniazid and rifapentine. A rifampicin-only regimen was associated with the fewest additional severe adverse events (seven [IQR 5 to 8] per 1000 adults aged 18-34 years and 35-64 years, and 17 [9 to 23] per 1000 adults older than 64 years).Based on the available data, giving preventive therapy to all household contacts would probably reduce the incidence of tuberculosis cases in high-burden settings. Adverse events could be minimised by using non-Isoniazid regimens and, in adults older than 18 years, focusing treatment on individuals with a positive infection test.Bill & Melinda Gates Foundation, UK Medical Research Council, and UK Department for International Development. |
| 2020 | A 21-Year-Old Immune-Competent Man With Recurrent Cough. | Chest | A 21-year-old Chinese man presented with a nonproductive cough for the past 5 months. He denied fevers, chills, night sweats, chest pain, dyspnea, hemoptysis, or weight loss. He was an undergraduate with an unremarkable medical history. He denied any sick contacts and he never smoked. Laboratory tests showed a leukocyte count of 11,200/μL (normal range, 3,500-9,500/μL) with a high neutrophil count and a raised erythrocyte sedimentation rate of 81 mm/h. The purified protein derivative skin test result was positive, and a TB test (T.SPOT.TB; Oxford Immunotec) produced a positive result. The HIV test result was negative. The lung window of the patient's thoracic CT scan showed mottled, patchy opacification in the right lower lobe, and enlarged mediastinal and right hilar lymph nodes (Fig 1A). Bronchoscopy showed mucosal swelling and congestion (Fig 1B). A lymph node (station 11R) biopsy, obtained by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) (Fig 1C), showed nonspecific necrosis. An acid-fast bacillus smear of bronchial secretion produced negative results. He was administered empiric anti-TB therapy (ethambutol, Isoniazid, pyrazinamide, and rifapentine). But his cough had not improved by 4 months later. Thus he came to our hospital for a second opinion. |
| 2020 | Once-weekly rifapentine and isoniazid for tuberculosis prevention in patients with HIV taking dolutegravir-based antiretroviral therapy: a phase 1/2 trial. | Lancet HIV | Short-course preventive therapy with 12 doses of once-weekly rifapentine (900 mg) plus Isoniazid (900 mg) could greatly improve tuberculosis control, especially in areas with high co-endemicity with HIV. However, a small previous trial of such therapy with dolutegravir in healthy, HIV-negative adults was halted early after two of the four patients developed serious adverse events. Because of the potential use of this therapy, and variable safety outcomes of tuberculosis drugs seen in patients with and without HIV, we aimed to characterise safety, pharmacokinetics, and virological suppression in adults who are HIV positive.DOLPHIN was a phase 1/2, single-arm trial done at The Aurum Institute (Tembisa Clinical Research Site, Tembisa, South Africa), with pharmacokinetic visits done at VxPharma (Pretoria, South Africa). Adults (≥18 years) with HIV infection and undetectable viral load (<40 copies per mL) after at least 8 weeks of efavirenz-based or dolutegravir-based regimens were recruited in three consecutive groups, subject to approval by the independent safety monitoring committee. Participants received 50 mg of daily dolutegravir in place of efavirenz for 8 weeks, then began once-weekly rifapentine (900 mg)-Isoniazid (900 mg) for 12 weeks. Groups 1A (n=12) and 1B (n=18) had intensive dolutegravir pharmacokinetic sampling at week 8 (before rifapentine-Isoniazid), at week 11 (after the third dose of rifapentine)-Isoniazid and at week 16 after the eighth dose. Group 2 (n=30) were treated with the same schedule and had sparse dolutegravir pharmacokinetic sampling at weeks 8, 11, and 16. Participants were followed 4 weeks after completion of prophylactic tuberculosis treatment. HIV viral loads were measured at baseline and at weeks 11 and 24. Primary endpoints were adverse events (grade 3 or higher) and dolutegravir population pharmacokinetics, assessed in participants who began rifapentine-Isoniazid. This trial was registered at ClinicalTrials.gov, NCT03435146.Between Jan 24, 2018, and Nov 25, 2018, 61 participants were enrolled into three groups; one participant withdrew (from group 1A). 43 (70%) of 60 participants were women and all participants were black African. Median age was 40 years (IQR 35-48), CD4 cell count was 683 cells per μL (447-935), and body-mass index was 28·9 kg/m (24·0-32·9). Three grade 3 adverse events occurred; two elevated creatinine and one hypertension. Rifapentine-Isoniazid increased dolutegravir clearance by 36% (relative standard error 13%) resulting in a 26% decrease in dolutegravir area under the curve. Overall geometric mean ratio of trough concentrations with versus without rifapentine-Isoniazid was 0·53 (90% CI 0·49-0·56) though this ratio varied by day after rifapentine-Isoniazid dose. All but one trough value was above the 90% maximal inhibitory concentration for dolutegravir and HIV viral loads were less than 40 copies per mL in all patients.Our results suggest 12 doses of once-weekly rifapentine-Isoniazid can be given for tuberculosis prophylaxis to patients with HIV taking dolutegravir-based antiretroviral therapy, without dose adjustments. Further exploration of the pharmacokinetics, safety, and efficacy in children and pharmacodynamics in individuals naive to antiretroviral therapy is needed.UNITAID. |
| 2020 | Cost-effectiveness of IGRA/QFT-Plus for TB screening of migrants in Oman. | Int J Infect Dis | To estimate the cost of a screening program for identifying latent tuberculosis (TB) infections in migrants to Oman.A Markov model was used to estimate the cost of screening using an interferon-gamma release assay (IGRA) applied to all migrants from high TB endemic countries, followed by preventive TB treatment.The model compared seven different scenarios, with a comparison of the direct cost and the quality-adjusted life-years (QALYs) saved.IGRA testing followed by 3 months of preventive treatment with rifapentine/Isoniazid (3HP) was the most cost-effective intervention. |
| 2020 | Management of latent tuberculosis infection in China: Exploring solutions suitable for high-burden countries. | Int J Infect Dis | China is one of the countries with a high burden of tuberculosis (TB) and latent tuberculosis infection (LTBI). It was recently estimated that China had the highest LTBI burden in the world, with approximately 350 million persons living with the infection. The prevalence of LTBI in China is overestimated by tuberculin skin test (TST) as compared to interferon-gamma release assay (IGRA). A population-based study found that IGRA positivity rates ranged between 13.5% and 19.8%. The annual TB infection rate in the rural population was 1.5% based on persistent positive IGRA results in converters. The development of active TB from LTBI in the general rural population was 0.87 per 100 person-years in the first 2 years among individuals who newly converted to IGRA-positive. TB control in students has been paid more attention by the government, which also improved LTBI management among students in close contact with active TB patients. A 3-month regimen of twice-weekly rifapentine plus Isoniazid (3HP, both with a maximum dose of 600 mg) has been practiced for LTBI treatment in China for years. With respect to LTBI management in populations using immune inhibitors, an expert consensus on TB prevention and management in tumor necrosis factor antagonist application was published in 2013 in China. In order to achieve the global goals of the End TB Strategy, China needs innovative ideas and technologies to reduce the TB incidence by management of LTBI, such as the identification of populations for LTBI testing and treatment, selecting and developing reliable LTBI tests, exploring safe and effective preventive treatment tools, and establishing a set of optimized LTBI management systems. |
| 2020 | Frequency, Risk Factors, and Outcome of Active Tuberculosis following Allogeneic Hematopoietic Stem Cell Transplantation. | Biol Blood Marrow Transplant | We aimed to investigate the frequency, risk factors, and outcome of active tuberculosis (TB) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). This retrospective, nested, case-control study reviewed data from 6236 patients who received allo-HSCT from January 2008 to December 2018 at a single center; thirty-three patients (0.5%) with active TB and 99 controls without active TB after allo-HSCT were identified. We performed propensity score matching by randomly selecting 3 controls for each identified active TB patient according to the time of transplantation and follow-up period. History of pretransplant active TB previously treated and inactive at time of transplantation (P< .001) was an independent risk factor. No significant differences in overall survival (P= .342), nonrelapse mortality (P= .497), or incidence of relapse (P= .807) were found. Thirty (90.9%) patients were treated with 4-drug (Isoniazid, rifampicin/three rifapentine, pyrazinamide, and ethambutol) or 3-drug combination first-line therapy, with a response rate of 76.7%. Twenty-six (78.8%) patients were treated with first-line and second-line combined therapy, and the response rate was 76.9%. Five (15.2%) patients developed hepatotoxicity. In conclusion, history of pretransplant active TB previously treated and inactive at time of transplantation was an independent risk factor of active TB after allo-HSCT. No significant differences in prognosis between the TB and control groups were found. More studies are needed to help develop standardized therapeutic strategies for patients with post-transplant TB. |
| 2020 | Dynamic changes of interferon gamma release assay results with latent tuberculosis infection treatment. | Clin Microbiol Infect | Using QuantiFERON-TB Gold In-Tube (QFT-GIT) for monitoring tuberculosis (TB) and latent TB infection treatment effect is controversial. The present study aimed to evaluate the dynamic changes of interferon gamma (IFN-γ) levels along with latent TB infection treatment via a randomized controlled study.A total of 910 participants treated with 8 weeks of once-weekly rifapentine plus Isoniazid (group A), 890 treated with 6 weeks of twice-weekly rifapentine plus Isoniazid (group B) and 818 untreated controls (group C) were followed for 2 years to track active TB development. QFT-GIT tests were repeated three times for all groups: before treatment (T0), at completion of treatment (T1) and 3 months after completion of treatment (T2).Similar rates of persistent QFT-GIT reversion were observed in groups A (19.0%, 173/910), B (18.5%, 165/890) and C (20.7%, 169/818) (p 0.512). The dynamic changes of IFN-γ levels were not statistically significant among the three groups. In treated participants, individuals with higher baseline IFN-γ levels showed increased TB occurrence (1.0%, 9/896) compared to those with lower baseline levels (0.2%, 2/904) (p 0.037). A similar but statistically insignificant trend was also observed in untreated controls (1.8% (7/400) vs. 0.5% (2/418), p 0.100). When TB cases were matched with non-TB cases on baseline IFN-γ levels, no significant differences were found with respect to the dynamic changes in IFN-γ levels with time, regardless of whether they received treatment.QFT-GIT reversion or decreased IFN-γ levels should not be used for monitoring host response to latent TB infection treatment. |
| 2020 | Guidelines for the Treatment of Latent Tuberculosis Infection: Recommendations from the National Tuberculosis Controllers Association and CDC, 2020. | MMWR Recomm Rep | Comprehensive guidelines for treatment of latent tuberculosis infection (LTBI) among persons living in the United States were last published in 2000 (American Thoracic Society. CDC targeted tuberculin testing and treatment of latent tuberculosis infection. Am J Respir Crit Care Med 2000;161:S221-47). Since then, several new regimens have been evaluated in clinical trials. To update previous guidelines, the National Tuberculosis Controllers Association (NTCA) and CDC convened a committee to conduct a systematic literature review and make new recommendations for the most effective and least toxic regimens for treatment of LTBI among persons who live in the United States.The systematic literature review included clinical trials of regimens to treat LTBI. Quality of evidence (high, moderate, low, or very low) from clinical trial comparisons was appraised using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) criteria. In addition, a network meta-analysis evaluated regimens that had not been compared directly in clinical trials. The effectiveness outcome was tuberculosis disease; the toxicity outcome was hepatotoxicity. Strong GRADE recommendations required at least moderate evidence of effectiveness and that the desirable consequences outweighed the undesirable consequences in the majority of patients. Conditional GRADE recommendations were made when determination of whether desirable consequences outweighed undesirable consequences was uncertain (e.g., with low-quality evidence).These updated 2020 LTBI treatment guidelines include the NTCA- and CDC-recommended treatment regimens that comprise three preferred rifamycin-based regimens and two alternative monotherapy regimens with daily Isoniazid. All recommended treatment regimens are intended for persons infected with Mycobacterium tuberculosis that is presumed to be susceptible to Isoniazid or rifampin. These updated guidelines do not apply when evidence is available that the infecting M. tuberculosis strain is resistant to both Isoniazid and rifampin; recommendations for treating contacts exposed to multidrug-resistant tuberculosis were published in 2019 (Nahid P, Mase SR Migliori GB, et al. Treatment of drug-resistant tuberculosis. An official ATS/CDC/ERS/IDSA clinical practice guideline. Am J Respir Crit Care Med 2019;200:e93-e142). The three rifamycin-based preferred regimens are 3 months of once-weekly Isoniazid plus rifapentine, 4 months of daily rifampin, or 3 months of daily Isoniazid plus rifampin. Prescribing providers or pharmacists who are unfamiliar with rifampin and rifapentine might confuse the two drugs. They are not interchangeable, and caution should be taken to ensure that patients receive the correct medication for the intended regimen. Preference for these rifamycin-based regimens was made on the basis of effectiveness, safety, and high treatment completion rates. The two alternative treatment regimens are daily Isoniazid for 6 or 9 months; Isoniazid monotherapy is efficacious but has higher toxicity risk and lower treatment completion rates than shorter rifamycin-based regimens.In summary, short-course (3- to 4-month) rifamycin-based treatment regimens are preferred over longer-course (6-9 month) Isoniazid monotherapy for treatment of LTBI. These updated guidelines can be used by clinicians, public health officials, policymakers, health care organizations, and other state and local stakeholders who might need to adapt them to fit individual clinical circumstances. |
| 2020 | Addressing Latent Tuberculosis Infection Treatment Through a Collaborative Care Model With Community Pharmacies and a Health Department. | Prev Chronic Dis | The objective of this study was to evaluate a novel collaborative care model using community pharmacies as additional access points for latent tuberculosis infection (LTBI) treatment for patients using combination weekly therapy with Isoniazid and rifapentine (3HP) plus directly observed therapy for 12 weeks.This prospective pilot study included adult patients diagnosed with LTBI. Patients were eligible for study participation if they spoke English or Spanish and were followed by the New Mexico Department of Health (NM DOH). Patients were excluded if they were pregnant, receiving concomitant HIV antiretroviral therapy, or had contraindications to 3HP due to allergy or drug interactions. Community pharmacy sites included chain, independent, and hospital outpatient pharmacies in Albuquerque and Santa Fe, New Mexico.A total of 40 patients initiated treatment with 3HP and were included. Most were female (55%) and had a mean age of 46 years (standard deviation, 12.6 y). A total of 75.0% of patients completed LTBI treatment with 3HP in a community pharmacy site. Individuals of Hispanic ethnicity were more likely to complete treatment (76.7% vs 40.0%, P = .04). Most patients (60%; n = 24) reported experiencing an adverse drug event (ADE) with 3HP therapy. Patients who completed treatment were less likely to experience an ADE than patients who discontinued treatment (50.0% vs 90.0%, P = .03). Pharmacists performed 398 LTBI treatment visits (40 initial visits, 358 follow-up visits), saving the NM DOH approximately 143 hours in patient contact time.High completion rates and safe administration of LTBI treatment can be achieved in the community pharmacy setting. |
| 2020 | Advances in the diagnosis and treatment of latent tuberculosis infection. | Curr Opin Infect Dis | This review describes the major developments in the rationale for treating latent tuberculosis infection; new approaches to identifying persons with latent infection who are most likely to progress to active disease; and the development of novel short-course regimens for treatment of latent tuberculosis.As many as one-third of the world's population has latent infection with Mycobacterium tuberculosis. Models demonstrate that tuberculosis will not be eliminated without large-scale treatment of persons with latent TB. Current tools for identifying persons at risk for active tuberculosis disease include TST and IGRA, which have poor positive predictive values. Newer approaches using gene expression profiling show promise and are being studied in the ongoing trials. Development of short-course regimens are a major advance in treatment of latent TB. Three months of rifapentine with Isoniazid, 4 months of rifampin, and 1 month of rifapentine with Isoniazid have been found to be noninferior to the standard 9 months of Isoniazid.Progress towards TB elimination can be accelerated by instituting public health measures that take into account new developments in identifying and treating persons with latent tuberculosis infection who are most likely to progress to active disease. |
| 2020 | Treatment of latent tuberculosis infection with short-course regimens in potential living kidney donors. | Transpl Infect Dis | Treatment data for latent tuberculosis infection (LTBI) among potential living kidney donors are scarce.This retrospective study was performed to evaluate the prevalence of positive QuantiFERON-TB Gold In-Tube (QFT-GIT) among potential living kidney donors that were screened from 2009 to 2017. We investigated if there was any difference in the time to donation between QFT-GIT-positive and QFT-GIT-negative donors. We assessed the regimens used to treat LTBI and whether the recipients of QFT-GIT-positive donors developed active tuberculosis (TB).Forty out of 427 (9%) potential living kidney donors had a positive QFT-GIT. QFT-GIT-positive donors were as likely as negative donors to undergo donation (30 [75%] vs 315 [81%], P = .33). The time from QFT-GIT testing to donation was longer among QFT-GIT-positive donors (median 221 days [range: 4-1139] vs 86 days [range: 3-1887], P = .001). Twelve-week rifapentine (RPT)/Isoniazid (INH) was the most common treatment used and was not associated with significant adverse reactions. There was a trend toward longer time to donation among QFT-GIT-positive donors who were treated for LTBI compared with QFT-GIT-positive donors who were not (252 days [range: 88-1139] vs 95 days [range: 4-802], P = .05). Twenty-nine recipients of QFT-GIT-positive living kidney donors were evaluated. Eleven of these recipients received kidneys from donors that were not treated for LTBI. Two of these recipients were treated with INH post-transplantation.The time from QFT-GIT testing to donation was longer among QFT-GIT-positive donors. The short-course regimens appear to be excellent options for LTBI treatment among living kidney donors and avoid delaying organ donation further. |
| 2019 | Association of Drug Metabolic Enzyme Genetic Polymorphisms and Adverse Drug Reactions in Patients Receiving Rifapentine and Isoniazid Therapy for Latent Tuberculosis. | Int J Environ Res Public Health | Weekly rifapentine and Isoniazid therapy (3HP) is the most frequent treatment for latent tuberculosis infection (LTBI). However, the association between major adverse drug reactions (ADRs) and drug metabolic enzyme single-nucleotide polymorphisms (SNPs) remains unclear. In this study, 377 participants who received the 3HP regimen were recruited and examined for genotyping of CYP5A6, CYP2B6, CYP2C19, CYP2E1, and NAT2 SNPs. In our study, 184 participants (48.4%) developed ADRs. Moreover, CYP2C19 rs4986893 (TT vs. CC+CT, odds ratio [OR] [95% CI]: 2.231 [1.015-4.906]), CYP2E1 rs2070676 (CC vs. CG+GG, OR [95% CI]: 1.563 [1.022-2.389]), and CYP2E1 rs2515641 (CC vs. CT+TT, OR [95% CI]: 1.903 [1.250-2.898]) were associated with ADR development. In conclusion, CYP2C19 and CYP2E1 SNPs may provide useful information regarding ADRs in LTBI patients receiving the 3HP regimen. |
| 2020 | Infection risk in patients undergoing treatment for inflammatory arthritis: non-biologics versus biologics. | Expert Rev Clin Immunol | : Despite the therapeutic effectiveness of biologics targeting immune cells or cytokines in patients with inflammatory arthritis, which reflects their pathogenic roles, an increased infection risk is observed in those undergoing biological treatment. However, there are limited data regarding the comparison of infection risks in inflammatory arthritis patients treated with non-biologics (csDMARDs), biologics (bDMARDs), including tumor necrosis factor (TNF) inhibitors and non-TNF inhibitors, or targeted synthetic (ts)DMARDs.: Through a review of English-language literature as of 30 June 2019, we focus on the existing evidence on the risk of infections caused by bacteria, , and hepatitis virus in inflammatory arthritis patients undergoing treatment with csDMARDs, bDMARDs, or tsDMARDs.: While the risks of bacterial and mycobacterial infection are increased in arthritis patients treated with csDMARDs, the risks are further higher in those receiving bDMARDs therapy, particularly TNF inhibitors. Regarding HBV infection, antiviral therapy may effectively prevent HBV reactivation in patients receiving bDMARDs, especially rituximab. However, more data are needed to establish effective preventive strategies for HBsAg-negative/HBcAb-positive patients. It seems safe to use cyclosporine and TNF inhibitors in patients with HCV infection, while those undergoing rituximab therapies should be frequently monitored for HCV activity.: ABT: abatacept; ADA: adalimumab; AS: ankylosing spondylitis; bDMARDs: biologic disease-modifying anti-rheumatic drugs; CKD: chronic kidney disease; COPD: chronic obstructive pulmonary disease; CS: corticosteroids; CsA: cyclosporine A; csDMARDs: conventional synthetic disease-modifying anti-rheumatic drugs; CZP: certolizumab; DAAs: direct-acting antiviral agents; DM: diabetes mellitus; DOT: directly observed therapy; EIN: Emerging Infections Network; ETN: etanercept; GOL: golimumab; GPRD: General Practice Research Database; HBV: hepatitis B virus; HBVr: HBV reactivation; HBsAg+: HBsAg-positive; HBsAg-/anti-HBc+: HBsAg-negative anti-HBc antibodies-positive; HCV: hepatitis C virus; HCQ: hydroxychloroquine: IFX: infliximab; IL-6: interleukin-6; JAK: Janus kinase; LEF: leflunomide; LTBI: latent tuberculosis infection; mAb: monoclonal antibody; MTX: methotrexate; OR: odds ratio; PsA: psoriatic arthritis; PMS: post-marketing surveillance; RA: rheumatoid arthritis; TNF: tumor necrosis factor; TNFi: tumor necrosis factor inhibitor; SCK: secukinumab; SSZ: sulfasalazine; TOZ: tocilizumab; RCT: randomized controlled trial; RR: relative risk; RTX: rituximab; 3HP: 3-month once-weekly Isoniazid plus rifapentine; TB: tuberculosis; tsDMARDs: targeted synthetic disease-modifying anti-rheumatic drugs; UTK: ustekinumab; WHO: World Health Organization. |
| 2019 | Shortened treatment regimens versus the standard regimen for drug-sensitive pulmonary tuberculosis. | Cochrane Database Syst Rev | Tuberculosis causes more deaths than any other infectious disease worldwide, with pulmonary tuberculosis being the most common form. Standard first-line treatment for drug-sensitive pulmonary tuberculosis for six months comprises Isoniazid, rifampicin, pyrazinamide, and ethambutol (HRZE) for two months, followed by HRE (in areas of high TB drug resistance) or HR, given over a four-month continuation phase. Many people do not complete this full course. Shortened treatment regimens that are equally effective and safe could improve treatment success.To evaluate the efficacy and safety of shortened treatment regimens versus the standard six-month treatment regimen for individuals with drug-sensitive pulmonary tuberculosis.We searched the following databases up to 10 July 2019: the Cochrane Infectious Diseases Group Specialized Register; the Central Register of Controlled Trials (CENTRAL), in the Cochrane Library; MEDLINE (PubMed); Embase; the Latin American Caribbean Health Sciences Literature (LILACS); Science Citation Index-Expanded; Indian Medlars Center; and the South Asian Database of Controlled Clinical Trials. We also searched the World Health Organization (WHO) International Clinical Trials Registry Platform, ClinicalTrials.gov, the Clinical Trials Unit of the International Union Against Tuberculosis and Lung Disease, the UK Medical Research Council Clinical Trials Unit, and the Clinical Trials Registry India for ongoing trials. We checked the reference lists of identified articles to find additional relevant studies.We searched for randomized controlled trials (RCTs) or quasi-RCTs that compared shorter-duration regimens (less than six months) versus the standard six-month regimen for people of all ages, irrespective of HIV status, who were newly diagnosed with pulmonary tuberculosis by positive sputum culture or GeneXpert, and with presumed or proven drug-sensitive tuberculosis. The primary outcome of interest was relapse within two years of completion of anti-tuberculosis treatment (ATT).Two review authors independently selected trials, extracted data, and assessed risk of bias for the included trials. For dichotomous outcomes, we used risk ratios (RRs) with 95% confidence intervals (CIs). When appropriate, we pooled data from the included trials in meta-analyses. We assessed the certainty of evidence using the GRADE approach.We included five randomized trials that compared fluoroquinolone-containing four-month ATT regimens versus standard six-month ATT regimens and recruited 5825 adults with newly diagnosed drug-sensitive pulmonary tuberculosis from 14 countries with high tuberculosis transmission in Asia, Africa, and Latin Ameria. Three were multi-country trials that included a total of 572 HIV-positive people. These trials excluded children, pregnant or lactating women, people with serious comorbid conditions, and those with diabetes mellitus. Four trials had multiple treatment arms. Moxifloxacin replaced ethambutol in standard four-month, daily or thrice-weekly ATT regimens in two trials; moxifloxacin replaced Isoniazid in four-month ATT regimens in two trials, was given daily in one trial, and was given with rifapentine instead of rifampicin daily for two months and twice weekly for two months in one trial. Moxifloxacin was added to standard ATT drugs for three to four months in one ongoing trial that reported interim results. Gatifloxacin replaced ethambutol in standard ATT regimens given daily or thrice weekly for four months in two trials. Follow-up ranged from 12 months to 24 months after treatment completion for the majority of participants. Moxifloxacin-containing four-month ATT regimens Moxifloxacin-containing four-month ATT regimens that replaced ethambutol or Isoniazid probably increased the proportions who experienced relapse after successful treatment compared to standard ATT regimens (RR 3.56, 95% CI 2.37 to 5.37; 2265 participants, 3 trials; moderate-certainty evidence). For death from any cause, there was probably little or no difference between the two regimens (2760 participants, 3 trials; moderate-certainty evidence). Treatment failure was rare, and there was probably little or no difference in proportions with treatment failure between ATT regimens (2282 participants, 3 trials; moderate-certainty evidence). None of the participants given moxifloxacin-containing regimens developed resistance to rifampicin, and these regimens may not increase the risk of acquired resistance (2282 participants, 3 trials; low-certainty evidence). Severe adverse events were probably little or no different with moxifloxacin-containing four-month regimens that replaced ethambutol or Isoniazid, and with three- to four-month regimens that augmented standard ATT with moxifloxacin, when compared to standard six-month ATT regimens (3548 participants, 4 trials; moderate-certainty evidence). Gatifloxacin-containing four-month ATT regimens Gatifloxacin-containing four-month ATT regimens that replaced ethambutol probably increased relapse compared to standard six-month ATT regimens in adults with drug-sensitive pulmonary tuberculosis (RR 2.11, 95% CI 1.56 to 2.84; 1633 participants, 2 trials; moderate-certainty evidence). The four-month regimen probably made little or no difference in death compared to the six-month regimen (1886 participants, 2 trials; moderate-certainty evidence). Treatment failure was uncommon and was probably little or no different between the four-month and six-month regimens (1657 participants, 2 trials; moderate-certainty evidence). Acquired resistance to Isoniazid or rifampicin was not detected in those given the gatifloxacin-containing shortened ATT regimen, but we are uncertain whether acquired drug resistance is any different in the four- and six-month regimens (429 participants, 1 trial; very low-certainty evidence). Serious adverse events were probably no different with either regimen (1993 participants, 2 trials; moderate-certainty evidence).Evidence to date does not support the use of shortened ATT regimens in adults with newly diagnosed drug-sensitive pulmonary tuberculosis. Four-month ATT regimens that replace ethambutol with moxifloxacin or gatifloxacin, or Isoniazid with moxifloxacin, increase relapse substantially compared to standard six-month ATT regimens, although treatment success and serious adverse events are little or no different. The results of six large ongoing trials will help inform decisions on whether shortened ATT regimens can replace standard six-month ATT regimens. 9 December 2019 Up to date All studies incorporated from most recent search All eligible published studies found in the last search (10 Jul, 2019) were included. |
| 2020 | Simple and sensitive method for the analysis of 14 antituberculosis drugs using liquid chromatography/tandem mass spectrometry in human plasma. | Rapid Commun Mass Spectrom | Monitoring plasma concentration and adjusting doses of antituberculosis (TB) drugs are beneficial for improving responses to drug treatment and avoiding adverse drug reactions. A simple and sensitive liquid chromatography/tandem mass spectrometry method was developed to measure the plasma concentrations of 14 anti-TB drugs: ethambutol, Isoniazid, pyrazinamide, levofloxacin, gatifloxacin, moxifloxacin, prothionamide, linezolid, rifampin, rifapentine, rifabutin, cycloserine, p-aminosalicylic acid, and clofazimine.Human plasma was precipitated by acetonitrile and was subsequently separated by an AQ-C18 column with a gradient elution. Drug concentrations were determined using multiple reaction monitoring in positive ion electrospray ionization mode. According to pharmacokinetic data of patients, the peak concentration ranges and the timing of blood collection were determined.Intra- and interday precision was < 14.8%. Linearity, accuracy, extraction recovery, and matrix effect were acceptable for each drug. The stability of the method satisfied different storage conditions.The method allowed the sensitive and reproducible determination of 14 frequently used anti-TB drugs which has already been of benefit for some TB patients. |
| 2020 | Preventive tuberculosis treatment effect on QuantiFERON TB-Gold in-tube testing in a high tuberculosis-endemic country: A clinical trial. | Int J Infect Dis | Whether T-cell interferon-γ responses to Mycobacterium tuberculosis-specific antigens can be influenced by tuberculosis preventive treatment in a high-endemic country is uncertain.In this prospective, open-label, controlled study, 513 individuals with silicosis were randomly selected for TB preventive treatment with rifapentine and Isoniazid or for observation. QuantiFERON-TB Gold in-tube (QFT-GIT) assay was used to measure IFN-γ response to M. tuberculosis antigens at baseline (T0) and at 6 (T1) and 33 (T2) months after completion of therapy.A total of 220 subjects were included in the final analysis: 105 and 115 in the prevention and observation arms, respectively. The proportions of QFT-GIT reversion from baseline to T1 were similar in the prevention and observation arms (18.4% vs 12.8%, P=0.566). However, reversion from baseline to T2 was more frequent in the prevention arm than in the observation arm, but the difference was not significant (24.2% vs 6.3%, P=0.881). No significant difference was observed in the quantitative responses of QFT-GIT between the two arms during follow-up at T1 (P=0.648) and T2 (P=0.918).Preventive tuberculosis treatment has no effect on interferon-γ responses measured by serial QFT-GIT assays in a high tuberculosis-endemic country.http://www.clinicaltrials.gov NCT02430259. |
| 2020 | Treatment for latent tuberculosis infection in low- and middle-income countries: progress and challenges with implementation and scale-up. | Expert Rev Respir Med | : Treatment of latent tuberculosis infection (LTBI) is a crucial but neglected component of global tuberculosis control. The 2018 United Nations High-Level Meeting committed world leaders to provide LTBI treatment to at least 30 million people, including 4 million children<5 years, 20 million other household contacts and 6 million HIV-infected people by 2022.: This review searched MEDLINE between 1990 and 2019 and discussed: i) high-risk groups to be prioritized for diagnosis and treatment of LTBI; ii) challenges with diagnosing LTBI in programmatic settings; iii) LTBI treatment options including Isoniazid monotherapy, shorter regimens (rifampicin-monotherapy, rifampicin-Isoniazid and rifapentine-Isoniazid) and treatments for contacts of drug-resistant patients; iv) issues with programmatic scale-up of treatment including policy considerations, ruling out active TB, time to start treatment, safety, uninterrupted drug supplies and treatment adherence; and v) recording and reporting.: In 2017, <1.5 million persons were reported to be treated for LTBI. This must rapidly increase to 6 million persons annually. If HIV programs focus on HIV-infected people already accessing or about to start antiretroviral therapy and TB programs focus on household contacts, these targets could be achieved. Isoniazid remains the current treatment of choice although shorter courses of rifapentine-Isoniazid are possible alternatives. |
| 2019 | Treatment of Latent Tuberculosis Infection-An Update. | Clin Chest Med | Treatment of latent tuberculosis infection (LTBI) is an important component of TB control and elimination. LTBI treatment regimens include once-weekly Isoniazid plus rifapentine for 3 months, daily rifampin for 4 months, daily Isoniazid plus rifampin for 3-4 months, and daily Isoniazid for 6-9 months. Isoniazid monotherapy is efficacious in preventing TB disease, but the rifampin- and rifapentine-containing regimens are shorter and have similar efficacy, adequate safety, and higher treatment completion rates. Novel vaccine strategies, host immunity-directed therapies and ultrashort antimicrobial regimens for TB prevention, such as daily Isoniazid plus rifapentine for 1 month, are under evaluation. |
| 2020 | Evaluation of 3 Months of Once-Weekly Rifapentine and Isoniazid for Latent Tuberculosis Infection. | Ann Pharmacother | Centers for Disease Control and Prevention recommends 3 months of once-weekly rifapentine/Isoniazid (3HP) for latent tuberculosis infection (LTBI) treatment given by directly observed therapy (DOT) or self-administered therapy (SAT) in patients ≥2 years old. 3HP has been associated with increased incidence of hepatic, gastrointestinal, flu-like, and cutaneous adverse drug reactions (ADRs) compared with Isoniazid monotherapy. This study evaluated 3HP completion rates and tolerability for LTBI treatment in a real-world setting. A single-center retrospective cohort with a nested case-control study, comparing patients experiencing ADRs with those who did not, evaluated patients ≥18 years old receiving 3HP by DOT or SAT for LTBI at Cleveland Clinic from October 2011 through July 2018. Information on baseline characteristics, 3HP administrations, and ADRs were collected. Of 199 patients screened, 144 were included (111 DOT, 33 SAT). 3HP completion rates were high at 82.6% and similar between DOT and SAT groups. During treatment, 92/144 (63.9%) patients experienced any ADR. The most common ADR included flu-like symptoms (38.2%) and gastrointestinal (31.9%) and hepatic (2.1%) reactions. Despite high rate of overall ADRs, rates of significant ADRs (grade 2 or higher) were 4.2%. Overall, 9% of patients discontinued 3HP because of ADRs. After adjusting for other factors associated with ADRs at baseline, SAT was not associated with increased incidence of ADRs, but female sex was a significant predictor (odds ratio = 2.61 [95% CI, 1.23 to 5.56]). This study observed high 3HP treatment completion rates, low incidence of significant ADRs, and low discontinuation rates resulting from ADRs. |
| 2020 | Nonparticipation reasons in a randomized international trial of a new latent tuberculosis infection regimen. | Clin Trials | Efficient recruitment of eligible participants, optimizing time and sample size, is a crucial component in conducting a successful clinical trial. Inefficient participant recruitment can impede study progress, consume staff time and resources, and limit quality and generalizability or the power to assess outcomes. Recruitment for disease prevention trials poses additional challenges because patients are asymptomatic. We evaluated candidates for a disease prevention trial to determine reasons for nonparticipation and to identify factors that can be addressed to improve recruitment efficiency.During 2001-2009, the Tuberculosis Trials Consortium conducted Study 26 (PREVENT TB), a randomized clinical trial at 26 sites in four countries, among persons with latent tuberculosis infection at high risk for tuberculosis disease progression, comparing 3 months of directly observed once-weekly rifapentine plus Isoniazid with 9 months of self-administered daily Isoniazid. During March 2005-February 2008, non-identifying demographic information, risk factors for experiencing active tuberculosis disease, and reasons for not enrolling were collected from screened patients to facilitate interpretation of trial data, to meet Consolidated Standards of Reporting Trials standards, and to evaluate reasons for nonparticipation.Of the 7452 candidates screened in Brazil, Canada, Spain, and the United States, 3584 (48%) were not enrolled, because of ineligibility (41%), site decision (10%), or patient choice (49%). Among those who did not enroll by own choice, and for whom responses were recorded on whether they would accept treatment outside of the study (n = 1430), 68% reported that they planned to accept non-study latent tuberculosis infection treatment. Among 1305 patients with one or more reported reasons for nonparticipation, study staff recorded a total of 1886 individual reasons (reason count: median = 1/patient; range = 1-9) for why patients chose not to enroll, including grouped concerns about research (24% of 1886), work or school conflicts (20%), medication or health beliefs (16%), latent tuberculosis infection beliefs (11%), and patient lifestyle and family concerns (10%).Educational efforts addressing clinical research concerns and beliefs about medication and health, as well as study protocols that accommodate patient-related concerns (e.g. work, school, and lifestyle) might increase willingness to enter clinical trials. Findings from this evaluation can support development of communication and education materials for clinical trial sites at the beginning of a trial to allow study staff to address potential participant concerns during study screening. |
| 2019 | Ulcerative intestinal tuberculosis case as a complication of treatment by infliximab for intestinal Behçet's disease: A case report. | Medicine (Baltimore) | Intestinal Behçet's disease (BD) is characterized by intestinal ulcerations and gastrointestinal symptoms. Ulcerative intestinal tuberculosis (TB) is usually with dyspepsia, abdominal pain, vomiting, and weight loss. The 2 diseases exhibit similar clinical manifestations, but the most critical aspects of their clinical courses and required treatments are not at all similar.We present a case in which a patient with intestinal Behçet's disease developed a de novo ulcerative intestinal TB infection after the start of anti-tumor necrosis factor-α treatment. This was despite histopathologic examination without caseous necrosis granuloma and negative for acid-fast staining and latent TB screen.Intestinal Behçet's disease and intestinal TB.The patient was treated with quadruple antituberculous chemotherapy, comprising rifapentine, Isoniazid, ethambutol, and pyrazinamide.At follow-up about 3 months, the therapy of oral antituberculous drugs and thalidomide was continued and the patient's condition had stabilized.This case illustrates the importance of closely monitoring patients who are on infliximab for possible onset of TB, even without abdominal symptoms, and with negative screening results for latent TB. |
| 2020 | Isoniazid and Rifapentine Treatment Eradicates Persistent in Macaques. | Am J Respir Crit Care Med | The authors have informed the Journal that they have become aware that some of the data in this article may be unreliable. Therefore, we have added this expression of concern while the situation is being reviewed. Direct evidence for persistence of () during asymptomatic latent tuberculosis infection (LTBI) in humans is currently lacking. Moreover, although a 12-week regimen of once-weekly Isoniazid and rifapentine (3HP) is currently recommended by the CDC as treatment for LTBI, experimental evidence for 3HP-mediated clearance of persistent infection in human lungs has not been established. Using a nonhuman primate (NHP) model of TB, we sought to assess 3HP treatment-mediated clearance of infection in latently infected macaques. Sixteen NHPs were infected via inhalation with ∼10 cfu of CDC1551, after which asymptomatic animals were either treated with 3HP or left untreated. Pharmacokinetics of the 3HP regimen were measured. Following treatment, animals were coinfected with simian immunodeficiency virus to assess reactivation of LTBI and development of active TB disease. Fourteen NHPs remained free of clinical signs or microbiological evidence of active TB following infection with and were subsequently either treated with 3HP ( = 7) or left untreated ( = 7). Untreated NHPs were asymptomatic for 7 months but harbored persistent infection, as shown by reactivation of latent infection following simian immunodeficiency virus coinfection. However, none of the treated animals developed TB reactivation disease, and they remained without clinical or microbiological evidence of persistent bacilli, suggesting treatment-mediated clearance of bacteria. can persist in asymptomatic macaques for at least 7 months. Furthermore, 3HP treatment effectively cleared bacteria and prevented reactivation of TB in latently infected macaques. |
| Adverse event and treatment completion rates of a 12-dose weekly isoniazid and rifapentine course for South Korean healthcare workers. | Respir Med | We investigated the adverse events (AEs) and treatment completion rates of a 3 month course of once-weekly Isoniazid and rifapentine (3HP) in South Korean health care workers (HCWs) with latent tuberculosis infection (LTBI).HCWs who were candidates for LTBI treatment were enrolled from two tertiary referral centers between December 2016 and October 2017. From December 2016 through March 2017, HCWs who agreed were treated with the 3HP regimen (3HP group). Their compliance and AEs were prospectively collected. From April 2017 onward, HCWs who required LTBI treatment received 3 months of Isoniazid plus rifampin (3HR group), and their medical records were retrospectively reviewed.During the study period, 406 HCWs were treated, 226 (55.7%) in the 3HP group, and 180 (44.3%) in the 3HR group. The number of subjects with AEs was significantly greater in the 3HP group (75.2% vs 56.7%, P < 0.001), in particular a flu-like syndrome (19.0% vs. 0%, P < 0.001). However, hepatotoxicity occurred less frequently in those receiving 3HP (7.5% vs. 20.0%, P < 0.001). Per protocol definition, anaphylaxis developed in 1.8% of the 3HP group. The overall treatment completion rate was greater in the 3HP group (92.9% vs 86.7%, P = 0.036).The 3HP regimen had a higher treatment completion rate and lower hepatotoxicity compared with the 3HR regimen. However, it resulted in a higher rate of flu-like syndromes. Additionally, a few subjects had anaphylaxis, although there were no fatalities. |
| 2019 | Prevention of Opportunistic Infections in Women With HIV Infection. | Clin Obstet Gynecol | Opportunistic infections are those that are either more frequent or more severe as a result of the patient's immunosuppressed condition. Opportunistic infections are, of course, the distinguishing feature of HIV infection, and they can be the cause of serious morbidity and even mortality. Some opportunistic infections can be prevented by vaccination, for example, pneumococcal infection, meningococcal infection, influenza, hepatitis A and B, and varicella. Other major opportunistic infections require prophylactic antibiotics or antiviral medications. In obstetric patients, pneumocystis infections and toxoplasmosis are most effectively prevented by the administration of trimethoprim-sulfamethoxazole. The most effective agents for prevention of reactivation of tuberculosis are Isoniazid, rifampin, and rifapentine. Fluconazole is of value in preventing cryptococcal infection and candidiasis. Acyclovir, valacyclovir, and famiclovir are effective in preventing recurrent outbreaks of herpes simplex virus. Ultimately; however, the best way to prevent opportunistic infections is to treat the patient with highly active antiretroviral agents and restore her immune competence. |
| 2019 | Latent tuberculosis treatment completion rates from prescription drug administrative data. | Can J Public Health | In the province of Manitoba, Canada, given that latent tuberculosis infection (LTBI) treatment is provided at no cost to the patient, treatment completion rates should be optimal. The objective of this study was to estimate LTBI treatment completion using prescription drug administrative data and identify patient characteristics associated with completion.Prescription drug data (1999-2014) were used to identify individuals dispensed Isoniazid (INH) or rifampin (RIF) monotherapy. Treatment completion was defined as being dispensed INH for ≥ 180 days (INH180) or ≥ 270 days (INH270) or RIF for ≥ 120 days (RIF120). Logistic regression models tested socio-demographic and comorbidity characteristics associated with treatment completion.The study cohort comprised 4985 (90.4%) persons dispensed INH and 529 (9.6%) RIF. Overall treatment completion was 60.2% and improved from 43.1% in 1999-2003 to 67.3% in 2009-2014. INH180 showed the highest completion (63.8%) versus INH270 (40.4%) and RIF120 (27.0%). INH180 completion was higher among those aged 0-18 years (68.5%) compared with those aged 19+ (61.0%). Sex, geography, First Nations status, income quintile, and comorbidities were not associated with completion.Benchmark 80% treatment completion rates were not achieved in Manitoba. Factors associated with non-completion were older age, INH270, and RIF120. Access to shorter LTBI treatments, such as rifapentine/INH, may improve treatment completion. |
| 2019 | Isoniazid Concentration and Genotype Predict Risk of Systemic Drug Reactions during 3HP for LTBI. | J Clin Med | Weekly rifapentine and Isoniazid therapy (known as 3HP) for latent tuberculosis infection (LTBI) is increasingly used, but systemic drug reactions (SDR) remain a major concern. Methods: We prospectively recruited two LTBI cohorts who received the 3HP regimen. In the single-nucleotide polymorphism (SNP) cohort, we collected clinical information of SDRs and examined the , , and SNPs. In the pharmacokinetic (PK) cohort, we measured plasma drug and metabolite levels at 6 and 24 h after 3HP administration. The generalised estimating equation model was used to identify the factors associated with SDRs. Candidate SNPs predicting SDRs were validated in the PK cohort. A total of 177 participants were recruited into the SNP cohort and 129 into the PK cohort, with 14 (8%) and 13 (10%) in these two cohorts developing SDRs, respectively. In the SNP cohort, rs1041983 (TT vs. CC+CT, odds ratio [OR] [95% CI]: 7.00 [2.03-24.1]) and rs2070673 (AA vs. TT+TA, OR [95% CI]: 3.50 [1.02-12.0]) were associated with SDR development. In the PK cohort, Isoniazid level 24 h after 3HP administration (OR [95% CI]: 1.61 [1.15-2.25]) was associated with SDRs. Additionally, the association between the SNP and SDRs was validated in the PK cohort (rs1041983 TT vs. CC+CT, OR [95% CI]: 4.43 [1.30-15.1]). Conclusions: Isoniazid played a role in the development of 3HP-related SDRs. This could provide insight for further design of a more optimal regimen for latent TB infection. |
| Completion Rates, Adverse Effects, and Costs of a 3-Month and 9-Month Treatment Regimen for Latent Tuberculosis Infection in California Inmates, 2011-2014. | Public Health Rep | In California, about 80% of tuberculosis disease is caused by untreated latent tuberculosis infection (LTBI), and the rate of LTBI is higher among incarcerated persons (16%) than among nonincarcerated persons (6%). We compared 2 regimens to treat LTBI in an adult prison population in California: 9 months of twice-weekly Isoniazid (9H; previous standard of care) and 12 once-weekly doses of Isoniazid and rifapentine (3HP; introduced in 2011).We evaluated the rates of completion and discontinuation caused by hepatotoxicity among randomly selected patients with LTBI prescribed the 9H regimen in 2011 and among patients with LTBI prescribed the 3HP regimen who entered California prisons during September 2013-March 2014. We compared the cost per fully treated patient for the 2 regimens.Of 92 patients treated with the 9H regimen, the treatment completion rate was 42% and discontinuation due to hepatotoxicity was 14%. Of 122 patients who accepted the 3HP regimen, the completion rate was 90% and discontinuation due to hepatotoxicity was 2%. The cost per fully treated patient for the 9H regimen was $981 and for 3HP was $652.In an incarcerated population, the 3HP regimen had a higher completion rate, lower hepatotoxicity, and lower cost per fully treated patient than the 9H regimen. If coupled with a high treatment initiation rate, the high rate of LTBI treatment completion with 3HP may contribute to reducing tuberculosis morbidity in California. |
| 2018 | Addressing tuberculosis among Inuit in Canada. | Can Commun Dis Rep | The average annual rate of tuberculosis (TB) among Inuit in Canada is now more than 290 times higher than Canadian born non-Indigenous people. How did this happen? Using the Territory of Nunavut as a case example, the roots of this situation can largely be traced back to social determinants of health and challenges in access to health care. Half (52%) of all Nunavut residents live in social housing, often under overcrowded conditions. Many experience food insecurity, with food prices in Nunavut that are twice those in southern Canada. Sixty percent of Nunavut residents smoke. Challenges in health care delivery include the small isolated communities, with few roads and difficult weather conditions during the long winters, which impede the ability to reach or provide healthcare, staff that arrive with little TB experience or cultural knowledge, multiple competing health care demands, limited resources and high staff turnover. The housing shortage is not only a social determinant of health, it also impacts the ability to hire new staff or mount an effective response in the event of an outbreak. Yet despite these challenges, progress has been made. Tuberculosis care in Nunavut includes active case finding, contact tracing for all cases of infectious TB, and screening of school age children. Rapid testing with the GeneXpert platform has resulted in a quicker diagnosis of active TB, earlier treatment (preventing progression of disease) and less transmission. Progressively, there has been a switch from plain film to digital x-rays reducing x-ray turnaround time from as long as two to three weeks to one or two days. Standard treatment protocols include quadruple therapy until sensitivities are known, the use of home isolation for active cases and directly observed treatment (DOT) for both latent and active TB. Special access to rifapentine (Priftin), and its use in combination therapy (3HP), requires only once weekly treatments that can be completed in 12 visits instead of 78 visits for Isoniazid (INH) or 120 visits for rifampin, which increases adherence and greatly reduces the health care resources needed to treat TB. In October 2017, the Honourable Jane Philpott, then Minister of Health and now Minister of Indigenous Services, and Natan Obed, president of Inuit Tapiriit Kanatami (ITK) announced the establishment of a Task Force to develop an Inuit TB Elimination Action Framework, accompanied by regional action plans. It is hoped that the task force, and current efforts in Nunavut, will lead to the long term changes needed to ultimately eliminate TB among Inuit in Canada. |
| 2019 | Outlook for tuberculosis elimination in California: An individual-based stochastic model. | PLoS One | As part of the End TB Strategy, the World Health Organization calls for low-tuberculosis (TB) incidence settings to achieve pre-elimination (<10 cases per million) and elimination (<1 case per million) by 2035 and 2050, respectively. These targets require testing and treatment for latent tuberculosis infection (LTBI).To estimate the ability and costs of testing and treatment for LTBI to reach pre-elimination and elimination targets in California.We created an individual-based epidemic model of TB, calibrated to historical cases. We evaluated the effects of increased testing (QuantiFERON-TB Gold) and treatment (three months of Isoniazid and rifapentine). We analyzed four test and treat targeting strategies: (1) individuals with medical risk factors (MRF), (2) non-USB, (3) both non-USB and MRF, and (4) all Californians. For each strategy, we estimated the effects of increasing test and treat by a factor of 2, 4, or 10 from the base case. We estimated the number of TB cases occurring and prevented, and net and incremental costs from 2017 to 2065 in 2015 U.S. dollars. Efficacy, costs, adverse events, and treatment dropout were estimated from published data. We estimated the cost per case averted and per quality-adjusted life year (QALY) gained.In the base case, 106,000 TB cases are predicted to 2065. Pre-elimination was achieved by 2065 in three scenarios: a 10-fold increase in the non-USB and persons with MRF (by 2052), and 4- or 10-fold increase in all Californians (by 2058 and 2035, respectively). TB elimination was not achieved by any intervention scenario. The most aggressive strategy, 10-fold in all Californians, achieved a case rate of 8 (95% UI 4-16) per million by 2050. Of scenarios that reached pre-elimination, the incremental net cost was $20 billion (non-USB and MRF) to $48 billion. These had an incremental cost per QALY of $657,000 to $3.1 million. A more efficient but somewhat less effective single-lifetime test strategy reached as low as $80,000 per QALY.Substantial gains can be made in TB control in coming years by scaling-up current testing and treatment in non-USB and those with medical risks. |
| 2019 | One Month of Rifapentine plus Isoniazid to Prevent HIV-Related Tuberculosis. | N Engl J Med | Tuberculosis is the leading killer of patients with human immunodeficiency virus (HIV) infection. Preventive therapy is effective, but current regimens are limited by poor implementation and low completion rates.We conducted a randomized, open-label, phase 3 noninferiority trial comparing the efficacy and safety of a 1-month regimen of daily rifapentine plus Isoniazid (1-month group) with 9 months of Isoniazid alone (9-month group) in HIV-infected patients who were living in areas of high tuberculosis prevalence or who had evidence of latent tuberculosis infection. The primary end point was the first diagnosis of tuberculosis or death from tuberculosis or an unknown cause. Noninferiority would be shown if the upper limit of the 95% confidence interval for the between-group difference in the number of events per 100 person-years was less than 1.25.A total of 3000 patients were enrolled and followed for a median of 3.3 years. Of these patients, 54% were women; the median CD4+ count was 470 cells per cubic millimeter, and half the patients were receiving antiretroviral therapy. The primary end point was reported in 32 of 1488 patients (2%) in the 1-month group and in 33 of 1498 (2%) in the 9-month group, for an incidence rate of 0.65 per 100 person-years and 0.67 per 100 person-years, respectively (rate difference in the 1-month group, -0.02 per 100 person-years; upper limit of the 95% confidence interval, 0.30). Serious adverse events occurred in 6% of the patients in the 1-month group and in 7% of those in the 9-month group (P = 0.07). The percentage of treatment completion was significantly higher in the 1-month group than in the 9-month group (97% vs. 90%, P<0.001).A 1-month regimen of rifapentine plus Isoniazid was noninferior to 9 months of Isoniazid alone for preventing tuberculosis in HIV-infected patients. The percentage of patients who completed treatment was significantly higher in the 1-month group. (Funded by the National Institute of Allergy and Infectious Diseases; BRIEF TB/A5279 ClinicalTrials.gov number, NCT01404312.). |
| 2019 | Treatment of latent Mycobacterium tuberculosis infection with 12 once weekly directly-observed doses of isoniazid and rifapentine among persons experiencing homelessness. | PLoS One | To investigate treatment outcomes and associated characteristics of persons experiencing homelessness who received 12-weekly doses of directly observed Isoniazid and rifapentine (3HP/DOT) treatment for latent TB infection (LTBI).Among homeless persons treated with 3HP/DOT during July 2011 -June 2015 in 11 U.S. TB programs, we conducted descriptive analyses of observational data, and identified associations between sociodemographic factors and treatment outcomes. Qualitative interviews were conducted to understand programmatic experiences.Of 393 persons experiencing homelessness (median age: 50 years; range: 13-74 years), 301 (76.6%) completed treatment, 55 (14.0%) were lost to follow-up, 18 (4.6%) stopped because of an adverse event (AE), and 19 (4.8%) stopped after relocations or refusing treatment. Eighty-one (20.6%) had at least one AE. Persons aged ≥65 were more likely to discontinue treatment than persons aged 31-44 years. Programs reported difficulty in following up with persons experiencing homelessness because of relocations, mistrust, and alcohol or drug use.This study demonstrates the feasibility of administering the 3HP/DOT LTBI regimen to persons experiencing homelessness, a high-risk population. |
| 2019 | Recent Innovations in Diagnosis and Treatment of Pediatric Tuberculosis. | Curr Infect Dis Rep | Tuberculosis is leading cause of global morbidity and mortality and a significant proportion of the burden of disease occurs in children. In the past 5 years, a number of innovations have improved the diagnosis and treatment for children with both latent tuberculosis infection and active disease.This review discusses three key areas of innovation. First, we assess utilization and performance of interferon-gamma release assays (IGRAs) in different clinical and epidemiologic scenarios. Recent literature has demonstrated good performance of IGRAs for diagnosis of latent tuberculosis infection, particularly in low-incidence settings such as TB control programs in North America. For high-incidence populations, or when testing is done for possible active TB disease, IGRA performance has some important limitations, but IGRA sensitivity when measured against culture proven disease may be better than earlier studies suggested. The second area of innovation is in increased uptake of nucleic acid amplification (NAA) tests and broader application in non-sputum samples for both pediatric pulmonary and extrapulmonary tuberculosis. Finally, recent studies have provided solid evidence in support of shorter treatment courses for pediatric latent tuberculosis infection, such as 12 weeks of weekly Isoniazid and rifapentine or 4 months daily rifampin, that improve compliance and may reduce resources required for TB control. Many recent innovations in pediatric tuberculosis relate to an improved understanding of how to optimally use existing tests and treatments. Until diagnostic tests and interventions such as vaccination are developed that can dramatically alter the paradigm of pediatric TB management and control, it is important for stakeholders to have a nuanced understanding of tools currently available. |
| 2019 | Activity of a Long-Acting Injectable Bedaquiline Formulation in a Paucibacillary Mouse Model of Latent Tuberculosis Infection. | Antimicrob Agents Chemother | The potent antituberculosis activity and long half-life of bedaquiline make it an attractive candidate for use in long-acting/extended-release formulations for the treatment of latent tuberculosis infection (LTBI). Our objective was to evaluate a long-acting injectable (LAI) bedaquiline formulation in a validated paucibacillary mouse model of LTBI. Following immunization with rBCG30, BALB/c mice were challenged by aerosol infection with H37Rv. Treatment began 13 weeks after challenge infection with one of the following regimens: an untreated negative-control regimen; positive-control regimens of daily rifampin (10 mg/kg of body weight), once-weekly rifapentine (15 mg/kg) and Isoniazid (50 mg/kg), or daily bedaquiline (25 mg/kg); test regimens of one, two, or three monthly doses of LAI bedaquiline at 160 mg/dose (B); and test regimens of daily bedaquiline at 2.67 mg/kg (B), 5.33 mg/kg (B), or 8 mg/kg (B) to deliver the same total amount of bedaquiline as one, two, or three doses of B, respectively. All drugs were administered orally, except for B (intramuscular injection). The primary outcome was the decline in lung CFU counts during 12 weeks of treatment. The negative- and positive-control regimens performed as expected. One, two, and three doses of B resulted in decreases of 2.9, 3.2, and 3.5 log CFU/lung, respectively, by week 12. Daily oral dosing with B, B, and B decreased lung CFU counts by 1.6, 2.8, and 4.1 log, respectively. One dose of B exhibited activity for at least 12 weeks. The sustained activity of B indicates that it shows promise as a short-course LTBI treatment requiring few patient encounters to ensure treatment completion. |
| 2018 | Three-month weekly rifapentine plus isoniazid for tuberculosis preventive treatment: a systematic review. | Int J Tuberc Lung Dis | Uptake of preventive treatment for tuberculosis (TB) remains poor. A 3-month regimen of rifapentine (RPT) plus Isoniazid (INH) (3HP) could facilitate its scale-up. We conducted a systematic review to assess the effects of 3HP compared with daily 6- or 9-month INH monotherapy.We searched the following databases to identify randomised controlled trials: PubMed, Embase, the Web of Science, Cochrane Central Register of Controlled Trials, three ongoing trial registers and conference abstracts up to 24 January 2017. Where possible, we pooled data using a random-effects model.Four studies were included. Of those, we included two studies that compared 3HP with daily 6- or 9-month INH (6/9H) among adults with human immunodeficiency virus (HIV) co-infection, one among HIV-negative adults and one among predominantly HIV-negative children and adolescents. Risk of active TB was not significantly different between 3HP and 6/9H (risk ratio [RR] 0.73, 95%CI 0.23-2.29, in adults with HIV; RR 0.44, 95%CI 0.18-1.07, in adults without HIV; RR 0.13, 95%CI 0.01-2.54, in children and adolescents). Risk of hepatotoxicity was significantly lower in the 3HP group among adults with HIV (RR 0.26, 95%CI 0.12-0.55) and those without HIV (RR 0.16, 95%CI 0.10-0.27). 3HP was also associated with a higher completion rate in all subgroups.HP was shown to have a preventive effect similar to that of INH monotherapy, with fewer adverse events and higher completion rates. 3HP can contribute significantly to the scale-up of preventive treatment. |
| 2018 | Using Video Technology to Increase Treatment Completion for Patients With Latent Tuberculosis Infection on 3-Month Isoniazid and Rifapentine: An Implementation Study. | J Med Internet Res | Since January 2013, the New York City (NYC) Health Department Tuberculosis (TB) Program has offered persons diagnosed with latent TB infection (LTBI) the 3-month, once-weekly Isoniazid and rifapentine (3HP) treatment regimen. Patients on this treatment are monitored in-person under directly observed therapy (DOT). To address patient and provider barriers to in-person DOT, we piloted the use of a videoconferencing software app to remotely conduct synchronous DOT (video directly observed therapy; VDOT) for patients on 3HP.The objective of our study was to evaluate the implementation of VDOT for patients on 3HP and to assess whether treatment completion for these patients increased when they were monitored using VDOT compared with that using the standard in-person DOT.Between February and October 2015, patients diagnosed with LTBI at any of the four NYC Health Department TB clinics who met eligibility criteria for treatment with 3HP under VDOT (V3HP) were followed until 16 weeks after treatment initiation, with treatment completion defined as ingestion of 11 doses within 16 weeks. Treatment completion of patients on V3HP was compared with that of patients on 3HP under clinic-based, in-person DOT who were part of a prior study in 2013. Furthermore, outcomes of video sessions with V3HP patients were collected and analyzed.During the study period, 70% (50/71) of eligible patients were placed on V3HP. Treatment completion among V3HP patients was 88% (44/50) compared with 64.9% (196/302) among 3HP patients on clinic DOT (P<.001). A total of 360 video sessions were conducted for V3HP patients with a median of 8 (range: 1-11) sessions per patient and a median time of 4 (range: 1-59) minutes per session. Adherence issues (eg, >15 minutes late) during video sessions occurred 104 times. No major side effects were reported by V3HP patients.The NYC TB program observed higher treatment completion with VDOT than that previously seen with clinic DOT among patients on 3HP. Expanding the use of VDOT may improve treatment completion and corresponding outcomes for patients with LTBI. |
| 2018 | Treatment completion for latent tuberculosis infection in Norway: a prospective cohort study. | BMC Infect Dis | Successful treatment of latent tuberculosis infection (LTBI) is essential to reduce tuberculosis (TB) incidence rates in low-burden countries. This study measures treatment completion and determinants of non-completion of LTBI treatment in Norway in 2016.This prospective cohort study included all individuals notified with LTBI treatment to the Norwegian Surveillance System for Infectious Diseases (MSIS) in 2016. We obtained data from MSIS and from a standardized form that was sent to health care providers at the time of patient notification to MSIS. We determined completion rates. Pearson's chi squared test was used to study associations between pairs of categorical variables and separate crude and multivariable logistic regression models were used to identify factors associated with treatment completion and adverse drug effects.We obtained information on treatment completion from 719 of the 726 individuals notified for LTBI treatment in 2016. Overall, 91% completed treatment. Treatment completion was highest in the foreign-born group [foreign-born, n = 562 (92%) vs Norwegian-born, n = 115 (85%), p = 0.007]. Treatment completion did not differ significantly between prescribed regimens (p = 0.124). Adverse events were the most common reason for incomplete treatment. We found no significant differences in adverse events when comparing weekly rifapentine (3RPH) with three months daily Isoniazid and rifampicin (3RH). However, there were significantly fewer adverse events with 3RPH compared to other regimens (p = 0.037). Age over 35 years was significantly associated with adverse events irrespective of regimen (p = 0.024), whereas immunosuppression was not significantly associated with adverse events after adjusting for other variables (p = 0.306). Treatment under direct observation had a significant effect on treatment completion for foreign-born (multivariate Wald p-value = 0.017), but not for Norwegian-born (multivariate Wald p-value = 0.408) individuals.We report a very high treatment completion rate, especially among individuals from countries with high TB incidence. The follow-up from tuberculosis-coordinators and the frequent use of directly observed treatment probably contributes to this. Few severe adverse events were reported, even with increased age and in individuals that are more susceptible. While these results are promising, issues of cost-effectiveness and targeting treatment to individuals at highest risk of TB are important components of public health impact. |
| 2018 | Short-course regimens of rifapentine plus isoniazid to treat latent tuberculosis infection in older Chinese patients: a randomised controlled study. | Eur Respir J | Latent tuberculosis infection (LTBI) management is now a critical component of the World Health Organization's End TB Strategy.In this randomised controlled trial (Chinese Clinical Trial Registry identifier ChiCTR-IOR-15007202), two short-course regimens with rifapentine plus Isoniazid (a 3-month once-weekly regimen and a 2-month twice-weekly regimen) were initially designed to be evaluated for rural residents aged 50-69 years with LTBI in China.Due to the increasingly rapid growth and unexpected high frequency of adverse effects, the treatments were terminated early (after 8 weeks for the once-weekly regimen and after 6 weeks for the twice-weekly regimen). In the modified intention-to-treat analysis on the completed doses, the cumulative rate of active disease during 2 years of follow-up was 1.21% (14 out of 1155) in the untreated controls, 0.78% (10 out of 1284) in the group that received the 8-week once-weekly regimen and 0.46% (six out of 1299) in the group that received the 6-week twice-weekly regimen. The risk of active disease was decreased, with an adjusted hazard ratio of 0.63 (95% CI 0.27-1.43) and 0.41 (95% CI 0.15-1.09) for the treatments, respectively. No significant difference was found in the occurrence of hepatotoxicity (1.02% (13 out of 1279) 1.17% (15 out of 1279); p=0.704).The short regimens tested must be used with caution among the elderly because of the high rates of adverse effects. Further work is necessary to test the ultrashort regimens in younger people with LTBI. |
| 2018 | Improved treatment completion with shorter treatment regimens for latent tuberculous infection. | Int J Tuberc Lung Dis | Four New York City (NYC) Health Department tuberculosis (TB) clinics.To assess the effectiveness of preferentially offering two shorter treatment regimens-4 months of daily rifampin (4R) and 3 months of once-weekly Isoniazid and rifapentine (3HP)-as an alternative to 9 months of daily Isoniazid (9H) for the treatment of latent tuberculous infection (LTBI).Retrospective analysis of patients treated for LTBI from January to June 2015. Poisson regression with robust standard error was used to examine the factors associated with treatment completion.Of the patients on 9H, 49% (27/55) completed treatment compared with 70% (187/269) of patients on 4R ( 0.003) and 79% (99/125) of patients on 3HP ( < 0.001). When adjusting for age, sex, and TB risk factors, patients on 4R (adjusted risk ratio [aRR] 1.39, 95%CI 1.07-1.81) and 3HP (aRR 1.67, 95%CI 1.27-2.19) were more likely to complete treatment than patients on 9H. Treatment was discontinued due to side effects in 1% (3/269) of patients on 4R, 2% (2/125) of patients on 3HP, and 4% (2/55) of patients on 9H.Most patients were placed on shorter regimens for LTBI treatment, and higher treatment completion was observed. Encouraging community providers to use shorter regimens for LTBI treatment would reduce the TB disease burden in NYC. |
| 2019 | Cost-effectiveness of 3 months of weekly rifapentine and isoniazid compared with other standard treatment regimens for latent tuberculosis infection: a decision analysis study. | J Antimicrob Chemother | Latent tuberculosis infection (LTBI) is a critical driver of the global burden of active TB, and therefore LTBI treatment is key for TB elimination. Treatment regimens for LTBI include self-administered daily Isoniazid for 6 (6H) or 9 (9H) months, self-administered daily rifampicin plus Isoniazid for 3 months (3RH), self-administered daily rifampicin for 4 months (4R) and weekly rifapentine plus Isoniazid for 3 months self-administered (3HP-SAT) or administered by a healthcare worker as directly observed therapy (3HP-DOT). Data on the relative cost-effectiveness of these regimens are needed to assist policymakers and clinicians in selecting an LTBI regimen.To evaluate the cost-effectiveness of all regimens for treating LTBI.We developed a Markov model to investigate the cost-effectiveness of 3HP-DOT, 3HP-SAT, 4R, 3RH, 9H and 6H for LTBI treatment in a cohort of 10000 adults with LTBI. Cost-effectiveness was evaluated from a health system perspective over a 20 year time horizon.Compared with no preventive treatment, 3HP-DOT, 3HP-SAT, 4R, 3RH, 9H and 6H prevented 496, 470, 442, 418, 370 and 276 additional cases of active TB per 10000 patients, respectively. All regimens reduced costs and increased QALYs compared with no preventive treatment. 3HP was more cost-effective under DOT than under SAT at a cost of US$27948 per QALY gained.Three months of weekly rifapentine plus Isoniazid is more cost-effective than other regimens. Greater recognition of the benefits of short-course regimens can contribute to the scale-up of prevention and achieving the 'End TB' targets. |
| 2018 | Updates in the Treatment of Active and Latent Tuberculosis. | Semin Respir Crit Care Med | First-line therapy for active tuberculosis (TB) has remained unchanged for nearly 40 years. Isoniazid, rifampin, pyrazinamide, and ethambutol for the initial two-month phase followed by Isoniazid and rifampin for 4 to 7 months is standard treatment for people at low risk for drug-resistant disease. Directly-observed therapy (DOT) remains the standard of care for pulmonary TB. Virtual treatment monitoring using digital technologies is becoming more common as a way to provide a more patient-centered approach to care. Attempts to shorten treatment duration have been unsuccessful based on recent clinical trials evaluating the role of fluoroquinolones. Treatment-shortening trials using higher doses of rifamycins are currently underway. Recently approved medications for TB treatment are recommended only for drug-resistant disease, but novel agents in varying stages of development are being evaluated. Rifamycin-based regimens for latent TB infection (LTBI) have been successful in preventing progression to TB disease. Once-weekly Isoniazid and rifapentine for 12 weeks by DOT was shown to be safe and effective compared with 9 months of Isoniazid. The same regimen was shown to have acceptable treatment completion when given self-administered. Newer studies are investigating even shorter LTBI treatment with durations of less than 2 months. Treatment of LTBI in people likely infected with multidrug resistant TB is very limited, but one observational study found that fluoroquinolones appear to be effective. The first randomized trials for treating LTBI in contacts to MDR-TB are currently enrolling. |
| 2018 | Twelve-dose weekly rifapentine plus isoniazid for latent tuberculosis infection: A multicentre randomised controlled trial in Taiwan. | Tuberculosis (Edinb) | Treatment of latent tuberculosis (TB) infection (LTBI) effectively prevents its progression to active TB. However, long treatment duration and drug-related hepatotoxicity limit the effectiveness of the 9-month daily Isoniazid (9H). Data on the 3-month weekly rifapentine plus Isoniazid (3 HP) in Asian populations are currently unavailable. We prospectively randomised the LTBI contacts aged ≥12 years with positive tuberculin skin test into 9H and 3 HP groups in four hospitals between January 2014 and May 2016 in Taiwan. The primary and secondary outcomes were treatment completion rate and adverse drug reactions (ADRs), respectively. Overall, 263 participants with LTBI were randomised into the 3 HP (n = 132) and 9H groups (n = 131); 14 (10.6%) and 29 (22.1%) participants in the 3 HP and 9H groups, respectively, discontinued therapy (p = 0.011). Discontinuation rates owing to ADRs were 9.1% (3 HP) and 5.3% (9H) (p = 0.241). Clinically relevant hepatotoxicity was more common in the 9H than in the 3 HP group (5.3% vs. 1.5%; p = 0.103), whereas systemic drug reaction was more common in the 3 HP than in the 9H group (3.8% vs. 0%; p = 0.060). Women had a significantly higher rate of Grade II fever than men (13.7% vs. 1.2%; p = 0.003). Compared with the 9H regimen, the 3 HP regimen had a higher completion rate with lower hepatotoxicity and well-tolerated ADR.number NCT02208427. |
| High Completion Rate for 12 Weekly Doses of Isoniazid and Rifapentine as Treatment for Latent Mycobacterium tuberculosis Infection in the Federal Bureau of Prisons. | J Public Health Manag Pract | Correctional facilities provide unique opportunities to diagnose and treat persons with latent tuberculosis infection (LTBI). Studies have shown that 12 weekly doses of Isoniazid and rifapentine (INH-RPT) to treat LTBI resulted in high completion rates with good tolerability.To evaluate completion rates and clinical signs or reported symptoms associated with discontinuation of 12 weekly doses of INH-RPT for LTBI treatment.During July 2012 to February 2015, 7 Federal Bureau of Prisons facilities participated in an assessment of 12 weekly doses of INH-RPT for LTBI treatment among 463 inmates.Fisher exact test was used to assess the associations between patient sociodemographic characteristics and clinical signs or symptoms with discontinuation of treatment.Of 463 inmates treated with INH-RPT, 424 (92%) completed treatment. Reasons for discontinuation of treatment for 39 (8%) inmates included the following: 17 (44%) signs/symptoms, 9 (23%) transfer or release, 8 (21%) treatment refusal, and 5 (13%) provider error. A total of 229 (49.5%) inmates reported experiencing at least 1 sign or symptom during treatment; most frequently reported were fatigue (16%), nausea (13%), and abdominal pain (7%). Among these 229 inmates, signs/symptoms significantly associated with discontinuation of treatment included abdominal pain (P < .001), appetite loss (P = .02), fever/chills (P = .01), nausea (P = .03), sore muscles (P = .002), and elevation of liver transaminases 5× upper limits of normal or greater (P = .03).The LTBI completion rates were high for the INH-RPT regimen, with few inmates discontinuing because of signs or symptoms related to treatment. This regimen also has practical advantages to aid in treatment completion in the correctional setting and can be considered a viable alternative to standard LTBI regimens. |
| 2018 | Modelling the long-acting administration of anti-tuberculosis agents using PBPK: a proof of concept study. | Int J Tuberc Lung Dis | Anti-tuberculosis formulations necessitate uninterrupted treatment to cure tuberculosis (TB), but are characterised by suboptimal adherence, which jeopardises therapeutic efficacy. Long-acting injectable (LAI) formulations or implants could address these associated issues.niazid, rifapentine, bedaquiline and delamanid-in adults for treatment for latent tuberculous infection (LTBI).PBPK models were developed and qualified against available clinical data by integrating drug physicochemical properties and in vitro and population pharmacokinetic data into a mechanistic description of drug distribution. Combinations of optimal dose and release rates were simulated such that plasma concentrations were maintained over the epidemiological cut-off or minimum inhibitory concentration for the dosing interval.The PBPK model identified 1500 mg of delamanid and 250 mg of rifapentine as sufficient doses for monthly intramuscular administration, if a formulation or device can deliver the required release kinetics of 0.001-0.0025 h-1 and 0.0015-0.0025 h-1, respectively. Bedaquiline and Isoniazid would require weekly to biweekly intramuscular dosing.We identified the theoretical doses and release rates of LAI anti-tuberculosis formulations. Such a strategy could ease the problem of suboptimal adherence provided the associated technological complexities for LTBI treatment are addressed. |
| 2018 | Update of Recommendations for Use of Once-Weekly Isoniazid-Rifapentine Regimen to Treat Latent Mycobacterium tuberculosis Infection. | MMWR Morb Mortal Wkly Rep | Treatment of latent tuberculosis infection (LTBI) is critical to the control and elimination of tuberculosis disease (TB) in the United States. In 2011, CDC recommended a short-course combination regimen of once-weekly Isoniazid and rifapentine for 12 weeks (3HP) by directly observed therapy (DOT) for treatment of LTBI, with limitations for use in children aged <12 years and persons with human immunodeficiency virus (HIV) infection (1). CDC identified the use of 3HP in those populations, as well as self-administration of the 3HP regimen, as areas to address in updated recommendations. In 2017, a CDC Work Group conducted a systematic review and meta-analyses of the 3HP regimen using methods adapted from the Guide to Community Preventive Services. In total, 19 articles representing 15 unique studies were included in the meta-analysis, which determined that 3HP is as safe and effective as other recommended LTBI regimens and achieves substantially higher treatment completion rates. In July 2017, the Work Group presented the meta-analysis findings to a group of TB experts, and in December 2017, CDC solicited input from the Advisory Council for the Elimination of Tuberculosis (ACET) and members of the public for incorporation into the final recommendations. CDC continues to recommend 3HP for treatment of LTBI in adults and now recommends use of 3HP 1) in persons with LTBI aged 2-17 years; 2) in persons with LTBI who have HIV infection, including acquired immunodeficiency syndrome (AIDS), and are taking antiretroviral medications with acceptable drug-drug interactions with rifapentine; and 3) by DOT or self-administered therapy (SAT) in persons aged ≥2 years. |
| 2019 | Three months of rifapentine and isoniazid for latent tuberculosis infection in hemodialysis patients: High rates of adverse events. | J Microbiol Immunol Infect | The consequences of once-weekly rifapentine plus Isoniazid for 3 months (3HP) against latent tuberculosis infections in hemodialysis patients have not been studied before. This is the first study to evaluate the safety and tolerability of 3HP in this population and revealed a completion rate of 65.4%. The therapy was not associated with hepatotoxicity, but with high rates of adverse events (69.2%). |
| 2018 | Latent tuberculosis infection: Opportunities and challenges. | Respirology | Diagnosing and treating latent tuberculosis (TB) infection (LTBI) is recognized by the World Health Organization as an important strategy to accelerate the decline in global TB and achieve TB elimination. Even among low-TB burden countries that have achieved high rates of detection and successful treatment for active TB, a number of barriers have prevented implementing or expanding LTBI treatment programmes. Of those infected with TB, relatively few will develop active disease and the current diagnostic tests have a low predictive value. LTBI treatment using Isoniazid (INH) has low completion rates due to the long duration of therapy and poor tolerability. Both patients and physicians often perceive the risk of toxicity to be greater than the risk of reactivation TB. As a result, LTBI treatment has had a limited or negligible role outside of countries with high resources and low burden of disease. New tools have emerged including the interferon-gamma release assays that more accurately diagnose LTBI, particularly in people vaccinated with Bacillus Calmette-Guerin (BCG). Shorter, better tolerated treatment using rifamycins are proving safe and effective alternatives to INH. While still imperfect, TB prevention using these new diagnostic and treatment tools appear cost effective in modelling studies in the United States and have the potential to improve TB prevention efforts globally. Continued research to understand the host-organism interactions within the spectrum of LTBI is needed to develop better tools. Until then, overcoming the barriers and optimizing our current tools is essential for progressing toward TB elimination. |
| 2018 | Ethambutol and isoniazid induced severe neurotoxicity in a patient undergoing continuous ambulatory peritoneal dialysis. | BMJ Case Rep | Ethambutol (EMB) and Isoniazid (INH) are the first-line antituberculosis (anti-TB) drugs. However, their neurotoxicity could cause adverse effect and the patients with end-stage renal disease are especially vulnerable due to the reduction in renal drug clearance. Here, we report a 36-year-old man receiving peritoneal dialysis developed progressive paralysis in lower extremities, vision loss and hoarseness 4 months after anti-TB treatment with INH, EMB and rifapentine because of concomitant pulmonary tuberculosis. A diagnosis of EMB/INH-induced peripheral neuropathy, retrobulbar neuritis and laryngoparalysis was made. The patient's neuropathy gradually improved 2 years after discontinuation of EMB/INH. Since EMB and INH may cause simultaneously severe and complex multineuropathy in dialysis patients, their adverse effects should be closely supervised in dialysis patients. |
| 2018 | Cost-effectiveness of Preventive Therapy for Tuberculosis With Isoniazid and Rifapentine Versus Isoniazid Alone in High-Burden Settings. | Clin Infect Dis | A short-course regimen of 3 months of weekly rifapentine and Isoniazid (3HP) has recently been recommended by the World Health Organization as an alternative to at least 6 months of daily Isoniazid (Isoniazid preventive therapy [IPT]) for prevention of tuberculosis (TB). The contexts in which 3HP may be cost-effective compared to IPT among people living with human immunodeficiency virus are unknown.We used a Markov state transition model to estimate the incremental cost-effectiveness of 3HP relative to IPT in high-burden settings, using a cohort of 1000 patients in a Ugandan HIV clinic as an emblematic scenario. Cost-effectiveness was expressed as 2017 US dollars per disability-adjusted life year (DALY) averted from a healthcare perspective over a 20-year time horizon. We explored the conditions under which 3HP would be considered cost-effective relative to IPT.Per 1000 individuals on antiretroviral therapy in the reference scenario, treatment with 3HP rather than IPT was estimated to avert 9 cases of TB and 1 death, costing $9402 per DALY averted relative to IPT. Cost-effectiveness depended strongly on the price of rifapentine, completion of 3HP, and prevalence of latent TB. At a willingness to pay of $1000 per DALY averted, 3HP is likely to be cost-effective relative to IPT only if the price of rifapentine can be greatly reduced (to approximately $20 per course) and high treatment completion (85%) can be achieved.3HP may be a cost-effective alternative to IPT in high-burden settings, but cost-effectiveness depends on the price of rifapentine, achievable completion rates, and local willingness to pay. |
| 2018 | A systematic review of adverse events of rifapentine and isoniazid compared to other treatments for latent tuberculosis infection. | Pharmacoepidemiol Drug Saf | Tuberculosis (TB) remains a common cause of death globally. A regimen of 12 doses of Isoniazid (INH) and rifapentine given once weekly (INH/RPT-3) has recently been recommended by the World Health Organization for the treatment of latent TB infection (LTBI). We aimed to determine whether the INH/RPT-3 regimen had similar or lesser rates of adverse events compared to other LTBI regimens, namely INH for 9 months, INH for 6 months, rifampin for 3 to 4 months, and rifampin plus INH for 3 to 4 months.We searched MEDLINE, Embase, CENTRAL, PubMed, ICTRP, clinicaltrials.gov, and Canadian Agency for Drugs and Technologies in Health's Gray Matters Light for randomized, postmarketing, and comparative nonrandomized studies of patients with confirmed LTBI that reported the frequency of at least 1 adverse event of relevance for a regimen of interest. The search included studies published until March 2017. The frequencies of adverse events were extracted and are presented descriptively.Data from 23 randomized and 55 nonrandomized studies were included. Although inconsistent event reporting and high heterogeneity limited comparisons, the adverse event profile of INH/RPT-3 appeared generally favorable. Flu-like reactions were reported with an increased frequency and hepatotoxicity with a lower frequency than standard treatment.While INH/RPT-3 had an overall low frequency of adverse events compared to INH monotherapy, reporting of adverse events for many regimens was limited meaning results should be interpreted cautiously. Future studies of LTBI treatment would benefit from more complete collection and reporting of adverse events and more consistent definitions of hepatotoxicity. |
| 2018 | Barriers to treatment adherence for individuals with latent tuberculosis infection: A systematic search and narrative synthesis of the literature. | Int J Health Plann Manage | We investigated the rates of initiation and completion of treatment for latent TB infection (LTBI), factors explaining nonadherence and interventions to improve treatment adherence in countries with low TB incidence.A systematic search was performed in PubMed and Embase. All included articles were assessed for risk of bias. A narrative synthesis of the results was conducted.There were 54 studies included in this review. The proportion of people initiating treatment varied from 24% to 98% and the proportion of people completing treatment varied from 19% to 90%. The main barriers to adherence included the fear or experience of adverse effects, long duration of treatment, financial barriers, lack of transport to clinics (for patients), and insufficient resources for LTBI control. While interventions like peer counseling, incentives, and culturally specific case management have been used to improve adherence, the proportion of people who initiate and complete LTBI treatment still remains low.To further improve treatment and LTBI control and to fulfill the World Health Organization goal of eliminating TB in low-incidence countries, greater priority should be given to the use of treatment regimens involving shorter durations and fewer adverse effects, like the 3-month regimen of weekly rifapentine plus Isoniazid, supported by innovative patient education and incentive strategies. |
| 2018 | Cytokine-Mediated Systemic Adverse Drug Reactions in a Drug-Drug Interaction Study of Dolutegravir With Once-Weekly Isoniazid and Rifapentine. | Clin Infect Dis | Once-weekly Isoniazid and rifapentine for 3 months is a treatment option in persons with human immunodeficiency virus and latent tuberculosis infection. This study aimed to examine pharmacokinetic drug-drug interactions between this regimen and dolutegravir, a first-line antiretroviral medication.This was a single-center, open-label, fixed-sequence, drug-drug interaction study in healthy volunteers. Subjects received oral dolutegravir 50 mg once daily alone (days 1-4) and concomitantly with once-weekly Isoniazid 900 mg, rifapentine 900 mg, and pyridoxine 50 mg (days 5-19). Dolutegravir concentrations were measured on days 4, 14, and 19, and rifapentine, 25-desacetyl-rifapentine, and Isoniazid concentrations were measured on day 19. Cytokines and antidrug antibodies to Isoniazid and rifapentine were examined at select time points.The study was terminated following the development of flu-like syndrome and elevated aminotransferase levels in 2 of 4 subjects after the third Isoniazid-rifapentine dose. Markedly elevated levels of interferon-γ, CXCL10, C-reactive protein, and other cytokines were temporally associated with symptoms. Antidrug antibodies were infrequently detected. Dolutegravir area under the curve (AUC) was decreased by 46% (90% confidence interval, 27-110%; P = .13) on day 14. Rifapentine and 25-desacetyl rifapentine levels on day 19 were comparable to reference data, whereas Isoniazid AUCs were approximately 67%-92% higher in the subjects who developed toxicities.The combined use of dolutegravir with once-weekly Isoniazid-rifapentine resulted in unexpected and serious toxicities that were mediated by endogenous cytokine release. Additional investigations are necessary to examine the safety and efficacy of coadministering these medications.NCT02771249. |
| 2018 | Exposure to Latent Tuberculosis Treatment during Pregnancy. The PREVENT TB and the iAdhere Trials. | Ann Am Thorac Soc | Data are limited regarding the safety of 12-dose once-weekly Isoniazid (H, 900 mg) plus rifapentine (P, 900 mg) (3HP) for latent infection treatment during pregnancy.To assess safety and pregnancy outcomes among pregnant women who were inadvertently exposed to study medications in two latent tuberculosis infection trials (PREVENT TB or iAdhere) evaluating 3HP and 9 months of daily Isoniazid (H, 300 mg) (9H).Data from reproductive-age (15-51 yr) women who received one or more study dose of 3HP or 9H in either trial were analyzed. Drug exposure during pregnancy occurred if the estimated date of conception was on or before the last dose date.Of 126 pregnancies (125 participants) that occurred during treatment or follow-up, 87 were exposed to study drugs. Among these, fetal loss was reported for 4/31 (13%) and 8/56 (14%), 3HP and 9H, respectively (difference, 13% - 14% = -1%; 95% confidence interval = -17% to +18%) and congenital anomalies in 0/20 and 2/41 (5%) live births, 3HP and 9H, respectively (difference, 0% - 5% = -5%; 95% confidence interval = -18% to +16%). All fetal losses occurred in pregnancies of less than 20 weeks. Of the total 126 pregnancies, fetal loss was reported in 8/54 (15%) and 9/72 (13%), 3HP and 9H, respectively; and congenital anomalies in 1/37 (3%) and 2/56 (4%) live births, 3HP and 9H, respectively. The overall proportion of fetal loss (17/126 [13%]) and anomalies (3/93 [3%]) were similar to those estimated for the United States, 17% and 3%, respectively.Among reported pregnancies in these two latent tuberculosis infection trials, there was no unexpected fetal loss or congenital anomalies. These data offer some preliminary reassurance to clinicians and patients in circumstances when these drugs and regimens are the best option in pregnancy or in women of child-bearing potential. This work used the identifying trial registration numbers NCT00023452 and NCT01582711, corresponding to the primary clinical trials PREVENT TB and iAdhere (Tuberculosis Trials Consortium Study 26 and 33). |
| 2018 | Completion Rate and Safety of Tuberculosis Infection Treatment With Shorter Regimens. | Pediatrics | The traditional treatment of tuberculosis (TB) infection (9 months of daily Isoniazid [9H]) is safe but completion rates of <50% are reported. Shorter regimens (3 months of once-weekly Isoniazid and rifapentine [3HP] or 4 months of daily rifampin [4R]) are associated with improved adherence in adults.This was a retrospective cohort study (2014-2017) of children (0-18 years old) seen at a children's TB clinic in a low-incidence nation. We compared the frequency of completion and adverse events (AEs) in children receiving 3HP, 4R, and 9H; the latter 2 regimens could be administered by families (termed self-administered therapy [SAT]) or as directly observed preventive therapy (DOPT); 3HP was always administered under DOPT.TB infection treatment was started in 667 children: 283 (42.4%) 3HP, 252 (37.8%) 9H, and 132 (19.8%) 4R. Only 52% of children receiving 9H via SAT completed therapy. Children receiving 3HP were more likely to complete therapy than the 9H (SAT) group (odds ratio [OR] 27.4, 95% confidence interval [CI]: 11.8-63.7). Multivariate analyses found receipt of medication under DOPT (OR: 5.72, 95% CI: 3.47-9.43), increasing age (OR: 1.09, 95% CI: 1.02-1.17), and the absence of any AE (OR: 1.70, 95% CI: 0.26-0.60) to be associated with completing therapy. AEs were more common in the 9H group (OR: 2.51, 95% CI: 1.48-4.32). Two (0.9%) children receiving 9H developed hepatotoxicity; no child receiving 3HP or 4R developed hepatotoxicity.Shorter regimens are associated with increased completion rates and fewer AEs than 9H. |
| 2018 | Treatment of Latent Tuberculosis Infection and Its Clinical Efficacy. | Tuberc Respir Dis (Seoul) | The role of the treatment for latent tuberculosis infection (LTBI) has been underscored in the intermediate tuberculosis (TB) burden countries like South Korea. LTBI treatment is recommended only for patients at risk for progression to active TB-those with frequent exposure to active TB cases, and those with clinical risk factors (e.g., immunocompromised patients). Recently revised National Institute for Health and Care Excellence (NICE) guideline recommended that close contacts of individuals with active pulmonary or laryngeal TB, aged between 18 and 65 years, should undergo LTBI treatment. Various regimens for LTBI treatment were recommended in NICE, World Health Organization (WHO), and Centers for Disease Control and Prevention guidelines, and superiority of one recommended regimen over another was not yet established. Traditional 6 to 9 months of Isoniazid (6H or 9H) regimen has an advantage of the most abundant evidence for clinical efficacy-60%-90% of estimated protective effect. However, 6H or 9H regimen is related with hepatotoxicity and low compliance. Four months of rifampin regimen is characterized by less hepatotoxicity and better compliance than 9H, but has few evidence of clinical efficacy. Three months of Isoniazid plus rifampin was proved equivalence with 6H or 9H regimen in terms of efficacy and safety, which was recommended in NICE and WHO guidelines. The clinical efficacy of Isoniazid plus rifapentine once-weekly regimen for 3 months was demonstrated recently, which is not yet introduced into South Korea. |
| 2017 | SIRCLE: a randomised controlled cost comparison of self-administered short-course isoniazid and rifapentine for cost-effective latent tuberculosis eradication. | Intern Med J | Currently, treatment of latent tuberculosis infection (LTBI) in Australia consists most commonly of a 9-month course of Isoniazid (9H). A 3-month course of weekly Isoniazid and rifapentine (3HP) has been shown to be as effective as 9 months of daily Isoniazid, and associated with less hepatotoxicity; however, rifapentine is not currently available in Australia. Introduction of this regimen would have apparent advantages for people with LTBI in Victoria by safely shortening duration of LTBI therapy. However, the cost benefit of this new therapeutic approach is uncertain.Cost-analysis of standard and short-course therapy for LTBI in an Australian context.Single-centre randomised controlled trial conducted between December 2013-March 2016. Participants underwent 1:1 randomisation to either a 9-month course of daily Isoniazid or a 12-week course of weekly Isoniazid and rifapentine. The primary outcome measure was total healthcare system costs (in Australian dollars; AUD) per completed course of LTBI therapy. Secondary cost analyses were performed to consider varying assumptions regarding commercial cost of rifapentine.Overall, 34 of 40 (85%) participants in the 9H group and 36/40 (90%) in the 3HR group completed therapy. One patient in the 3HP group was hospitalised for a febrile illness; no hospitalisations were recorded in the 9H group. The cost per completed course of 9H was 601 AUD, while that of 3HP was significantly lower at 511 AUD (P < 0.01).This study provides cost analysis evidence to support the use of 3HP for the treatment of LTBI in Australia. |
| 2017 | Self-administered Versus Directly Observed Once-Weekly Isoniazid and Rifapentine Treatment of Latent Tuberculosis Infection: A Randomized Trial. | Ann Intern Med | Expanding latent tuberculosis treatment is important to decrease active disease globally. Once-weekly Isoniazid and rifapentine for 12 doses is effective but limited by requiring direct observation.To compare treatment completion and safety of once-weekly Isoniazid and rifapentine by self-administration versus direct observation.An open-label, phase 4 randomized clinical trial designed as a noninferiority study with a 15% margin. Seventy-five percent or more of study patients were enrolled from the United States for a prespecified subgroup analysis. (ClinicalTrials.gov: NCT01582711).Outpatient tuberculosis clinics in the United States, Spain, Hong Kong, and South Africa.1002 adults (aged ≥18 years) recommended for treatment of latent tuberculosis infection.Participants received once-weekly Isoniazid and rifapentine by direct observation, self-administration with monthly monitoring, or self-administration with weekly text message reminders and monthly monitoring.The primary outcome was treatment completion, defined as 11 or more doses within 16 weeks and measured using clinical documentation and pill counts for direct observation, and self-reports, pill counts, and medication event-monitoring devices for self-administration. The main secondary outcome was adverse events.Median age was 36 years, 48% of participants were women, and 77% were enrolled at the U.S. sites. Treatment completion was 87.2% (95% CI, 83.1% to 90.5%) in the direct-observation group, 74.0% (CI, 68.9% to 78.6%) in the self-administration group, and 76.4% (CI, 71.3% to 80.8%) in the self-administration-with-reminders group. In the United States, treatment completion was 85.4% (CI, 80.4% to 89.4%), 77.9% (CI, 72.7% to 82.6%), and 76.7% (CI, 70.9% to 81.7%), respectively. Self-administered therapy without reminders was noninferior to direct observation in the United States; no other comparisons met noninferiority criteria. A few drug-related adverse events occurred and were similar across groups.Persons with latent tuberculosis infection enrolled in South Africa would not routinely be treated programmatically.These results support using self-administered, once-weekly Isoniazid and rifapentine to treat latent tuberculosis infection in the United States, and such treatment could be considered in similar settings when direct observation is not feasible.Centers for Disease Control and Prevention. |
| 2017 | Cost-effectiveness of Testing and Treatment for Latent Tuberculosis Infection in Residents Born Outside the United States With and Without Medical Comorbidities in a Simulation Model. | JAMA Intern Med | Testing for and treating latent tuberculosis infection (LTBI) is among the main strategies to achieve TB elimination in the United States. The best approach to testing among non-US born residents, particularly those with comorbid conditions, is uncertain.To estimate health outcomes, costs, and cost-effectiveness of LTBI testing and treatment among non-US born residents with and without medical comorbidities.Decision analytic tree and Markov cohort simulation model among non-US born residents with no comorbidities, with diabetes, with HIV infection, or with end-stage renal disease (ESRD) using a health care sector perspective with 3% annual discounting. Strategies compared included no testing, tuberculin skin test (TST), interferon gamma release assay (IGRA), confirm positive (initial TST, IGRA only for TST-positive results; both tests positive indicates LTBI), and confirm negative (initial IGRA, then TST for IGRA-negative; any test positive indicates LTBI). All strategies were coupled to treatment with 3 months of self-administered rifapentine and Isoniazid.Number needed to test and treat to prevent 1 case of TB reactivation, discounted quality-adjusted life-years (QALYs), discounted lifetime medical costs, and incremental cost-effectiveness ratios (ICERs).Improving health outcomes increased costs, with choice of test dependent on willingness to pay. Strategies ranked by ascending costs and benefits: no testing, confirm positive, TST, IGRA, and confirm negative. The ICERs varied by non-US born patient risk group: patients with no comorbidities, IGRA was likely cost-effective at $83 000/QALY; patients with diabetes, both confirm positive ($53 000/QALY) and IGRA ($120 000/QALY) were likely cost-effective; patients with HIV, confirm negative was clearly preferred ($63 000/QALY); and patients with ESRD, no testing was cost-effective. Increased LTBI prevalence and reduced return for TST reading improved IGRA's relative performance. In 10 000 probabilistic simulations among non-US born patients with no comorbidities, with diabetes, and with HIV, some form of testing was virtually always cost-effective. These simulations highlight the uncertainty of test choice for non-US born patients with no comorbidities and non-US born patients with diabetes, but strategies including IGRA were preferred in over 60% of simulations for all non-US born populations except those with ESRD.Testing for and treating LTBI among non-US born residents with and without selected comorbidities is likely cost-effective except among those with ESRD in whom competing risks of death limit benefits. Strategies including IGRA fell below a $100 000/QALY willingness-to-pay threshold for non-US born patients with no comorbidities, patients with diabetes, and patients with HIV. |
| 2017 | Management of Latent Tuberculosis Infection Among Healthcare Workers: 10-Year Experience at a Single Center. | Clin Infect Dis | The risk of infection with Mycobacterium tuberculosis among healthcare workers (HCWs) is estimated to be higher than the general population. However, HCW acceptance and compliance with available latent tuberculosis infection (LTBI) treatment regimens has been problematic. Recently, regimens have become available that might improve HCW acceptance and compliance with LTBI treatment.A retrospective single-center review of Employee Health and Wellness Services records of all HCWs diagnosed with LTBI was conducted. HCWs diagnosed with LTBI were offered 9-month Isoniazid (INH), 4-month rifampin (RIF), weekly rifapentine/Isoniazid (RPT/INH) for 12 weeks, or no treatment. Acceptance, completion rates, and side effects were reported for each regimen. Comparisons of regimens were assessed using Fisher exact test.Between 2005 and 2014, 363 of 927 (39%) HCWs diagnosed with LTBI accepted treatment. Of 363, 202 chose INH, 106 RIF, and 55 RPT/INH. Completion rates for each regimen were 58%, 80%, and 87%, respectively. HCWs were significantly more likely to have completed treatment with RIF (P < .0001) or RPT/INH (P < .0001) than INH. Rates of discontinuation owing to side effects were 35% for INH, 21% for RIF, and 10% for RPT/INH. Discontinuation of therapy due to side effects was significantly more frequent in the INH than the RPT/INH group (P = .0042).Completion of RIF and RPT/INH for LTBI in an HCW population is more likely than INH. Rates of discontinuation due to side effects were lower among those taking RPT/INH. Shorter LTBI treatment regimens should be more widely considered for HCWs in the United States. |
| 2017 | Use of Rifapentine and Isoniazid Directly Observed Therapy for the Treatment of Latent Tuberculosis Infection in a Military Clinic. | Mil Med | There are 8.6 million cases of active tuberculosis (TB) worldwide, and an estimated one-third of the world population has latent tuberculosis infection (LTBI). In the United States, up to 80% of active cases may be caused by untreated reactivated latent infection. A case of TB can spread rapidly impacting the readiness of a unit. To prevent the development of TB, it is critical that active duty service members with LTBI complete treatment. The use of Isoniazid (INH) and rifapentine (RPT) as a directly observed therapy (DOT) treatment option was recommended by the Centers for Disease Control and Prevention in late 2011. Since then, there have been limited studies on the use of this treatment regimen in a civilian clinic setting and to our knowledge no studies within a military setting.This study compares the completion rate of LTBI treatment in 2 military public health clinics, using a retrospective chart review of 179 subjects who attempted treatment with INH/RPT DOT and 186 with the non-INH/RPT non-DOT regimen.When compared to other LTBI regimens completed or attempted in this period, completion rates were higher in INH/RPT DOT regimens. The INH/RPT DOT treatment regimen allowed enough flexibility with completion between 11 and 16 weeks for active duty service members to increase completion to 94.6%, compared to 73% in the non-INH/RPT regimen.This project demonstrated the feasibility of INH/RPT DOT treatment within the military population resulting in a higher completion rate than the non-INH/RPT non-DOT regimen. The use of the INH/RPT DOT regimen should be considered for use in all military or similar populations. |
| 2017 | Immunodeficiency and Intermittent Dosing Promote Acquired Rifamycin Monoresistance in Murine Tuberculosis. | Antimicrob Agents Chemother | More-permissive preclinical models may be useful in evaluating antituberculosis regimens for their propensity to select drug-resistant mutants. To evaluate whether acquired rifamycin monoresistance could be recapitulated in mice and, if so, to evaluate the effects of immunodeficiency, intermittent dosing, and drug exposures, athymic nude and BALB/c mice were infected. Controls received daily rifapentine alone or 2 months of rifampin, Isoniazid, pyrazinamide, and ethambutol, followed by 4 months of rifampin/Isoniazid, either daily or twice weekly with one of two Isoniazid doses. Test groups received the same intensive regimen followed by once-weekly rifapentine or Isoniazid/rifapentine with rifapentine doses of 10, 15, or 20 mg/kg of body weight plus one of two Isoniazid doses. All combination regimens rendered BALB/c mouse cultures negative but selected mutants resistant to Isoniazid (8.5%, 12/140) or rifampin (3.5%, 5/140) in nude mice ( < 0.001). Intermittently dosed intensive-phase therapy selected Isoniazid and rifampin resistance in 10% (8/80, < 0.001) and 20% (16/80, = 0.009) of nude mice, respectively, compared to 0% treated with a daily regimen. Once-weekly rifapentine-containing continuation-phase regimens selected rifampin-resistant mutants at a rate of 18.0% (18/100, = 0.035 compared to rifampin/Isoniazid regimens). Higher Isoniazid doses in the intermittent-treatment control regimen and higher rifapentine doses in once-weekly regimens were associated with less selection of Isoniazid resistance. Acquired resistance, including rifamycin monoresistance, was more likely to occur in nude mice despite administration of combination therapy. These results recapitulate clinical outcomes and indicate that nude mice may be useful for evaluating the ability of novel regimens to prevent the selection of resistance. |
| 2017 | NOS2-deficient mice with hypoxic necrotizing lung lesions predict outcomes of tuberculosis chemotherapy in humans. | Sci Rep | During active TB in humans a spectrum of pulmonary granulomas with central necrosis and hypoxia exists. BALB/c mice, predominantly used in TB drug development, do not reproduce this complex pathology thereby inaccurately predicting clinical outcome. We found that Nos2 mice incapable of NO-production in immune cells as microbial defence uniformly develop hypoxic necrotizing lung lesions, widely observed in human TB. To study the impact of hypoxic necrosis on the efficacy of antimycobacterials and drug candidates, we subjected Nos2 mice with TB to monotherapy before or after establishment of human-like pathology. Isoniazid induced a drug-tolerant persister population only when necrotic lesions were present. Rifapentine was more potent than rifampin prior to development of human-like pathology and equally potent thereafter, in agreement with recent clinical trials. Pretomanid, delamanid and the pre-clinical candidate BTZ043 were bactericidal independent of pulmonary pathology. Linezolid was bacteriostatic in TB-infected Nos2 mice but significantly improved lung pathology. Hypoxic necrotizing lesions rendered moxifloxacin less active. In conclusion, Nos2 mice are a predictive TB drug development tool owing to their consistent development of human-like pathology. |
| Fighting tuberculosis by drugs targeting nonreplicating bacilli. | Int J Mycobacteriol | Current tuberculosis (TB) treatment requires 6 months of combination therapy with Isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), and ethambutol for active TB and 9 months of INH or 3 months of rifapentine (RFP) + INH for latent TB. The lungs of patients with active and latent TB contain heterogeneous mixtures of cellular and caseous granulomas harboring Mycobacterium tuberculosis bacilli ranging from actively replicating (AR) to nonreplicating (NR), phenotypically drug-resistant stages. Several in vitro models to obtain NR cells were reported, including exposure to hypoxia, nutrient starvation, acid + nitric oxide, and stationary phase. Overall, these models showed that RIF, RFP, PA-824 (PA), metronidazole (MZ), bedaquiline (BQ), and fluoroquinolones were the most active drugs against NR M. tuberculosis. In hypoxia at pH 5.8, some combinations killed AR plus NR cells, as shown by lack of regrowth in liquid media, whereas in hypoxia at pH 7.3 (the pH of the caseum), only RIF and RFP efficiently killed NR bacilli while several other drugs showed little effect. In conventional mouse models, combinations containing RFP, BQ, PA, PZA, moxifloxacin, sutezolid, linezolid, and clofazimine sterilized animals in ≤2 months, as shown by lack of viable bacilli in lung homogenates after 3 months without therapy. Drugs were less effective in C3HeB/FeJ mice forming caseous granulomas. Overall, in vitro observations and in vivo studies suggest that the search for new TB drugs could be addressed to low lipophilic molecules (e.g., new rpoB inhibitors with clogP < 3) killing NR M. tuberculosis in hypoxia at neutral pH and reaching high rates of unbound drug in the caseum. |
| 2017 | Treatment of Latent Tuberculosis Infection: An Updated Network Meta-analysis. | Ann Intern Med | Treatment of latent tuberculosis infection (LTBI) is an important component of tuberculosis (TB) control, and this study updates a previous network meta-analysis of the best LTBI treatment options to inform public health action and programmatic management of LTBI.To evaluate the comparative efficacy and harms of LTBI treatment regimens aimed at preventing active TB among adults and children.PubMed, Embase, and Web of Science from indexing to 8 May 2017; clinical trial registries; and conference abstracts. No language restrictions were applied.Randomized controlled trials that evaluated human LTBI treatments and recorded at least 1 of 2 prespecified end points (hepatotoxicity and prevention of active TB).2 investigators independently extracted data from eligible studies and assessed study quality according to a standard protocol.The network meta-analysis of 8 new and 53 previously included studies showed that Isoniazid regimens of 6 months (odds ratio [OR], 0.65 [95% credible interval {CrI}, 0.50 to 0.83]) or 12 to 72 months (OR, 0.50 [CrI, 0.41 to 0.62]), rifampicin-only regimens (OR, 0.41 [CrI, 0.19 to 0.85]), rifampicin-Isoniazid regimens of 3 to 4 months (OR, 0.53 [CrI, 0.36 to 0.78]), rifampicin-Isoniazid-pyrazinamide regimens (OR, 0.35 [CrI, 0.19 to 0.61]), and rifampicin-pyrazinamide regimens (OR, 0.53 [CrI, 0.33 to 0.84]) were efficacious compared with placebo. Evidence existed for efficacy of weekly rifapentine-Isoniazid regimens compared with no treatment (OR, 0.36 [CrI, 0.18 to 0.73]). No conclusive evidence showed that HIV status altered treatment efficacy.Evidence was sparse for many comparisons and hepatotoxicity outcomes, and risk of bias was high or unknown for many studies.Evidence exists for the efficacy and safety of 6-month Isoniazid monotherapy, rifampicin monotherapy, and combination therapies with 3 to 4 months of Isoniazid and rifampicin.U.K. National Institute for Health Research. (PROSPERO: CRD42016037871). |
| 2017 | A Review of Moxifloxacin for the Treatment of Drug-Susceptible Tuberculosis. | J Clin Pharmacol | Moxifloxacin, an 8-methoxy quinolone, is an important drug in the treatment of multidrug-resistant tuberculosis and is being investigated in novel drug regimens with pretomanid, bedaquiline, and pyrazinamide, or rifapentine, for the treatment of drug-susceptible tuberculosis. Early results of these studies are promising. Although current evidence does not support the use of moxifloxacin in treatment-shortening regimens for drug-susceptible tuberculosis, it may be recommended in patients unable to tolerate standard first-line drug regimens or for Isoniazid monoresistance. Evidence suggests that the standard 400-mg dose of moxifloxacin used in the treatment of tuberculosis may be suboptimal in some patients, leading to worse tuberculosis treatment outcomes and emergence of drug resistance. Furthermore, a drug interaction with the rifamycins results in up to 31% reduced plasma concentrations of moxifloxacin when these are combined for treatment of drug-susceptible tuberculosis, although the clinical relevance of this interaction is unclear. Moxifloxacin exhibits extensive interindividual pharmacokinetic variability. Higher doses of moxifloxacin may be needed to achieve drug exposures required for improved clinical outcomes. Further study is, however, needed to determine the safety of proposed higher doses and clinically validated targets for drug exposure to moxifloxacin associated with improved tuberculosis treatment outcomes. We discuss in this review the evidence for the use of moxifloxacin in drug-susceptible tuberculosis and explore the role of moxifloxacin pharmacokinetics, pharmacodynamics, and drug interactions with rifamycins, on tuberculosis treatment outcomes when used in first-line tuberculosis drug regimens. |
| Factors That Influence Treatment Completion for Latent Tuberculosis Infection. | J Am Board Fam Med | The aim of this study is to describe factors associated with noncompletion of latent tuberculosis infection (LTBI) therapy.We conducted a retrospective cohort study of adults who initiated LTBI treatment with Isoniazid, rifampin, or Isoniazid-rifapentine at 5 clinics. Demographic, treatment, and monitoring characteristics were abstracted. We estimated descriptive statistics and compared differences between completers and noncompleters using tests and χ tests.The rate of completion across LTBI regimens was 66% (n = 393). A greater proportion of noncompleters were unmarried, used tobacco and/or alcohol, and had more medical problems than completers (all < .05). A larger proportion of noncompleters received charity care compared with completers ( < .001). The most common reason for treatment discontinuation was loss to follow-up; the majority of these participants were treated with the longest Isoniazid-only regimen.Patients at risk of progression to active tuberculosis with factors associated with noncompletion may benefit from interventions that enhance adherence to LTBI therapy. These interventions could include enhanced outreach, incentive programs, or home visits. |
| 2017 | High Rate of Treatment Completion in Program Settings With 12-Dose Weekly Isoniazid and Rifapentine for Latent Mycobacterium tuberculosis Infection. | Clin Infect Dis | Randomized controlled trials have demonstrated that the newest latent tuberculosis (LTBI) regimen, 12 weekly doses of directly observed Isoniazid and rifapentine (3HP), is as efficacious as 9 months of Isoniazid, with a greater completion rate (82% vs 69%); however, 3HP has not been assessed in routine healthcare settings.Observational cohort of LTBI patients receiving 3HP through 16 US programs was used to assess treatment completion, adverse drug reactions, and factors associated with treatment discontinuation.Of 3288 patients eligible to complete 3HP, 2867 (87.2%) completed treatment. Children aged 2-17 years had the highest completion rate (94.5% [155/164]). Patients reporting homelessness had a completion rate of 81.2% (147/181). In univariable analyses, discontinuation was lowest among children (relative risk [RR], 0.44 [95% confidence interval {CI}, .23-.85]; P = .014), and highest in persons aged ≥65 years (RR, 1.72 [95% CI, 1.25-2.35]; P < .001). In multivariable analyses, discontinuation was lowest among contacts of patients with tuberculosis (TB) disease (adjusted RR [ARR], 0.68 [95% CI, .52-.89]; P = .005) and students (ARR, 0.45 [95% CI, .21-.98]; P = .044), and highest with incarceration (ARR, 1.43 [95% CI, 1.08-1.89]; P = .013) and homelessness (ARR, 1.72 [95% CI, 1.25-2.39]; P = .001). Adverse drug reactions were reported by 1174 (35.7%) patients, of whom 891 (76.0%) completed treatment.Completion of 3HP in routine healthcare settings was greater overall than rates reported from clinical trials, and greater than historically observed using other regimens among reportedly nonadherent populations. Widespread use of 3HP for LTBI treatment could accelerate elimination of TB disease in the United States. |
| 2017 | Treatment of Latent Tuberculosis Infection. | Microbiol Spectr | There are approximately 56 million people who harbor Mycobacterium tuberculosis that may progress to active tuberculosis (TB) at some point in their lives. Modeling studies suggest that if only 8% of these individuals with latent TB infection (LTBI) were treated annually, overall global incidence would be 14-fold lower by 2050 compared to incidence in 2013, even in the absence of additional TB control measures. This highlights the importance of identifying and treating latently infected individuals, and that this intervention must be scaled up to achieve the goals of the Global End TB Strategy. The efficacy of LTBI treatment is well established, and the most commonly used regimen is 9 months of daily self-administered Isoniazid. However, its use has been hindered by limited provider awareness of the benefits, concern about potential side effects such as hepatotoxicity, and low rates of treatment completion. There is increasing evidence that shorter rifamycin-based regimens are as effective, better tolerated, and more likely to be completed compared to Isoniazid. Such regimens include four months of daily self-administered rifampin monotherapy, three months of once weekly directly observed Isoniazid-rifapentine, and three months of daily self-administered Isoniazid-rifampin. The success of LTBI treatment to prevent additional TB disease relies upon choosing an appropriate regimen individualized to the patient, monitoring for potential adverse clinical events, and utilizing strategies to promote adherence. Safer, more cost-effective, and more easily completed regimens are needed and should be combined with interventions to better identify, engage, and retain high-risk individuals across the cascade from diagnosis through treatment completion of LTBI. |
| 2017 | Use of Video Directly Observed Therapy for Treatment of Latent Tuberculosis Infection - Johnson County, Kansas, 2015. | MMWR Morb Mortal Wkly Rep | Tuberculosis (TB) is caused by the bacterium Mycobacterium tuberculosis and is spread from person to person through the air. TB can be spread in congregate settings, such as school environments, to varying degrees, based on factors including duration of contact and air ventilation (1); therefore, evaluating potential contacts and exposures can be challenging. In February 2015, a student at a Kansas high school received a diagnosis of active pulmonary TB disease. Screening of 385 (91%) school contacts, four (100%) household contacts, and 19 (90%) social contacts resulted in the identification of 50 persons with latent TB infection. Johnson County Department of Health and Environment (JCDHE) Public Health Emergency Preparedness personnel used their experience with points of distribution logistics to optimize testing clinic layouts and implement the incident command structure. Open communication with students, school staff members, the public, and the media about the investigation from the outset was imperative to reduce rumors and unease that can accompany a large communicable disease investigation. The large number of persons needing treatment for latent TB overwhelmed JCDHE's two TB nurses. As a result, JCDHE developed a policy and procedure to allow persons who met eligibility requirements to complete 12 weekly doses of Isoniazid and rifapentine treatment using video directly observed therapy (VDOT) rather than traditional in-person directly observed therapy (DOT). This procedure facilitated treatment compliance and completion; among the eligible 15 persons who chose the 12-week VDOT option, 14 (93%) completed treatment. State and local health departments might consider use of VDOT to monitor treatment of persons with latent TB infection. |
| 2017 | Efficacy and completion rates of rifapentine and isoniazid (3HP) compared to other treatment regimens for latent tuberculosis infection: a systematic review with network meta-analyses. | BMC Infect Dis | We conducted a systematic review and network meta-analysis (NMA) to examine the efficacy and completion rates of treatments for latent tuberculosis infection (LTBI). While a previous review found newer, short-duration regimens to be effective, several included studies did not confirm LTBI, and analyses did not account for variable follow-up or assess completion.We searched MEDLINE, Embase, CENTRAL, PubMed, and additional sources to identify RCTs in patients with confirmed LTBI that involved a regimen of interest and reported on efficacy or completion. Regimens of interest included Isoniazid (INH) with rifapentine once weekly for 12 weeks (INH/RPT-3), 6 and 9 months of daily INH (INH-6; INH-9), 3-4 months daily INH plus rifampicin (INH/RFMP 3-4), and 4 months daily rifampicin alone (RFMP-4). NMAs were performed to compare regimens for both endpoints.Sixteen RCTs (n = 44,149) and 14 RCTs (n = 44,128) were included in analyses of efficacy and completion. Studies were published between 1968 and 2015, and there was diversity in patient age and comorbidities. All regimens of interest except INH-9 showed significant benefits in preventing active TB compared to placebo. Comparisons between active regimens did not reveal significant differences. While definitions of regimen completion varied across studies, regimens of 3-4 months were associated with a greater likelihood of adequate completion.Most of the active regimens showed an ability to reduce the risk of active TB relative to no treatment, however important differences between active regimens were not found. Shorter rifamycin-based regimens may offer comparable benefits to longer INH regimens. Regimens of 3-4 months duration are more likely to be completed than longer regimens. |
| 2017 | Three months of weekly rifapentine plus isoniazid for latent tuberculosis treatment in solid organ transplant candidates. | Infection | Isoniazid daily for 9 months is the recommended regimen for latent tuberculosis infection (LTBI) in solid organ transplant (SOT) candidates, but its use is controversial, due to reports of hepatotoxicity and low treatment completion rates. A 12-week course of once weekly directly observed therapy (DOT) with Isoniazid plus rifapentine (3HP) is a new LTBI treatment regimen. Tolerability and safety data of 3HP LTBI treatment in SOT candidates are limited.Twelve consecutive SOT candidates who underwent DOT with 3HP for LTBI at Westchester Medical Center, Valhalla, New York, USA, between January 2013 and August 2016 were prospectively evaluated for tolerability and safety of 3HP. The diagnosis of LTBI was made in a person with a positive interferon-gamma release test, without a history of previously treated active or latent tuberculosis infection, and without signs, symptoms, or radiographic evidence of active tuberculosis. Patients were followed up 1 month after treatment completion and at routine follow-up visits with their transplant providers.Eleven patients were men, and the median age was 60 years (range 44-72). Eight patients were liver, and four kidney transplant candidates. The median Model for End-Stage Liver Disease (MELD score) was 17 (range 10-31). All patients completed treatment. Only a single patient developed transaminitis greater than twice the baseline value. Three patients underwent liver transplantation. None of them developed tuberculosis at 9, 22, or 40 months following transplantation.Directly observed 3HP LTBI treatment was not associated with hepatotoxicity, even in patients with higher MELD scores. Further studies are needed to confirm the safety and efficacy of this LTBI treatment regimen in the SOT population. |
| 2017 | A shorter treatment regimen for latent tuberculosis infection holds promise for at-risk Canadians. | Can Commun Dis Rep | Despite recent success in reducing its incidence, tuberculosis remains a considerable challenge in Canada, particularly among foreign-born and Indigenous populations. A key component of the strategy for controlling the disease is the treatment of latent tuberculosis infection. The standard treatment consists of Isoniazid (INH) daily for nine months. In recent years, shorter regimens have been developed in the hope of increasing rates of treatment acceptance and completion. Of these, the shortest and most recently developed is a combination of INH and rifapentine taken once weekly for 12 doses (3HP), typically using directly observed therapy (DOT). This regimen has been approved by the Food and Drug Administration in the United States but is not yet authorized in Canada. Based on a rapidly expanding number of observational studies and randomized controlled trials, 12 weeks of 3HP appears to have similar efficacy to nine months of INH, a favourable adverse event profile and potentially improved rates of treatment completion. Although rates of treatment acceptance, the role of self-administered therapy and the regimen's cost-effectiveness within the Canadian context remain uncertain, 3HP is a promising alternative to existing treatments for LTBI. |
| 2017 | The tuberculosis taboo. | Int J Tuberc Lung Dis | The treatment of latent tuberculous infection (TBI) is a productive and meaningful approach to tuberculosis (TB) control, and an important component of the World Health Organization's (WHO's) new End TB Strategy, especially in high-risk contacts. Unfortunately, although recognized and recommended by the WHO, it continues to be underutilized, and has even been ignored for decades in some high-risk groups, as though it were a taboo. Historical approaches to treating TBI in contacts of drug-susceptible and drug-resistant TB are presented and discussed as compelling experiences. In the United States, the Centers for Disease Control and Prevention have recently shown that a directly observed or even self-administered 12-month regimen to treat TBI with once-weekly Isoniazid (INH) and rifapentine is as effective as 9 months of daily INH. Treating TBI in drug-susceptible cases and their contacts should not still be considered taboo-such a short, effective regimen is more akin to the Holy Grail. While not yet confirmed in a clinical trial, treating contacts of drug-resistant TB with the same drugs that are effective in the source case would be expected intuitively and practically to prevent TB in contacts and should be introduced now instead of waiting until clinical trials are completed. |
| 2017 | Treatment completion for latent tuberculosis infection: a retrospective cohort study comparing 9 months of isoniazid, 4 months of rifampin and 3 months of isoniazid and rifapentine. | BMC Infect Dis | The U.S. Centers for Disease Control and Prevention (CDC) recommended a new regimen for treatment of latent tuberculosis (three months of weekly Isoniazid and rifapentine) in late 2011. While completion rates of this regimen were reported to be higher than nine months of Isoniazid, little is known about the completion rates of three months of Isoniazid and rifapentine compared to nine months of Isoniazid or four months of rifampin in actual use scenarios.We conducted a retrospective cohort study comparing treatment completion for latent tuberculosis (TB) infection in patients treated with nine months of Isoniazid, three months of Isoniazid and rifapentine or four months of rifampin in outpatient clinics and a public health TB clinic in Seattle, Washington. The primary outcome of treatment completion was defined as 270 doses of Isoniazid within 12 months, 120 doses of rifampin within six months and 12 doses of Isoniazid and rifapentine within four months.Three hundred ninety-three patients were included in the study. Patients were equally likely to complete three months of weekly Isoniazid and rifapentine or four months of rifampin (85% completion rate of both regimens), as compared to 52% in the nine months of Isoniazid group (p < 0.001). These associations remained statistically significant even after adjusting for clinic location and type of monitoring. Monitoring type (weekly versus monthly versus less often than monthly) had less impact on treatment completion than the type of treatment offered.Patients were equally as likely to complete the three months of Isoniazid and rifapentine as four months of rifampin. Four months of rifampin is similar in efficacy compared to placebo as Isoniazid and rifapentine but does not require directly observed therapy (DOT), and is less expensive compared to combination therapy with Isoniazid and rifapentine, and thus can be the optimal treatment regimen to achieve the maximal efficacy in a community setting. |
| 2016 | Activity of drugs against dormant Mycobacterium tuberculosis. | Int J Mycobacteriol | Heterogeneous mixtures of cellular and caseous granulomas coexist in the lungs of tuberculosis (TB) patients, with Mycobacterium tuberculosis (Mtb) existing from actively replicating (AR) to dormant, nonreplicating (NR) stages. Within cellular granulomas, the pH is estimated to be less than 6, whereas in the necrotic centres of hypoxic, cholesterol/triacylglycerol-rich, caseous granulomas, the pH varies between 7.2 and 7.4. To combat TB, we should kill both AR and NR stages of Mtb. Dormant Mtb remodels lipids of its cell wall, and so lipophilic drugs may be active against NR Mtb living in caseous, lipid-rich, granulomas. Lipophilicity is expressed as logP, that is, the logarithm of the partition coefficient (P) ratio P/P. In this study, the activity of lipophilic drugs (logP>0) and hydrophilic drugs (logP⩽0) against AR and NR Mtb was measured in hypoxic conditions under acidic and slightly alkaline pHs.The activity of drugs was determined against AR Mtb (5-day-old aerobic cells: A5) and NR Mtb (12- and 19-day-old hypoxic cells: H12 and H19) in a Wayne dormancy model of Mtb H37Rv at pH 5.8, to mimic the environment of cellular granulomas. Furthermore, AR and NR bacilli were grown for 40days in Wayne models at pH 6.6, 7.0, 7.4, and 7.6, to set up conditions mimicking the caseous granulomas (hypoxia+slightly alkaline pH), to measure drug activity against NR cells. Mtb viability was determined by colony-forming unit (CFU) counts.At pH 5.8, lipophilic drugs (rifampin, rifapentine, bedaquiline, PA-824, clofazimine, nitazoxanide: logP⩾2.14) reduced CFU of all cells (H12, H19, and A5) by ⩾2log. Among hydrophilic drugs (Isoniazid, pyrazinamide, ethambutol, amikacin, moxifloxacin, metronidazole: logP⩽0.01), none reduced H12 and H19 CFUs by ⩾2log, with the exception of metronidazole. When Mtb was grown at different pHs the following Mtb growth was noted: at pH 6.6, AR cells grew fluently while NR cells grew less, with a CFU increase up to Day 15, followed by a drop to Day 40. AR and NR Mtb grown at pH 7.0, 7.4, and 7.6 showed up to 1 log CFU lower than their growth at pH 6.6. The pHs of all AR cultures tended to reach pH 7.2-7.4 on Day 40. The pHs of all NR cultures remained stable at their initial values (6.6, 7.0, 7.4, and 7.6) up to Day 40. The activity of drugs against H12 and H19 cells was tested in hypoxic conditions at a slightly alkaline pH. Under these conditions, some lipophilic drugs were more active (>5 log CFU decrease after 21days of exposure) against H12 and H19 cells than clofazimine, nitazoxanide, Isoniazid, pyrazinamide, amikacin (<1 log CFU decrease after 21days of exposure). Testing of other drugs is in progress.Lipophilic drugs were more active than hydrophilic agents against dormant Mtb in hypoxic conditions at pH 5.8. The Wayne model under slightly alkaline conditions was set up, and in hypoxic conditions at a slightly alkaline pH some lipophilic drugs were more active than other drugs against NR Mtb. Overall, these models can be useful for testing drug activity against dormant Mtb under conditions mimicking the environments of cellular and caseous granulomas. |
| 2017 | Mycobacterium tuberculosis Is Selectively Killed by Rifampin and Rifapentine in Hypoxia at Neutral pH. | Antimicrob Agents Chemother | The activities of rifampin, rifapentine, bedaquiline, PA-824, clofazimine, nitazoxanide, Isoniazid, amikacin, moxifloxacin, niclosamide, thioridazine, and pyrazinamide were tested against nonreplicating (dormant) H37Rv under conditions of hypoxia at pHs 5.8 and 7.3, mimicking environments of cellular granulomas and caseous granulomas, respectively. At pH 5.8, several drugs killed dormant bacilli, with the best being rifampin and rifapentine. At pH 7.3, only rifampin and rifapentine efficiently killed dormant bacilli, while all other drugs showed little activity. |
| Cost effectiveness of interferon-gamma release assay for tuberculosis screening using three months of rifapentine and isoniazid among long-term expatriates from low to high incidence countries. | Travel Med Infect Dis | Long-term expatriates from low to high tuberculosis (TB) incidence countries get high rates of active TB and latent TB infection (LTBI). TB screening for expatriates is important for occupational health. Interferon-gamma release assays are more accurate than tuberculin skin test (TST). Rifapentine plus Isoniazid for 3 months (3HP) is as effective as 9 months of Isoniazid (9H) with a higher treatment-completion rate.Decision trees and Markov models were constructed using a societal perspective on a lifetime horizon. The target population was a hypothetical cohort of 30 year-old expatriates. Seven strategies; TST with 3HP or 9H, QuantiFERON-TB Gold In-Tube (QFT) with 3HP or 9H, T-SPOT.TB (TSPOT) with 3HP or 9H and chest X-ray examination (CXR) were modeled. The main outcome measure of effectiveness was quality-adjusted life-years (QALYs) gained.QFT with 3HP yielded the greatest benefits with the lowest cost ($US 674.8; 25.95660 QALYs [year 2012 values]). CXR was the least cost-effective ($US 13,666.8; 24.62917 QALYs). Cost-effectiveness was sensitive to adherence rate of 3HP and QFT specificity, but not to BCG vaccination rate.Entry LTBI screening using QFT treated with 3HP is recommended on the basis of cost effectiveness among long-term expatriates from low to high incidence countries. |
| 2016 | Predictors of Latent Tuberculosis Infection Treatment After Introduction of a New Regimen: A Retrospective Cohort Study at an Inner City Clinic. | Open Forum Infect Dis | Despite the low and decreasing prevalence of tuberculosis (TB) in the United States, there remain certain high-risk groups with high incidence rates. The targeted screening and treatment of latent TB infection (LTBI) among these high-risk groups are needed to achieve TB elimination; however, by most accounts, LTBI treatment completion rates remain low. We retrospectively studied all patients accepting treatment for LTBI at the Fulton County Health Department TB clinic over 2 years. Medical chart abstraction was performed to collect information on sociodemographics, medical, and LTBI treatment history. Treatment completion was defined as finishing ≥88% of the prescribed regimen. Logistic regression analysis was performed to identify predictors of treatment completion. Among 547 adults offered LTBI treatment, 424 (78%) accepted treatment and 298 of 424 (70%) completed treatment. The median age was 42 years, most patients were black (77%), and close to one third did not have stable housing. No significant difference in completion rates was found between the 3 regimens of 9 months Isoniazid (65%), 4 months rifampin (71%), and 3 months of weekly rifapentine and Isoniazid (79%). In multivariate analysis, having stable housing increased the odds of finishing treatment, whereas tobacco use and an adverse event decreased the odds. Utilizing comprehensive case management, we demonstrated high rates of LTBI treatment completion, including among those receiving a 3-month regimen. Completion rates were higher among persons with stable housing, and this finding highlights the need to develop strategies that will improve adherence among homeless persons. |
| 2016 | Primary Care Screening and Treatment for Latent Tuberculosis Infection in Adults: Evidence Report and Systematic Review for the US Preventive Services Task Force. | JAMA | Five to ten percent of individuals with latent tuberculosis infection (LTBI) progress to active tuberculosis (TB) disease. Identifying and treating LTBI is a key component of the strategy for reducing the burden of TB disease.To review the evidence about targeted screening and treatment for LTBI among adults in primary care settings to support the US Preventive Services Task Force in updating its 1996 recommendation.MEDLINE, Cochrane Library, and trial registries, searched through August 3, 2015; references from pertinent articles; and experts. Literature surveillance was conducted through May 31, 2016.English-language studies of LTBI screening, LTBI treatment with recommended pharmacotherapy, or accuracy of the tuberculin skin test (TST) or interferon-gamma release assays (IGRAs). Studies of individuals for whom LTBI screening and treatment is part of public health surveillance or disease management were excluded.Two investigators independently reviewed abstracts and full-text articles. When at least 3 similar studies were available, random-effects meta-analysis was used to generate pooled estimates of outcomes.Sensitivity, specificity, reliability, active TB disease, mortality, hepatotoxicity, and other harms.The review included 72 studies (n = 51 711). No studies evaluated benefits and harms of screening compared with no screening. Pooled estimates for sensitivity of the TST at both 5-mm and 10-mm induration thresholds were 0.79 (5-mm: 95% CI, 0.69-0.89 [8 studies, n = 803]; 10 mm: 95% CI, 0.71-0.87 [11 studies; n = 988]), and those for IGRAs ranged from 0.77 to 0.90 (57 studies; n = 4378). Pooled estimates for specificity of the TST at the 10-mm and 15-mm thresholds and for IGRAs ranged from 0.95 to 0.99 (34 studies; n = 23 853). A randomized clinical trial (RCT) of 24 weeks of Isoniazid in individuals with pulmonary fibrotic lesions and LTBI (n = 27 830) found a reduction in absolute risk of active TB at 5 years from 1.4% to 0.5% (relative risk [RR], 0.35 [95% CI, 0.24-0.52]) and an increase in absolute risk for hepatoxicity from 0.1% to 0.5% (RR, 4.59 [95% CI, 2.03-10.39]) for 24 weeks of daily Isoniazid compared with placebo. An RCT (n = 6886) found that 3 months of once-weekly rifapentine plus Isoniazid was noninferior to 9 months of Isoniazid alone for preventing active TB. The risk difference for hepatoxicity comparing Isoniazid with rifampin ranged from 3% to 7%, with a pooled RR of 3.29 (95% CI, 1.72-6.28 [3 RCTs; n = 1327]).No studies evaluated the benefits and harms of screening compared with no screening. Both the TST and IGRAs are moderately sensitive and highly specific within countries with low TB burden. Treatment reduced the risk of active TB among the populations included in this review. Isoniazid is associated with higher rates of hepatotoxicity than placebo or rifampin. |
| 2016 | Impacts of 12-dose regimen for latent tuberculosis infection: Treatment completion rate and cost-effectiveness in Taiwan. | Medicine (Baltimore) | Treatment of latent tuberculosis infection (LTBI) is essential for eradicating tuberculosis (TB). Moreover, the patient adherence is crucial in determining the effectiveness of TB control. Isoniazid given by DOTS daily for 9 months (9H) is the standard treatment for LTBI in Taiwan. However, the completion rate is low due to the long treatment period and its side effects. The combined regimen using a high dose of rifapentine/Isoniazid once weekly for 12 weeks (3HP) has been used as an alternative treatment option for LTBI in the United States. This may result in a higher completion rate. In this pilot study, patient adherence and cost of these 2 treatment regimens were investigated. Thus, we aimed to assess the treatment completion rate and costs of 3HP and compare to those with 9H.Data from 691 cases of LTBI treatments including 590 cases using the conventional regimen and 101 cases with rifapentine/Isoniazid were collected. The cost was the sum of the cost of treatment with Isoniazid for 9 months or with rifapentin/Isoniazid for 3 months of all contacts. The effectiveness was the cost of cases of tuberculosis avoided.In this study, the treatment completion rate for patients prescribed with the 3 months rifapentine/Isoniazid regimen (97.03%) was higher than those given the conventional 9-month Isoniazid regimen (87.29%) (P <0.001). The cost of 3HP and 9H was US$261.24 and US$717.3, respectively. The cost-effectiveness ratio with Isoniazid for 9 months was US$ 15392/avoided 1 case of tuberculosis and US$ 5225/avoided 1 case of tuberculosis with 3HP. In addition, when compared with the conventional regimen, there were fewer patients discontinued with rifapentine/Isoniazid regimen due to undesirable side effects.This was the first study to compare the 2 treatment regimens in Taiwan, and it showed that a short-term high-dosage rifapentine/Isoniazid treatment regimen reduced costs and resulted in higher treatment completion than the standard LTBI Isoniazid treatment. |
| 2017 | Twelve-Week Rifapentine Plus Isoniazid Versus 9-Month Isoniazid for the Treatment of Latent Tuberculosis in Renal Transplant Candidates. | Transplantation | Renal transplant candidates (RTC) with latent tuberculosis infection (LTBI) are at significant risk for tuberculosis reactivation. Twelve-week rifapentine (RPT)/Isoniazid (INH) is effective for LTBI but clinical experience in RTC is scarce.We conducted a retrospective study of RTC with LTBI treated with either 12-week RPT/INH or 9-month INH from March 1, 2012, through February 28, 2014. We evaluated both groups for differences in rates of treatment completion, monthly follow-up visit compliance, transaminase elevations, and adverse reactions leading to discontinuation of LTBI treatment. The utility of weekly reminders was also evaluated in the 12-week regimen. Direct observed therapy was not performed in our study.Of 153 patients, 43 (28%) and 110 (72%) were started on 12-week RPT/INH and 9-month INH, respectively. The treatment completion and monthly follow-up visit compliance rates were higher in the 12-week RPT/INH group (40 [93%] vs 52 [47%], P < 0.001) and (11/40 [28%] vs 13/104 [13%], P = 0.03), respectively. Transaminase elevations were not observed in the RPT/INH group, but occurred in 6 (5%) of the INH group. There were no differences in adverse reactions leading to discontinuation of LTBI treatment.Twelve-week RPT/INH appears to be an excellent choice for LTBI in RTC. It has a higher treatment completion rate and causes less transaminase elevations, and weekly reminders may be an alternative when direct observed therapy is not feasible. |
| 2016 | Rifapentine for the treatment of latent tuberculosis. | Expert Rev Clin Pharmacol | The goal of this article is to review the use of rifapentine in the treatment of latent tuberculosis infection (LTBI). Controlling LTBI is an important part of the global strategy to end the spread of tuberculosis. Rifapentine's potent sterilizing effect against Mycobacterium tuberculosis combined with its long half-life make it an attractive LTBI treatment option. Areas covered: A systematic literature search of Pubmed using the terms 'rifapentine' and 'tuberculosis' was performed. Articles identified were cross-referenced for other relevant publications. The mechanisms of action and resistance, pharmacokinetic and pharmacodynamics, potential drug interactions and side effects are discussed. Expert commentary: Rifapentine in combination with Isoniazid for twelve weeks is the best available option for treating latent TB in the majority of patients in the United States due to its favorable safety profile and the increased likelihood of completing therapy. Currently, rifapentine is not registered or available in other countries. |
| 2016 | Three months of weekly rifapentine and isoniazid for treatment of Mycobacterium tuberculosis infection in HIV-coinfected persons. | AIDS | Compare the effectiveness, tolerability, and safety of 3 months of weekly rifapentine and Isoniazid under direct observation (3HP) versus 9 months of daily Isoniazid (9H) in HIV-infected persons.Prospective, randomized, and open-label noninferiority trial.The United States , Brazil, Spain, Peru, Canada, and Hong Kong.HIV-infected persons who were tuberculin skin test positive or close contacts of tuberculosis cases.3HP versus 9H.The effectiveness endpoint was tuberculosis; the noninferiority margin was 0.75%. The tolerability endpoint was treatment completion; the safety endpoint was drug discontinuation because of adverse drug reaction.Median baseline CD4 cell counts were 495 (IQR 389-675) and 538 (IQR 418-729) cells/μl in the 3HP and 9H arms, respectively (P = 0.09). In the modified intention-to-treat analysis, there were two tuberculosis cases among 206 persons [517 person-years (p-y) of follow-up] in the 3HP arm (0.39 per 100 p-y) and six tuberculosis cases among 193 persons (481 p-y of follow-up) in the 9H arm (1.25 per 100 p-y). Cumulative tuberculosis rates were 1.01 versus 3.50% in the 3HP and 9H arms, respectively (rate difference: -2.49%; upper bound of the 95% confidence interval of the difference: 0.60%). Treatment completion was higher with 3HP (89%) than 9H (64%) (P < 0.001), and drug discontinuation because of an adverse drug reaction was similar (3 vs. 4%; P = 0.79) in 3HP and 9H, respectively.Among HIV-infected persons with median CD4 cell count of approximately 500 cells/μl, 3HP was as effective and safe for treatment of latent Mycobacterium tuberculosis infection as 9H, and better tolerated. |
| 2016 | A Phase 2 Randomized Trial of a Rifapentine plus Moxifloxacin-Based Regimen for Treatment of Pulmonary Tuberculosis. | PLoS One | The combination of rifapentine and moxifloxacin administered daily with other anti-tuberculosis drugs is highly active in mouse models of tuberculosis chemotherapy. The objective of this phase 2 clinical trial was to determine the bactericidal activity, safety, and tolerability of a regimen comprised of rifapentine, moxifloxacin, Isoniazid, and pyrazinamide administered daily during the first 8 weeks of pulmonary tuberculosis treatment.Adults with sputum smear-positive pulmonary tuberculosis were randomized to receive either rifapentine (approximately 7.5 mg/kg) plus moxifloxacin (investigational arm), or rifampin (approximately 10 mg/kg) plus ethambutol (control) daily for 8 weeks, along with Isoniazid and pyrazinamide. The primary endpoint was sputum culture status at completion of 8 weeks of treatment.121 participants (56% of accrual target) were enrolled. At completion of 8 weeks of treatment, negative cultures using Löwenstein-Jensen (LJ) medium occurred in 47/60 (78%) participants in the investigational arm vs. 43/51 (84%, p = 0.47) in the control arm; negative cultures using liquid medium occurred in 37/47 (79%) in the investigational arm vs. 27/41 (66%, p = 0.23) in the control arm. Time to stable culture conversion was shorter for the investigational arm vs. the control arm using liquid culture medium (p = 0.03), but there was no difference using LJ medium. Median rifapentine area under the concentration-time curve (AUC0-24) was 313 mcg*h/mL, similar to recent studies of rifapentine dosed at 450-600 mg daily. Median moxifloxacin AUC0-24 was 28.0 mcg*h/mL, much lower than in trials where rifapentine was given only intermittently with moxifloxacin. The proportion of participants discontinuing assigned treatment for reasons other than microbiological ineligibility was higher in the investigational arm vs. the control arm (11/62 [18%] vs. 3/59 [5%], p = 0.04) although the proportions of grade 3 or higher adverse events were similar (5/62 [8%] in the investigational arm vs. 6/59 [10%, p = 0.76] in the control arm).For intensive phase daily tuberculosis treatment in combination with Isoniazid and pyrazinamide, a regimen containing moxifloxacin plus low dose rifapentine was at least as bactericidal as the control regimen containing ethambutol plus standard dose rifampin.www.ClinicalTrials.gov NCT00728507. |
| 2016 | Safety and Adherence for 12 Weekly Doses of Isoniazid and Rifapentine for Pediatric Tuberculosis Infection. | Pediatr Infect Dis J | Traditional treatment of tuberculosis infection (TBI) is efficacious, but adherence is low. Eighty children with TBI received a 12-dose once-weekly Isoniazid/rifapentine regimen; 79 (99%) completed therapy, 94% reported no adverse events, 1 child had mildly elevated transaminases but 1 adolescent later developed pulmonary TB. Isoniazid/rifapentine is safe, is well tolerated and has much higher completion rates than traditional TBI regimens. |
| 2016 | School-based Study to Identify and Treat Adolescent Students at Risk for Tuberculosis Infection. | Pediatr Infect Dis J | Screening for and treating tuberculosis (TB) infection in children and adolescents is an effective way of decreasing future TB cases. However, current approaches leave many children at risk for TB unidentified.We recruited adolescent students from 2 public high schools (a magnet and a low-income) in the Houston Independent School District. Compared with the magnet school, the student population at the low-income school was larger, primarily Hispanic and economically disadvantaged. Students were educated about TB, and parents completed a risk factor questionnaire. Students with TB risk factors were tested using 2 interferon gamma release assays (IGRAs). Those with a positive IGRA received a 12-dose regimen of weekly Isoniazid/rifapentine (3HP) administered via direct observation at school.Nine hundred twenty-five students received TB education; 73% of their parents submitted the TB questionnaire. Eighty-six percent of students (n = 415) with a TB risk factor identified on the study questionnaire agreed to IGRA testing. Sixteen students had at least one positive IGRA (1% [magnet], 4.1% [low-income]; P = 0.005). Recent student travel to a high-risk country (7) or contact with TB disease (2) were associated with IGRA positivity (P < 0.05). All students with a positive IGRA accepted, tolerated and completed 3HP treatment at school.School-based TB education, screening, testing using IGRAs and administration of 3HP treatment is feasible to improve the identification and treatment of adolescent students at risk for TB. |
| 2016 | Factors Associated With Noncompletion of Latent Tuberculosis Infection Treatment: Experience From the PREVENT TB Trial in the United States and Canada. | Clin Infect Dis | Overall rates of noncompletion of treatment (NCT) for latent tuberculosis infection (LTBI) in the PREVENT TB trial were 18% for 3 months of directly observed once-weekly rifapentine (maximum dose, 900 mg) plus Isoniazid (maximum dose, 900 mg) (3HP-DOT) and 31% for 9 months of daily self-administered Isoniazid (maximum dose, 300 mg; 9H-SAT). NCT for LTBI reduces its effectiveness. The study objective was to assess factors associated with NCT for LTBI among adult participants enrolled at US and Canadian sites of the PREVENT TB trial.This was a post hoc exploratory analysis of the randomized, open-label PREVENT TB trial. Factors were analyzed by univariate and multivariate logistic regression (with enrollment site as a random effect).From 6232 participants analyzed, 1406 (22.6%) did not complete LTBI treatment (317 NCT attributed to an adverse event [NCT-AE] and 1089 NCT attributed to reasons other than an adverse event [NCT-O]). The proportion of NCT-AE was similar with both regimens (3HP-DOT = 6.4% vs 9H-SAT = 5.9%; P = .23); NCT-O was higher among participants enrolled in 9H-SAT (9H-SAT = 24.5% vs 3HP-DOT = 12.7%; P = .02). Among those in the NCT-AE group, being non-Hispanic and receiving 3HP-DOT, having cirrhosis and receiving 9H-SAT, alcohol consumption among men, and use of concomitant medication were associated with NCT-AE. Among those in the NCT-O group, receiving 9H-SAT, missing ≥1 early visit, men receiving 9H-SAT, men with a history of incarceration, alcohol abuse, use ever of intravenous drugs, younger age receiving 9H-SAT, and smoking were associated with NCT-O.Factors associated with NCT, such as missing a clinic visit early during treatment, might help identify persons for whom tailored interventions could improve completion of LTBI treatment.NCT00023452. |
| 2016 | Completion Rate and Side-Effect Profile of Three-Month Isoniazid and Rifapentine Treatment for Latent Tuberculosis Infection in an Urban County Jail. | Open Forum Infect Dis | In an urban jail population, 3 months of Isoniazid and rifapentine (3HP) was associated with an 85% latent tuberculosis infection treatment completion rate compared with 18% in a standard 9-month Isoniazid treatment group. Among the 91 patients who started 3HP therapy, there were 2 treatment discontinuations from adverse drug reactions. |
| 2015 | Improving Treatment Completion Rates for Latent Tuberculosis Infection: A Review of Two Treatment Regimens at a Community Health Center. | J Health Care Poor Underserved | Prophylactic treatment of latent tuberculosis infection (LTBI) is necessary for controlling TB in low-incidence settings. However, treatment is often limited by poor completion rates.At a community health center serving low-income Hispanics, treatment completion among patients accepting 12 weekly doses of Isoniazid (INH) plus rifapentine (RPT) administered as directly observed therapy (DOT) was compared with that among patients accepting nine months of daily self-administered INH during 2012 and 2013 (n=139).Among patients who agreed to treatment, INH-RPT combination therapy was associated with higher completion rates (OR 3.06; 95% CI, 1.23-7.62; p=.016) when compared to INH only. Overall completion rates were 77.8% (35/45) for INH-RPT combination therapy and 52.1% (49/94) for INH monotherapy.High completion rates for LTBI treatment can be achieved at a community health center using INH-RPT administered via DOT. Greater success treating with INH-RPT may be attributed to DOT strategy and a shorter treatment regimen. |
| Rifapentine for latent tuberculosis infection treatment in the general population and human immunodeficiency virus-positive patients: summary of evidence. | Rev Soc Bras Med Trop | Latent tuberculosis infection (LTBI) and human immunodeficiency virus (HIV)-coinfection are challenges in the control of tuberculosis transmission. We aimed to assess and summarize evidence available in the literature regarding the treatment of LTBI in both the general and HIV-positive population, in order to support decision making by the Brazilian Tuberculosis Control Program for LTBI chemoprophylaxis. We searched MEDLINE, Cochrane Library, Centre for Reviews and Dissemination, Embase, LILACS, SciELO, Trip database, National Guideline Clearinghouse, and the Brazilian Theses Repository to identify systematic reviews, randomized clinical trials, clinical guidelines, evidence-based synopses, reports of health technology assessment agencies, and theses that investigated rifapentine and Isoniazid combination compared to Isoniazid monotherapy. We assessed the quality of evidence from randomized clinical trials using the Jadad Scale and recommendations from other evidence sources using the Grading of Recommendations, Assessment, Development, and Evaluations approach. The available evidence suggests that there are no differences between rifapentine + Isoniazid short-course treatment and the standard 6-month Isoniazid therapy in reducing active tuberculosis incidence or death. Adherence was better with directly observed rifapentine therapy compared to self-administered Isoniazid. The quality of evidence obtained was moderate, and on the basis of this evidence, rifapentine is recommended by one guideline. Available evidence assessment considering the perspective of higher adherence rates, lower costs, and local peculiarity context might support rifapentine use for LTBI in the general or HIV-positive populations. Since novel trials are ongoing, further studies should include patients on antiretroviral therapy. |
| 2015 | Management of latent Mycobacterium tuberculosis infection: WHO guidelines for low tuberculosis burden countries. | Eur Respir J | Latent tuberculosis infection (LTBI) is characterised by the presence of immune responses to previously acquired Mycobacterium tuberculosis infection without clinical evidence of active tuberculosis (TB). Here we report evidence-based guidelines from the World Health Organization for a public health approach to the management of LTBI in high risk individuals in countries with high or middle upper income and TB incidence of <100 per 100 000 per year. The guidelines strongly recommend systematic testing and treatment of LTBI in people living with HIV, adult and child contacts of pulmonary TB cases, patients initiating anti-tumour necrosis factor treatment, patients receiving dialysis, patients preparing for organ or haematological transplantation, and patients with silicosis. In prisoners, healthcare workers, immigrants from high TB burden countries, homeless persons and illicit drug users, systematic testing and treatment of LTBI is conditionally recommended, according to TB epidemiology and resource availability. Either commercial interferon-gamma release assays or Mantoux tuberculin skin testing could be used to test for LTBI. Chest radiography should be performed before LTBI treatment to rule out active TB disease. Recommended treatment regimens for LTBI include: 6 or 9 month Isoniazid; 12 week rifapentine plus Isoniazid; 3-4 month Isoniazid plus rifampicin; or 3-4 month rifampicin alone. |
| 2015 | Uniform and amorphous rifampicin microspheres obtained by freezing induced LLPS during lyophilization. | Int J Pharm | By lyophilization of rifampicin (RIF) solution in TBA/water with various solvent compositions, uniform and amorphous rifampicin (RIF) microspheres were produced. Using 55% TBA solution, the obtained RIF microspheres have a mono-dispersive size distribution with diameters range from 1 to 3 μm. The RIF microspheres are found to be amorphous by X-ray diffraction, and are expected to dissolve much faster than the crystalline RIF upon inhalation. Mechanistic investigation revealed that the amorphous RIF microspheres were formed due to liquid-liquid phase separation (LLPS) occurred during the freezing of the TBA/water solution. We also observed that the RIF microspheres can be readily phagocytized by activated THP-1 cells within 15 min. The suitable size distribution, high solubility, and readiness for phagocytosis by macrophages, all suggest that the lyophilized amorphous RIF microspheres could be potentially used as an anti-tuberculosis inhalation therapy. In addition, similar process was used to lyophilize TBA/water solutions of several other drugs, including rifaximin, rifapentine, paclitaxel, and Isoniazid. We found that for drugs with appropriate physiochemical properties, such as paclitaxel and rifaximin, mono-dispersive microspheres could be obtained as well, which demonstrated that freezing induced LLPS could be utilized as a novel particle engineering methodology to produce drug microspheres by lyophilization. |
| 2016 | Treatment for Tuberculosis Infection With 3 Months of Isoniazid and Rifapentine in New York City Health Department Clinics. | Clin Infect Dis | Completion of treatment for tuberculosis infection (TBI) with 9 months of self-administered daily Isoniazid (9H) has historically been low (<50%) among New York City (NYC) Health Department tuberculosis clinic patients. Treatment of TBI with 3 months of once-weekly Isoniazid and rifapentine (3HP) administered under directly observed therapy (DOT) might increase treatment acceptance and completion.The study population included patients diagnosed with TBI at 2 NYC Health Department tuberculosis clinics from January 2013 through November 2013. Treatment acceptance and completion with 3HP were compared with historical estimates. Treatment outcomes, side effects, and reasons for refusing 3HP were described.Among 631 patients eligible for TBI treatment, 503 (80%) were offered 3HP; 302 (60%) accepted, 92 (18%) chose other treatment, and 109 (22%) refused treatment. The most common reason for refusing 3HP was the clinic-based DOT requirement. Forty (13%) patients treated with 3HP experienced side effects--9 were restarted on 3HP, 18 switched treatment regimens, and 13 discontinued. Although treatment acceptance did not differ from historical estimates (78% vs 79%, P = .75), treatment completion increased significantly (65% vs 34%, P < .01).Implementation of 3HP in 2 NYC Health Department tuberculosis clinics increased TBI treatment completion by 31 percentage points compared with historical estimates. More flexible DOT options may improve acceptance of 3HP. Wider use of 3HP may substantially improve TBI treatment completion in NYC and advance progress toward tuberculosis elimination. |
| 2015 | Three months of weekly rifapentine plus isoniazid is less hepatotoxic than nine months of daily isoniazid for LTBI. | Int J Tuberc Lung Dis | Nine months of daily Isoniazid (9H) and 3 months of once-weekly rifapentine plus Isoniazid (3HP) are recommended treatments for latent tuberculous infection (LTBI). The risk profile for 3HP and the contribution of hepatitis C virus (HCV) infection to hepatotoxicity are unclear.To evaluate the hepatotoxicity risk associated with 3HP compared to 9H, and factors associated with hepatotoxicity.Hepatotoxicity was defined as aspartate aminotransferase (AST) >3 times the upper limit of normal (ULN) with symptoms (nausea, vomiting, jaundice, or fatigue), or AST >5 x ULN. We analyzed risk factors among adults who took at least 1 dose of their assigned treatment. A nested case-control study assessed the role of HCV.Of 6862 participants, 77 (1.1%) developed hepatotoxicity; 52 (0.8%) were symptomatic; 1.8% (61/3317) were on 9H and 0.4% (15/3545) were on 3HP (P < 0.0001). Risk factors for hepatotoxicity were age, female sex, white race, non-Hispanic ethnicity, decreased body mass index, elevated baseline AST, and 9H. In the case-control study, HCV infection was associated with hepatotoxicity when controlling for other factors.The risk of hepatotoxicity during LTBI treatment with 3HP was lower than the risk with 9H. HCV and elevated baseline AST were risk factors for hepatotoxicity. For persons with these risk factors, 3HP may be preferred. |
| 2015 | Inhibitory Potential of Twenty Five Anti-tuberculosis Drugs on CYP Activities in Human Liver Microsomes. | Biol Pharm Bull | The direct inhibitory potential of twenty five anti-tuberculosis drugs on eight CYP-specific reactions in human liver microsomes was investigated to predict in vivo drug-drug interactions (DDIs) from in vitro data. Rifampicin, rifabutin, and thioacetazone inhibited one CYP reaction. Isoniazid and clofazimine had inhibitory effects on four CYP reactions, and rifapentine, ethionamide, and prothionamide widely inhibited CYP reactions. Based on the inhibition constant (Ki) and the therapeutic total inhibitor concentrations [I]max of eight drugs in human plasma, [I]max/Ki values were calculated to evaluate clinical DDIs. The [I]max/Ki values were 0.20 or less for rifampicin, rifabutin, and thioacetazone; 0.15-2.0 for Isoniazid; 0.14-1.5 for rifapentine; 0.29-1.4 for ethionamide; 0.41-2.2 for prothionamide; and 0.12-6.3 for clofazimine. The highest [I]max/Ki values were 2.0 for Isoniazid on CYP3A4 [testosterone (T)]; 1.5 for rifapentine on CYP3A4 [midazolam (M)]; 1.4 for ethionamide on CYP2C8; 2.2, 1.8, and 1.3 for prothionamide on CYP2B6, CYP2C19, and CYP2C8, respectively; and 6.3 and 5.7 for clofazimine on CYP3A4 (M) and CYP3A4 (T), respectively. These drugs with high [I]max/Ki values lead to clinical DDIs. Considering the drug regimens for tuberculosis (TB) and co-infection with TB and human immunodeficiency virus, the inhibitory potential for CYP3A4 and CYP2B6 is particularly important. These results suggest that clofazimine and prothionamide are likely to cause clinically relevant DDIs when co-administered with products metabolized by CYP3A4 and CYP2B6, respectively. Isoniazid and rifapentine may cause DDIs with drugs metabolized by CYP3A4. |
| 2015 | Efavirenz Pharmacokinetics and Pharmacodynamics in HIV-Infected Persons Receiving Rifapentine and Isoniazid for Tuberculosis Prevention. | Clin Infect Dis | Concomitant use of rifamycins to treat or prevent tuberculosis can result in subtherapeutic concentrations of antiretroviral drugs. We studied the interaction of efavirenz with daily rifapentine and Isoniazid in human immunodeficiency virus (HIV)-infected individuals receiving a 4-week regimen to prevent tuberculosis.Participants receiving daily rifapentine and Isoniazid with efavirenz had pharmacokinetic evaluations at baseline and weeks 2 and 4 of concomitant therapy. Efavirenz apparent oral clearance was estimated and the geometric mean ratio (GMR) of values before and during rifapentine and Isoniazid was calculated. HIV type 1 (HIV-1) RNA was measured at baseline and week 8.Eighty-seven participants were evaluable: 54% were female, and the median age was 35 years (interquartile range [IQR], 29-44 years). Numbers of participants with efavirenz concentrations ≥1 mg/L were 85 (98%) at week 0; 81 (93%) at week 2; 78 (90%) at week 4; and 75 (86%) at weeks 2 and 4. Median efavirenz apparent oral clearance was 9.3 L/hour (IQR, 6.42-13.22 L/hour) at baseline and 9.8 L/hour (IQR, 7.04-15.59 L/hour) during rifapentine/Isoniazid treatment (GMR, 1.04 [90% confidence interval, .97-1.13]). Seventy-nine of 85 (93%) participants had undetectable HIV-1 RNA (<40 copies/mL) at entry; 71 of 75 (95%) participants had undetectable HIV-1 RNA at week 8. Two participants with undetectable HIV-1 RNA at study entry were detectable (43 and 47 copies/mL) at week 8.The proportion of participants with midinterval efavirenz concentrations ≥1 mg/L did not cross below the prespecified threshold of >80%, and virologic suppression was maintained. Four weeks of daily rifapentine plus Isoniazid can be coadministered with efavirenz without clinically meaningful reductions in efavirenz mid-dosing concentrations or virologic suppression.NCT 01404312. |
| 2015 | Two-stage activity-safety study of daily rifapentine during intensive phase treatment of pulmonary tuberculosis. | Int J Tuberc Lung Dis | Rifapentine (RPT) has potent activity against Mycobacterium tuberculosis; however, the optimal dose for anti-tuberculosis treatment is unknown.To determine the antimicrobial activity, safety and tolerability of RPT 450 mg or 600 mg administered daily during the first 8 weeks of treatment for pulmonary tuberculosis (TB).In a two-stage, randomised open-label study, adults with sputum smear-positive TB were randomised to receive RPT 450 mg, RPT 600 mg or rifampicin (RMP) 600 mg daily for 8 weeks with Isoniazid, pyrazinamide and ethambutol. The primary endpoint was sputum culture status on Löwenstein-Jensen (LJ) medium at completion of 8 weeks of treatment.A total of 153 participants were enrolled. Both RPT regimens met pre-specified criteria to advance to stage 2. At completion of 8 weeks of treatment, LJ culture conversion occurred in 85% (35/41), 96% (43/45) and 94% (34/36) of participants in the RPT 450 mg, RPT 600 mg and RMP groups, respectively. The proportions of participants discontinuing treatment were similar (respectively 1/54 [2.0%], 1/51 [2.0%] and 4/48 [8.3%] in the RPT 450 mg, RPT 600 mg and RMP groups), as were ⩾grade 3 adverse events (0/54 [0%], 1/51 [2.0%] and 4/48 [8.3%]).There was a trend towards greater efficacy with RPT 600 mg than with RPT 450 mg. Daily RPT was safe and well-tolerated. |
| 2015 | Flu-like and Other Systemic Drug Reactions Among Persons Receiving Weekly Rifapentine Plus Isoniazid or Daily Isoniazid for Treatment of Latent Tuberculosis Infection in the PREVENT Tuberculosis Study. | Clin Infect Dis | Weekly rifapentine plus Isoniazid for 3 months (3HP) is as effective as daily Isoniazid for 9 months (9H) for latent tuberculosis infection in high-risk persons, but there have been reports of possible flu-like syndrome.We identified clinically significant systemic drug reactions (SDR) and evaluated risk factors in patients who did not complete treatment in the PREVENT Tuberculosis study.Among 7552 persons who received ≥ 1 dose of study drug, 153 had a SDR: 138/3893 (3.5%) with 3HP vs 15/3659 (0.4%) with 9H (P < .001). In the 3HP arm, 87 (63%) had flu-like syndrome and 23 (17%) had cutaneous reactions; 13/3893 (0.3%) had severe reactions (6 were hypotensive) and 6 reported syncope. Symptoms occurred after a median of 3 doses, and 4 hours after the dose; median time to resolution was 24 hours. There were no deaths. In multivariate logistic regression analysis, factors independently associated with SDR included receipt of 3HP (adjusted odds ratio [aOR] 9.4; 95% confidence interval [CI], 5.5, 16.2), white non-Hispanic race/ethnicity (aOR 3.3; 95% CI, 2.3, 4.7), female sex (aOR 2.0; 95% CI, 1.4, 2.9), age ≥ 35 years (aOR 2.0; 95% CI, 1.4, 2.9), and lower body mass index (body mass index [BMI]; P = .009). In a separate multivariate analysis among persons who received 3HP, severe SDR were associated with white non-Hispanic race/ethnicity (aOR 5.4; 95% CI, 1.8, 16.3), and receipt of concomitant non-study medications (aOR 5.9; 95% CI, 1.3, 27.1).SDR were more common with 3HP, and mostly flu-like. Persons of white race, female sex, older age, and lower BMI were at increased risk. Severe reactions were rare and associated with 3HP, concomitant medication, and white race. The underlying mechanism is unclear.NCT00023452. |
| 2015 | Treatment for preventing tuberculosis in children and adolescents: a randomized clinical trial of a 3-month, 12-dose regimen of a combination of rifapentine and isoniazid. | JAMA Pediatr | Three months of a once-weekly combination of rifapentine and Isoniazid for treatment of latent tuberculosis infection is safe and effective for persons 12 years or older. Published data for children are limited.To compare treatment safety and assess noninferiority treatment effectiveness of combination therapy with rifapentine and Isoniazid vs 9 months of Isoniazid treatment for latent tuberculosis infection in children.A pediatric cohort nested within a randomized, open-label clinical trial conducted from June 11, 2001, through December 17, 2010, with follow-up through September 5, 2013, in 29 study sites in the United States, Canada, Brazil, Hong Kong (China), and Spain. Participants were children (aged 2-17 years) who were eligible for treatment of latent tuberculosis infection.Twelve once-weekly doses of the combination drugs, given with supervision by a health care professional, for 3 months vs 270 daily doses of Isoniazid, without supervision by a health care professional, for 9 months.We compared rates of treatment discontinuation because of adverse events (AEs), toxicity grades 1 to 4, and deaths from any cause. The equivalence margin for the comparison of AE-related discontinuation rates was 5%. Tuberculosis disease diagnosed within 33 months of enrollment was the main end point for testing effectiveness. The noninferiority margin was 0.75%.Of 1058 children enrolled, 905 were eligible for evaluation of effectiveness. Of 471 in the combination-therapy group, 415 (88.1%) completed treatment vs 351 of 434 (80.9%) in the Isoniazid-only group (P = .003). The 95% CI for the difference in rates of discontinuation attributed to an AE was -2.6 to 0.1, which was within the equivalence range. In the safety population, 3 of 539 participants (0.6%) who took the combination drugs had a grade 3 AE vs 1 of 493 (0.2%) who received Isoniazid only. Neither arm had any hepatotoxicity, grade 4 AEs, or treatment-attributed death. None of the 471 in the combination-therapy group developed tuberculosis vs 3 of 434 (cumulative rate, 0.74%) in the Isoniazid-only group, for a difference of -0.74% and an upper bound of the 95% CI of the difference of +0.32%, which met the noninferiority criterion.Treatment with the combination of rifapentine and Isoniazid was as effective as Isoniazid-only treatment for the prevention of tuberculosis in children aged 2 to 17 years. The combination-therapy group had a higher treatment completion rate than did the Isoniazid-only group and was safe.clinicaltrials.gov Identifier: NCT00023452. |
| 2015 | Daily rifapentine for treatment of pulmonary tuberculosis. A randomized, dose-ranging trial. | Am J Respir Crit Care Med | Rifapentine has potent activity in mouse models of tuberculosis chemotherapy but its optimal dose and exposure in humans are unknown.We conducted a randomized, partially blinded dose-ranging study to determine tolerability, safety, and antimicrobial activity of daily rifapentine for pulmonary tuberculosis treatment.Adults with sputum smear-positive pulmonary tuberculosis were assigned rifapentine 10, 15, or 20 mg/kg or rifampin 10 mg/kg daily for 8 weeks (intensive phase), with Isoniazid, pyrazinamide, and ethambutol. The primary tolerability end point was treatment discontinuation. The primary efficacy end point was negative sputum cultures at completion of intensive phase.A total of 334 participants were enrolled. At completion of intensive phase, cultures on solid media were negative in 81.3% of participants in the rifampin group versus 92.5% (P = 0.097), 89.4% (P = 0.29), and 94.7% (P = 0.049) in the rifapentine 10, 15, and 20 mg/kg groups. Liquid cultures were negative in 56.3% (rifampin group) versus 74.6% (P = 0.042), 69.7% (P = 0.16), and 82.5% (P = 0.004), respectively. Compared with the rifampin group, the proportion negative at the end of intensive phase was higher among rifapentine recipients who had high rifapentine areas under the concentration-time curve. Percentages of participants discontinuing assigned treatment for reasons other than microbiologic ineligibility were similar across groups (rifampin, 8.2%; rifapentine 10, 15, or 20 mg/kg, 3.4, 2.5, and 7.4%, respectively).Daily rifapentine was well-tolerated and safe. High rifapentine exposures were associated with high levels of sputum sterilization at completion of intensive phase. Further studies are warranted to determine if regimens that deliver high rifapentine exposures can shorten treatment duration to less than 6 months. Clinical trial registered with www.clinicaltrials.gov (NCT 00694629). |
| 2014 | Rifamycins (rifampicin, rifabutin and rifapentine) compared to isoniazid for preventing tuberculosis in HIV-negative people at risk of active TB. | Evid Based Child Health | Preventing active tuberculosis (TB) from developing in people with latent tuberculosis infection (LTBI) is important for global TB control. Isoniazid (INH) for six to nine months has 60% to 90% protective efficacy, but the treatment period is long, liver toxicity is a problem, and completion rates outside trials are only around 50%. Rifampicin or rifamycin-combination treatments are shorter and may result in higher completion rates.To compare the effects of rifampicin monotherapy or rifamycin-combination therapy versus INH monotherapy for preventing active TB in HIV-negative people at risk of developing active TB.We searched the Cochrane Infectious Disease Group Specialized Register; Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE; EMBASE; LILACS; clinical trials registries; regional databases; conference proceedings; and references, without language restrictions to December 2012; and contacted experts for relevant published, unpublished and ongoing trials.Randomized controlled trials (RCTs) of HIV-negative adults and children at risk of active TB treated with rifampicin, or rifamycin-combination therapy with or without INH (any dose or duration), compared with INH for six to nine months.At least two authors independently screened and selected trials, assessed risk of bias, and extracted data. We sought clarifications from trial authors. We pooled relative risks (RRs) with their 95% confidence intervals (CIs), using a random-effects model if heterogeneity was significant. We assessed overall evidence quality using the GRADE approach.Ten trials are included, enrolling 10,717 adults and children, mostly HIV-negative (2% HIV-positive), with a follow-up period ranging from two to five years. Rifampicin (three/four months) vs. INH (six months) Five trials published between 1992 to 2012 compared these regimens, and one small 1992 trial in adults with silicosis did not detect a difference in the occurrence of TB over five years of follow up (one trial, 312 participants; very low quality evidence). However, more people in these trials completed the shorter course (RR 1.19, 95% CI 1.01 to 1.30; five trials, 1768 participants; moderate quality evidence). Treatment-limiting adverse events were not significantly different (four trials, 1674 participants; very low quality evidence), but rifampicin caused less hepatotoxicity (RR 0.12, 95% CI 0.05 to 0.30; four trials, 1674 participants; moderate quality evidence). Rifampicin plus INH (three months) vs. INH (six months) The 1992 silicosis trial did not detect a difference between people receiving rifampicin plus INH compared to INH alone for occurrence of active TB (one trial, 328 participants; very low quality evidence). Adherence was similar in this and a 1998 trial in people without silicosis (two trials, 524 participants; high quality evidence). No difference was detected for treatment-limiting adverse events (two trials, 536 participants; low quality evidence), or hepatotoxicity (two trials, 536 participants; low quality evidence). Rifampicin plus pyrazinamide (two months) vs. INH (six months) Three small trials published in 1994, 2003, and 2005 compared these two regimens, and two reported a low occurrence of active TB, with no statistically significant differences between treatment regimens (two trials, 176 participants; very low quality evidence) though, apart from one child from the 1994 trial, these data on active TB were from the 2003 trial in adults with silicosis. Adherence with both regimens was low with no statistically significant differences (four trials, 700 participants; very low quality evidence). However, people receiving rifampicin plus pyrazinamide had more treatment-limiting adverse events (RR 3.61, 95% CI 1.82 to 7.19; two trials, 368 participants; high quality evidence), and hepatotoxicity (RR 4.59, 95% 2.14 to 9.85; three trials, 540 participants; moderate quality evidence). Weekly, directly-observed rifapentine plus INH (three months) vs. daily, self-administered INH (nine months) A large trial conducted from 2001 to 2008 among close contacts of TB in the USA, Canada, Brazil and Spain found directly observed weekly treatment to be non-inferior to nine months self-administered INH for the incidence of active TB (0.2% vs 0.4%, RR 0.44, 95% CI 0.18 to 1.07, one trial, 7731 participants; moderate quality evidence). The directly-observed, shorter regimen had higher treatment completion (82% vs 69%, RR 1.19, 95% CI 1.16 to 1.22, moderate quality evidence), and less hepatotoxicity (0.4% versus 2.4%; RR 0.16, 95% CI 0.10 to 0.27; high quality evidence), though treatment-limiting adverse events were more frequent (4.9% versus 3.7%; RR 1.32, 95% CI 1.07 to 1.64 moderate quality evidence)Trials to date of shortened prophylactic regimens using rifampicin alone have not demonstrated higher rates of active TB when compared to longer regimens with INH. Treatment completion is probably higher and adverse events may be fewer with shorter rifampicin regimens. Shortened regimens of rifampicin with INH may offer no advantage over longer INH regimens. Rifampicin combined with pyrazinamide is associated with more adverse events. A weekly regimen of rifapentine plus INH has higher completion rates, and less liver toxicity, though treatment discontinuation due to adverse events is probably more likely than with INH. |
| 2014 | High-dose rifapentine with moxifloxacin for pulmonary tuberculosis. | N Engl J Med | Tuberculosis regimens that are shorter and simpler than the current 6-month daily regimen are needed.We randomly assigned patients with newly diagnosed, smear-positive, drug-sensitive tuberculosis to one of three regimens: a control regimen that included 2 months of ethambutol, Isoniazid, rifampicin, and pyrazinamide administered daily followed by 4 months of daily Isoniazid and rifampicin; a 4-month regimen in which the Isoniazid in the control regimen was replaced by moxifloxacin administered daily for 2 months followed by moxifloxacin and 900 mg of rifapentine administered twice weekly for 2 months; or a 6-month regimen in which Isoniazid was replaced by daily moxifloxacin for 2 months followed by one weekly dose of both moxifloxacin and 1200 mg of rifapentine for 4 months. Sputum specimens were examined on microscopy and after culture at regular intervals. The primary end point was a composite treatment failure and relapse, with noninferiority based on a margin of 6 percentage points and 90% confidence intervals.We enrolled a total of 827 patients from South Africa, Zimbabwe, Botswana, and Zambia; 28% of patients were coinfected with the human immunodefiency virus. In the per-protocol analysis, the proportion of patients with an unfavorable response was 4.9% in the control group, 3.2% in the 6-month group (adjusted difference from control, -1.8 percentage points; 90% confidence interval [CI], -6.1 to 2.4), and 18.2% in the 4-month group (adjusted difference from control, 13.6 percentage points; 90% CI, 8.1 to 19.1). In the modified intention-to-treat analysis these proportions were 14.4% in the control group, 13.7% in the 6-month group (adjusted difference from control, 0.4 percentage points; 90% CI, -4.7 to 5.6), and 26.9% in the 4-month group (adjusted difference from control, 13.1 percentage points; 90% CI, 6.8 to 19.4).The 6-month regimen that included weekly administration of high-dose rifapentine and moxifloxacin was as effective as the control regimen. The 4-month regimen was not noninferior to the control regimen. (Funded by the European and Developing Countries Clinical Trials Partnership and the Wellcome Trust; RIFAQUIN Current Controlled Trials number, ISRCTN44153044.). |
| 2013 | Diagnosis and treatment of latent tuberculosis infection: an update. | Curr Respir Care Rep | It is estimated that more than two billion people have latent infection, and this population serves as an important reservoir for future tuberculosis cases. Prevalence estimates are limited by difficulties in diagnosing the infection, including the lack of an ideal test, and an incomplete understanding of latency. Current tests include the tuberculin skin test and two interferon-γ release assays: QuantiFERON Gold In-Tube and T-SPOT.TB. This update focuses on recent publications regarding the ability of these tests to predict tuberculosis disease, their reproducibility over serial tests, and discordance between tests. We also discuss recent advances in the treatment of latent infection, including the three-month regimen of once-weekly rifapentine plus Isoniazid, and prolonged Isoniazid therapy for HIV-infected persons living in high-tuberculosis-incidence settings. We provide an update on the tolerability of the three-month regimen. |
| 2014 | Tuberculosis preventive therapy: an underutilised strategy to reduce individual risk of TB and contribute to TB control. | S Afr Med J | Tuberculosis (TB) remains a global health problem, and South Africa (SA) has one of the world's worst TB epidemics. The World Health Organization (WHO) estimated in 1999 that one-third of the world's population was latently infected with TB. In SA up to 88% of HIV-uninfected young adults (31 - 35 years) are latently infected with TB. In the most recent meta-analysis, 6 - 12 months of Isoniazid preventive therapy (IPT) was associated with a lower incidence of active TB than placebo (relative risk (RR) 0.68; 95% confidence interval (CI) 0.54 - 0.85), with the greatest benefit among individuals with a positive tuberculin skin test (TST) (RR 0.38; 95% CI 0.25 - 0.57). A clinical trial of IPT given with antiretroviral therapy (ART) for 12 months reduced TB incidence by 37% compared with ART alone (hazard ratio (HR) 0.63; 95% CI 0.41 - 0.94). The effect of IPT is limited in high-burden countries. IPT for 36 months v. 6 months reduced TB incidence among HIV-positive, TST-positive participants by 74% (HR 0.26; 95% CI 0.09 - 0.80). A study of more than 24 000 goldminers confirmed that IPT is safe, with only 0.5% experiencing adverse events. A meta-analysis of studies of IPT since 1951 did not show an increased risk of developing resistance. Alternative TB preventive therapy regimens, including high-dose Isoniazid and rifapentine given weekly for 3 months, have been shown to have similar efficacy to IPT. Mathematical modelling suggests that scaling up continuous IPT targeted to HIV-positive persons, when used in combination with other treatment and prevention strategies, may substantially improve TB control. |
| 2014 | The Case for Using Higher Doses of First Line Anti-Tuberculosis Drugs to Optimize Efficacy. | Curr Pharm Des | Apart from new anti-tuberculosis drug development, another approach for tuberculosis (TB) treatment optimization is to derive maximum benefit from current agents. However, the dosage of current anti-TB drug regimens has never been optimized according to the exposure-effect relationships of each drug. The objective of this article is to review the latest pharmacokinetic, pharmacodynamic, experimental, and clinical data concerning the use of higher doses of first-line anti-TB drugs to improve the efficacy of pulmonary tuberculosis treatment. Exposure-effect relationships have been described for all first-line anti-TB agents. There is convincing evidence that patients would benefit from higher rifamycin exposure. This could be achieved by using higher daily doses of rifampin, or more frequent dosing of rifapentine. The dose-dependent activity of pyrazinamide observed in hollow-fiber and animal models suggests that higher doses of pyrazimamide might be more efficacious, but the tolerability of such higher doses needs to be investigated in humans. It is likely that higher doses of ethambutol would be associated with higher antibacterial effect, but the dose-related ocular toxicity of the drug precludes such practice. For Isoniazid, dose individualization is required to optimize patient care. The use of higher than standard doses of Isoniazid in fast acetylators should result in greater early bactericidal activity. To conclude, the use of higher doses for some of the firstline anti-TB agents has definite potential for shortening or improving TB treatment. |
| 2014 | Update on latent tuberculosis infection. | Am Fam Physician | Latent tuberculosis infection refers to an asymptomatic, nontransmissible infection with Mycobacterium tuberculosis, carrying a 5% to 10% lifetime risk of progressing to active disease. One-half of this risk occurs within the first two years after infection. High-risk groups include recent immigrants from high-incidence countries, health care professionals, persons living or working in institutional settings, and homeless persons. Risk factors for progression to active disease include immunodeficiency, recent exposure to tuberculosis, and chronic kidney disease requiring dialysis. Tuberculin skin testing has several limitations, including the need for multiple office visits and the potential for false-positive results in patients who have received the bacillus Calmette-Guérin vaccine or been exposed to environmental mycobacteria. Interferon-gamma release assays address these deficiencies but are limited by their cost and requirement for blood processing. Interferon-gamma release assays are preferred in immigrants exposed to bacillus Calmette-Guérin and in patients who are not likely to return for interpretation of skin test results. Tuberculin skin testing is preferred for children younger than five years. Active disease should be excluded before initiating treatment. The newest treatment option of 12 weekly doses of Isoniazid and rifapentine has similar or better effectiveness than standard nine-month therapy with daily Isoniazid. A four-month regimen of daily rifampin is another alternative. |
| 2014 | Rifapentine Pharmacokinetics and Tolerability in Children and Adults Treated Once Weekly With Rifapentine and Isoniazid for Latent Tuberculosis Infection. | J Pediatric Infect Dis Soc | In a phase 3, randomized clinical trial (PREVENT TB) of 8053 people with latent tuberculosis infection, 12 once-weekly doses of rifapentine and Isoniazid had good efficacy and tolerability. Children received higher rifapentine milligram per kilogram doses than adults. In the present pharmacokinetic study (a component of the PREVENT TB trial), rifapentine exposure was compared between children and adults.Rifapentine doses in children ranged from 300 to 900 mg, and adults received 900 mg. Children who could not swallow tablets received crushed tablets. Sparse pharmacokinetic sampling was performed with 1 rifapentine concentration at 24 hours after drug administration (C24). Rifapentine area under concentration-time curve (AUC) was estimated from a nonlinear, mixed effects regression model (NLME).There were 80 children (age: median, 4.5 years; range, 2-11 years) and 77 adults (age: median, 40 years; all ≥18 years) in the study. The geometric mean rifapentine milligram per kilogram dose was greater in children than in adults (children, 23 mg/kg; adults, 11 mg/kg). Rifapentine geometric mean AUC and C24 were 1.3-fold greater in children (all children combined) than in adults. Children who swallowed whole tablets had 1.3-fold higher geometric mean AUC than children who received crushed tablets, and children who swallowed whole tablets had a 1.6-fold higher geometric mean AUC than adults. The higher rifapentine doses in children were well tolerated. To obtain rifapentine exposures comparable in children to adults, dosing algorithms modeled by NLME were developed.A 2-fold greater rifapentine dose for all children resulted in a 1.3-fold higher AUC compared to adults administered a standard dose. Use of higher weight-adjusted rifapentine doses for young children are warranted to achieve systemic exposures that are associated with successful treatment of latent tuberculosis infection in adults. |
| 2014 | Bedaquiline: a review of human pharmacokinetics and drug-drug interactions. | J Antimicrob Chemother | Bedaquiline has recently been approved for the treatment of pulmonary multidrug-resistant tuberculosis (TB) as part of combination therapy in adults. It is metabolized primarily by the cytochrome P450 isoenzyme 3A4 (CYP3A4) to a less-active N-monodesmethyl metabolite. Phase I and Phase II studies in healthy subjects and patients with drug-susceptible or multidrug-resistant TB have assessed the pharmacokinetics and drug-drug interaction profile of bedaquiline. Potential interactions have been assessed between bedaquiline and first- and second-line anti-TB drugs (rifampicin, rifapentine, Isoniazid, pyrazinamide, ethambutol, kanamycin, ofloxacin and cycloserine), commonly used antiretroviral agents (lopinavir/ritonavir, nevirapine and efavirenz) and a potent CYP3A inhibitor (ketoconazole). This review summarizes the pharmacokinetic profile of bedaquiline as well as the results of the drug-drug interaction studies. |
| 2014 | Ability of preventive therapy to cure latent Mycobacterium tuberculosis infection in HIV-infected individuals in high-burden settings. | Proc Natl Acad Sci U S A | Trials of Isoniazid preventive therapy (IPT) for people living with HIV in southern Africa have shown high rates of tuberculosis disease immediately after cessation of therapy. This could be due to the lack of cure following preventive therapy or reinfection with rapid progression to disease. Using a model fitted to trial data, we estimate the degree to which preventive therapies cure latent Mycobacterium tuberculosis infection in HIV-infected individuals in high-tuberculosis-burden settings. We identified randomized controlled trials that compared IPT to placebo or alternative regimen in HIV-positive, tuberculin skin test positive individuals. A mathematical model describing tuberculosis transmission in a closed cohort of HIV-positive, M. tuberculosis infected, antiretroviral therapy naive individuals following completion of preventive therapy (or placebo) was fitted to posttherapy tuberculosis rates to estimate the annual risk of M. tuberculosis reinfection and the proportion of individuals whose latent infection was cured after therapy. Three trials met our inclusion criteria. Estimated annual risks of reinfection ranged between 3.7 and 4.9%. Our results suggest 6 mo of Isoniazid cured in a small proportion [estimated proportion cured = 0% (interquartile range 0-30.9%)]. The proportion cured for 3-mo regimens containing rifampicin or rifapentine was 19-100%. IPT alone does not cure existing infections in the majority of HIV-infected individuals. In high-incidence settings, continuous IPT should be integrated with HIV care. Where the risk of reinfection is lower, preventive therapy with more curative drugs should be preferred for HIV-positive individuals to achieve durable patient benefit. |
| 2014 | Old and new approaches to diagnosing and treating latent tuberculosis in children in low-incidence countries. | Curr Opin Pediatr | The primary purpose is to review guidance on the testing and treatment of latent tuberculosis infection (LTBI) in children. Most children and adults with LTBI have positive tuberculin skin test (TST) or interferon gamma release assay (IGRA) results, normal examinations, and normal chest radiographs. Diagnosis of and treatment completion for LTBI are critical to diminish future cases of tuberculosis (TB) disease.Children should be screened for TB risk factors, and only children with risk factors should be tested with either a TST or an IGRA. IGRAs measure interferon gamma production by lymphocytes after they are stimulated ex vivo by antigens that are primarily Mycobacterium tuberculosis-specific. The foundation of LTBI therapy in the United States has been 9 months of daily Isoniazid, but shorter treatment regimens now exist, including a 12-dose regimen of weekly Isoniazid and rifapentine. These shorter regimens are associated with higher completion rates.There are two distinct modalities for LTBI diagnosis and several treatment regimens that can prevent TB disease in infected children. The selection of treatment regimen should take several factors into consideration, including adherence, drug susceptibility results of the presumed source case (if known), safety, cost, and patient preference. |
| 2013 | Cost-effectiveness of a 12-dose regimen for treating latent tuberculous infection in the United States. | Int J Tuberc Lung Dis | A large randomized controlled trial recently showed that for treating latent tuberculous infection (LTBI) in persons at high risk of progression to tuberculosis (TB) disease, a 12-dose regimen of weekly rifapentine plus Isoniazid (3HP) administered as directly observed treatment (DOT) can be as effective as 9 months of daily self-administered Isoniazid (9H).To assess the cost-effectiveness of 3HP compared to 9H.A computational model was designed to simulate individuals with LTBI treated with 9H or 3HP. Costs and health outcomes were estimated to determine the incremental costs per active TB case prevented and per quality-adjusted life year (QALY) gained by 3HP compared to 9H.Over a 20-year period, treatment of LTBI with 3HP rather than 9H resulted in 5.2 fewer cases of TB and 25 fewer lost QALYs per 1000 individuals treated. From the health system and societal perspectives, 3HP would cost respectively US$21,525 and $4294 more per TB case prevented, and respectively $4565 and $911 more per QALY gained.3HP may be a cost-effective alternative to 9H, particularly if the cost of rifapentine decreases, the effectiveness of 3HP can be maintained without DOT, and 3HP treatment is limited to those with a high risk of progression to TB disease. |
| 2014 | Short-course isoniazid plus rifapentine directly observed therapy for latent tuberculosis in solid-organ transplant candidates. | Transplantation | Short-course directly observed Isoniazid plus rifapentine (INH/RPT) combination could have potential advantages over a standard 9-month INH regimen for the treatment of latent tuberculosis infection in solid-organ transplant (SOT) candidates.We prospectively assessed the safety and tolerability of 12 weeks of INH/RPT given directly observed therapy in 17 consecutive SOT candidates with latent tuberculosis infection.The median age was 57 years and 82% were men. Of the 17 patients, 13 (76%) successfully completed therapy and 4 (24%) eventually underwent SOT. Treatment was prematurely discontinued in four patients. One of these patients underwent a kidney transplant. The overall dose compliance was 83% (169/204 scheduled doses), and 12 (71%) of 17 patients received 100% of scheduled doses. No patient developed transaminase elevations greater than twice baseline or greater than four times the upper limit of normal or clinical hepatotoxicity. No cases of TB developed during 20.4 months after transplant among INH/RPT-treated recipients.For carefully selected SOT candidates, combination INH/RPT weekly given as directly observed therapy seems to be reasonably well tolerated and is associated with a relatively high completion rate. Future larger prospective studies to confirm the safety and high completion rates reported here and to identify the most appropriate SOT candidates for this regimen are warranted. |
| 2013 | Pipeline of drugs for related diseases: tuberculosis. | Curr Opin HIV AIDS | For the first time in decades, there are multiple new drugs in the pipeline for the treatment of tuberculosis (TB). In addition, existing drugs are being repurposed or optimized for TB with the goal of shortened treatment duration for drug-sensitive TB and safer, shorter treatments for multidrug-resistant (MDR) TB. In this review, the results of recent trials evaluating novel combination regimens for TB disease and latent TB infection are described.High-dose rifamycins (rifampin and rifapentine) and fluoroquinolones directly observed have treatment-shortening potential when used for drug-sensitive TB disease, and a 12-dose once-weekly regimen of rifapentine along with Isoniazid effectively treats latent TB. Bedaquiline, an anti-TB drug with a novel mechanism of action, and delamanid, a nitroimidazole, are entering phase 3 trials. Both improve rates of sputum culture conversion among patients with MDR-TB. Other nitroimidazoles and oxazolidinones are in Phase 2 testing, as are combinations involving multiple new chemical entities.With the resurgence of anti-TB drug discovery efforts, we now have a modestly robust pipeline of new anti-TB drugs. Several promising new regimens involving investigational and existing drugs that may be capable of shortening treatment for drug-sensitive TB and improving management of drug-resistant TB are in late-phase clinical evaluation. |
| 2013 | Transmission of Mycobacterium tuberculosis in a High School and School-Based Supervision of an Isoniazid-Rifapentine Regimen for Preventing Tuberculosis - Colorado, 2011-2012. | MMWR Morb Mortal Wkly Rep | Mycobacterium tuberculosis, the bacterium that causes tuberculosis (TB), is spread from person to person by the airborne route. It can be transmitted extensively in congregate settings, making investigating exposures and treating infected contacts challenging. In December 2011, a student at a Colorado high school with 1,381 students and school personnel received a diagnosis of pulmonary TB disease. One of five household contacts had TB disease, and the other four had latent M. tuberculosis infection (LTBI). Screening of 1,249 school contacts (90%) found one person with pulmonary TB disease, who was fully treated, and 162 with LTBI, of whom 159 started an LTBI treatment regimen for preventing progression to TB disease and 153 completed a regimen. Only the index patient required inpatient care for TB, and TB caused no deaths. Use of short-course treatment regimens, either 12-dose weekly Isoniazid and rifapentine directly observed at school or 4 months of self-supervised rifampin daily, facilitated treatment completion. State and county incident command structures led by county TB control authorities guided a response team from multiple jurisdictions. News media reports brought public scrutiny, but meetings with the community addressed the concerns and enhanced public participation. Two contacts of the index patient outside of the school had TB disease diagnosed after the school investigation. As of July 2013, no additional TB disease associated with in-school exposure had been found. An emergency plan for focusing widespread resources, an integral public communications strategy, and new, efficient interventions should be considered in other large TB contact investigations. |
| 2013 | Treatment of latent tuberculosis infection. | Ther Adv Respir Dis | Treatment of latent tuberculosis (TB) infection is an important component of TB control programs in both high- and low-prevalence countries. Clinical trials of treatment of latent TB conducted over several decades have demonstrated that preventive treatment can reduce the risk of developing active TB up to 90%. Although 9 months of daily, self-administered Isoniazid has been the most widely used and recommended regimen for the treatment of latent infection, other regimens such as 3 months of daily Isoniazid and rifampin, or 4 months of daily rifampin alone have also been recommended and used. Most recently, a 12-dose regimen of once-weekly Isoniazid and rifapentine has been shown to be noninferior to 9 months of daily Isoniazid in a large and well conducted clinical trial. Adoption of such a regimen on a large scale could have significant implications for TB elimination efforts. |
| 2013 | Treatment of Latent Tuberculosis Infection in Children. | J Pediatric Infect Dis Soc | Treatment of latent tuberculosis infection (LTBI) is an effective way of preventing future cases of tuberculosis disease. We review pediatric and adult studies of LTBI treatment (Isoniazid and rifampin monotherapy, Isoniazid plus rifampin, Isoniazid plus rifapentine, and rifampin plus pyrazinamide). Based upon this review and our pediatric experience, we can offer recommendations for routine (Isoniazid) and alternative courses of therapy. |
| 2013 | Rifamycins (rifampicin, rifabutin and rifapentine) compared to isoniazid for preventing tuberculosis in HIV-negative people at risk of active TB. | Cochrane Database Syst Rev | Preventing active tuberculosis (TB) from developing in people with latent tuberculosis infection (LTBI) is important for global TB control. Isoniazid (INH) for six to nine months has 60% to 90% protective efficacy, but the treatment period is long, liver toxicity is a problem, and completion rates outside trials are only around 50%. Rifampicin or rifamycin-combination treatments are shorter and may result in higher completion rates.To compare the effects of rifampicin monotherapy or rifamycin-combination therapy versus INH monotherapy for preventing active TB in HIV-negative people at risk of developing active TB.We searched the Cochrane Infectious Disease Group Specialized Register; Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE; EMBASE; LILACS; clinical trials registries; regional databases; conference proceedings; and references, without language restrictions to December 2012; and contacted experts for relevant published, unpublished and ongoing trials.Randomized controlled trials (RCTs) of HIV-negative adults and children at risk of active TB treated with rifampicin, or rifamycin-combination therapy with or without INH (any dose or duration), compared with INH for six to nine months.At least two authors independently screened and selected trials, assessed risk of bias, and extracted data. We sought clarifications from trial authors. We pooled relative risks (RRs) with their 95% confidence intervals (CIs), using a random-effects model if heterogeneity was significant. We assessed overall evidence quality using the GRADE approach.Ten trials are included, enrolling 10,717 adults and children, mostly HIV-negative (2% HIV-positive), with a follow-up period ranging from two to five years. Rifampicin (three/four months) vs. INH (six months)Five trials published between 1992 to 2012 compared these regimens, and one small 1992 trial in adults with silicosis did not detect a difference in the occurrence of TB over five years of follow up (one trial, 312 participants; very low quality evidence). However, more people in these trials completed the shorter course (RR 1.19, 95% CI 1.01 to 1.30; five trials, 1768 participants; moderate quality evidence). Treatment-limiting adverse events were not significantly different (four trials, 1674 participants; very low quality evidence), but rifampicin caused less hepatotoxicity (RR 0.12, 95% CI 0.05 to 0.30; four trials, 1674 participants; moderate quality evidence). Rifampicin plus INH (three months) vs. INH (six months)The 1992 silicosis trial did not detect a difference between people receiving rifampicin plus INH compared to INH alone for occurrence of active TB (one trial, 328 participants; very low quality evidence). Adherence was similar in this and a 1998 trial in people without silicosis (two trials, 524 participants; high quality evidence). No difference was detected for treatment-limiting adverse events (two trials, 536 participants; low quality evidence), or hepatotoxicity (two trials, 536 participants; low quality evidence). Rifampicin plus pyrazinamide (two months) vs. INH (six months)Three small trials published in 1994, 2003, and 2005 compared these two regimens, and two reported a low occurrence of active TB, with no statistically significant differences between treatment regimens (two trials, 176 participants; very low quality evidence) though, apart from one child from the 1994 trial, these data on active TB were from the 2003 trial in adults with silicosis. Adherence with both regimens was low with no statistically significant differences (four trials, 700 participants; very low quality evidence). However, people receiving rifampicin plus pyrazinamide had more treatment-limiting adverse events (RR 3.61, 95% CI 1.82 to 7.19; two trials, 368 participants; high quality evidence), and hepatotoxicity (RR 4.59, 95% 2.14 to 9.85; three trials, 540 participants; moderate quality evidence). Weekly, directly-observed rifapentine plus INH (three months) vs. daily, self-administered INH (nine months)A large trial conducted from 2001 to 2008 among close contacts of TB in the USA, Canada, Brazil and Spain found directly observed weekly treatment to be non-inferior to nine months self-administered INH for the incidence of active TB (0.2% vs 0.4%, RR 0.44, 95% CI 0.18 to 1.07, one trial, 7731 participants; moderate quality evidence). The directly-observed, shorter regimen had higher treatment completion (82% vs 69%, RR 1.19, 95% CI 1.16 to 1.22, moderate quality evidence), and less hepatotoxicity (0.4% versus 2.4%; RR 0.16, 95% CI 0.10 to 0.27; high quality evidence), though treatment-limiting adverse events were more frequent (4.9% versus 3.7%; RR 1.32, 95% CI 1.07 to 1.64 moderate quality evidence)Trials to date of shortened prophylactic regimens using rifampicin alone have not demonstrated higher rates of active TB when compared to longer regimens with INH. Treatment completion is probably higher and adverse events may be fewer with shorter rifampicin regimens. Shortened regimens of rifampicin with INH may offer no advantage over longer INH regimens. Rifampicin combined with pyrazinamide is associated with more adverse events. A weekly regimen of rifapentine plus INH has higher completion rates, and less liver toxicity, though treatment discontinuation due to adverse events is probably more likely than with INH. |
| 2013 | Good response of malignant pleural effusion from carcinoma of unknown primary site to the anti-tuberculosis therapy: a case report. | Int J Clin Exp Pathol | Malignant pleural effusion in patients with cancers or malignant pleural mesothelioma may often appear at the late stage of disease and significantly affect the patients' life quality and survival. However, there is still no very effective treatment to control malignant pleural effusion. Here we report that malignant pleural effusion in one patient was completely relieved for 15 months by the anti-tuberculosis therapy.A 54-year-old female patient complained of cough, dyspnea, chest pain, night sweat and light fever in the afternoon. Computed tomography (CT) of the chest revealed bilateral pleural effusion. But no tumor was found in the lung, pleura and in other sites. Blood test revealed serum carcinoembryonic antigen (CEA) level at 300 ng/mL. One week after we tried anti-tuberculosis combined therapy with Isoniazid, pyrazinamide, rifapentine and ethambutol. The pleural effusion in patient was eliminated, along with decreasing CEA. But the CEA increased gradually again when the anti-tuberculosis treatment was forced to discontinuation. Sixteen months after anti-tuberculosis treatment, the symptoms of cough and breathing difficulty relapsed. Chest CT revealed left pleural effusion, pleural thickness and pericardium nodules. Thoracoscopy and biopsy were conducted. The pleural nodules specimen was pathologically diagnosed as squamous cell carcinoma.We reported a rare case of successfully treating malignant pleural effusion caused by squamous cell carcinoma of unknown primary site with the anti-tuberculosis combined. This report provides useful evidences for that the anti-tubercular agents may have potential anticancer activity in some carcinomas. |
| 2012 | Current management options for latent tuberculosis: a review. | Infect Drug Resist | Tuberculosis remains the world's second leading infectious cause of death, with nearly one-third of the global population latently infected. Treatment of latent tuberculosis infection is a mainstay of tuberculosis-control efforts in low-to medium-incidence countries. Isoniazid monotherapy has been the standard of care for decades, but its utility is impaired by poor completion rates. However, new, shorter-course regimens using rifamycins improve completion rates and are cost-saving compared with standard Isoniazid monotherapy. We review the currently available therapies for latent tuberculosis infection and their toxicities and include a brief economic comparison of the different regimens. |
| 2012 | Substitution of rifapentine for rifampin during intensive phase treatment of pulmonary tuberculosis: study 29 of the tuberculosis trials consortium. | J Infect Dis | Rifapentine administered 5 days per week has potent activity in mouse models of antituberculosis chemotherapy, but efficacy and safety data are limited in humans. We compared the antimicrobial activity and safety of rifapentine vs rifampin during the first 8 weeks of pulmonary tuberculosis treatment.In total, 531 adults with sputum smear-positive pulmonary tuberculosis were randomized to rifapentine 10 mg/kg/dose or rifampin 10 mg/kg/dose, administered 5 days per week for 8 weeks (intensive phase), with Isoniazid, pyrazinamide, and ethambutol. Coprimary outcomes were negative sputum culture on liquid and on solid media at completion of intensive phase.Negative cultures on solid media occurred in 145 of 174 participants (83.3%) in the rifampin group and 171 of 198 participants (86.4%) in the rifapentine group (difference, 3.0%; 95% confidence interval [CI]: -4.3, 10.5); negative cultures in liquid media occurred in 110 of 169 (65.1%) in the rifampin group and 133 of 196 (67.9%) in the rifapentine group (difference, 2.8%; 95% CI: -6.9, 12.4). Among 529 participants who received study therapy, 40 of 254 participants (15.7%) in the rifampin group and 40 of 275 participants (14.5%) in the rifapentine group prematurely discontinued treatment (P=.79).The rifapentine regimen was safe but not significantly more active than a standard rifampin regimen, by the surrogate endpoint of culture status at completion of intensive phase. Assessment of higher exposures to rifapentine for tuberculosis treatment is warranted.NCT00694629. |
| 2012 | Pharmacokinetic/pharmacodynamic parameters and the choice of high-dosage rifamycins. | Int J Tuberc Lung Dis | Clinical trials and the behaviour of bacterial persisters.To explain why the efficacies of Isoniazid (INH) and rifamycins during the treatment of tuberculosis (TB) are related not to the area under the curve (AUC)/minimum inhibitory concentration (MIC), but to peak drug concentrations.We examined the response in clinical trials with patients treated with INH alone and divided into slow and rapid acetylators of INH.The efficacy of INH is best related to peak concentrations, as repeated peaks can kill low-degree resistant mutants. A similar process might result in repeated peak concentrations of rifamycins killing low-tolerance persisters.If the efficacy of rifamycins is best related to peak concentrations, we can explain the discrepancy between mouse studies on daily rifapentine (RPT) and the failure to accelerate elimination of TB from sputum in the TBTC Study 29A, as daily RPT greatly increases the AUC but not the peak concentrations. High dosage rifampicin may be better able than RPT to cause high peaks. |
| 2012 | Dose-ranging comparison of rifampin and rifapentine in two pathologically distinct murine models of tuberculosis. | Antimicrob Agents Chemother | In previous experiments, replacing the 10-mg/kg of body weight daily dose of rifampin with 7.5 to 10 mg/kg of rifapentine in combinations containing Isoniazid and pyrazinamide reduced the duration of treatment needed to cure tuberculosis in BALB/c mice by approximately 50% due to rifapentine's more potent activity and greater drug exposures obtained. In the present study, we performed dose-ranging comparisons of the bactericidal and sterilizing activities of rifampin and rifapentine, alone and in combination with Isoniazid and pyrazinamide with or without ethambutol, in BALB/c mice and in C3HeB/FeJ mice, which develop necrotic lung granulomas after infection with Mycobacterium tuberculosis. Each rifamycin demonstrated a significant increase in sterilizing activity with increasing dose. Rifapentine was roughly 4 times more potent in both mouse strains. These results reinforce the rationale for ongoing clinical trials to ascertain the highest well-tolerated doses of rifampin and rifapentine. This study also provides an important benchmark for the efficacy of the first-line regimen in C3HeB/FeJ mice, a strain in which the lung lesions observed after M. tuberculosis infection may better represent the pathology of human tuberculosis. |
| 2012 | Treatment of latent tuberculosis infection in HIV: shorter or longer? | Curr HIV/AIDS Rep | Nine months of daily Isoniazid is efficacious in treating latent M. tuberculosis infection, but completion rates are low, limiting treatment effectiveness. In 2011, three important studies were published involving novel regimens for the treatment of latent M. tuberculosis infection. At least 36 months of Isoniazid was more effective than 6 months of Isoniazid in one study, but not in another-both of which were conducted among tuberculin skin test positive HIV-infected adults living in high tuberculosis incidence settings. Three months of once-weekly Isoniazid plus rifapentine or twice-weekly Isoniazid plus rifampin (both given under direct observation) resulted in tuberculosis rates similar to those seen with 6 months of Isoniazid among HIV-infected persons in high tuberculosis incidence settings. Three months of once-weekly, directly-observed Isoniazid plus rifapentine was at least as effective as 9 months of daily Isoniazid among predominantly HIV-uninfected persons living in low and medium tuberculosis incidence countries. The 3-month once-weekly Isoniazid plus rifapentine regimen demonstrates promise for treatment of latent M. tuberculosis infection in HIV-infected persons. |
| 2012 | Rifapentine is not more active than rifampin against chronic tuberculosis in guinea pigs. | Antimicrob Agents Chemother | Rifamycins are key sterilizing drugs in the current treatment of active tuberculosis (TB). Daily dosing of rifapentine (P), a potent rifamycin with high intracellular accumulation, in place of rifampin (R) in the standard antitubercular regimen significantly shortens the duration of treatment needed to prevent relapse in a murine model of active TB. We undertook the current study to compare directly the activities of human-equivalent doses of P and R in a guinea pig model of chronic TB, in which bacilli are predominantly extracellular within human-like necrotic granulomas. Hartley strain guinea pigs were aerosol infected with ~200 bacilli of Mycobacterium tuberculosis H37Rv, and treatment given 5 days/week was initiated 6 weeks later. R at 100 mg/kg of body weight and P at 100 mg/kg were given orally alone or in combination with Isoniazid (H) at 60 mg/kg and pyrazinamide (Z) at 300 mg/kg. Culture-positive relapse was assessed in subgroups of guinea pigs after completion of 1 and 2 months of treatment. Human-equivalent doses of R and P showed equivalent bactericidal activity when used alone and in combination therapy. In guinea pigs treated with rifampin, Isoniazid, and pyrazinamide (RHZ) or PHZ, microbiological relapse occurred in the lungs of 8/10 animals treated for 1 month and in 0/10 animals treated for 2 months. Substitution of P for R in the standard antitubercular regimen did not shorten the time to cure in this guinea pig model of chronic TB. Data from ongoing clinical trials comparing the activity of these two drugs are awaited to determine the relevance of the guinea pig TB model in preclinical drug screening. |
| 2012 | Sterilizing activities of novel combinations lacking first- and second-line drugs in a murine model of tuberculosis. | Antimicrob Agents Chemother | Novel oral regimens composed of new drugs with potent activity against Mycobacterium tuberculosis and no cross-resistance with existing agents are needed to shorten and simplify treatment for both drug-susceptible and drug-resistant tuberculosis. As part of a continuing effort to evaluate novel drug combinations for treatment-shortening potential in a murine model, we performed two long-term, relapse-based experiments. In the first experiment, several 3- and 4-drug combinations containing new agents currently in phase 2/3 trials (TMC207 [bedaquiline], PA-824 and PNU-100480 [sutezolid], and/or clofazimine) proved superior to the first-line regimen of rifampin, pyrazinamide, and Isoniazid. TMC207 plus PNU-100480 was the most effective drug pair. In the second experiment, in which 3- and 4-drug combinations composed of TMC207 and pyrazinamide plus rifapentine, clofazimine, PNU-100480, or both rifapentine and clofazimine were evaluated, the rank order of drugs improving the sterilizing activity of TMC207 and pyrazinamide was as follows: rifapentine plus clofazimine ≥ clofazimine ≥ rifapentine > PNU-100480. The results revealed potential new building blocks for universally active short-course regimens for drug-resistant tuberculosis. The inclusion of pyrazinamide against susceptible isolates may shorten the duration of treatment further. |
| 2012 | Drugs for tuberculosis. | Treat Guidel Med Lett | The standard treatment for latent tuberculosis is nine months of Isoniazid taken daily, or twice weekly under direct observation by a healthcare worker. Taking Isoniazid and rifapentine once weekly for 12 weeks under direct observation is an alternative for patients >12 years old. Initial therapy for patients with active or suspected tuberculosis should include Isoniazid, rifampin,pyrazinamide and ethambutol until susceptibility is known. In patients with drug-susceptible pulmonary tuberculosis, the continuation phase of treatment should be a combination of Isoniazid and either rifampin or rifapentine, taken for 4 or 7 months depending on risk factors. Confirmed multidrug-resistant tuberculosis or extensively drug-resistant tuberculosis should be treated with directly observed therapy in collaboration with a clinician familiar with management of these conditions. Treatment must include at least 4 drugs to which the organism is susceptible; the duration of therapy should usually be 18-24 months. Directly observed therapy by a healthcare worker should be offered to all patients with active tuberculosis to minimize treatment failure, relapse and the emergence of drug resistance. |
| 2012 | Tuberculosis outbreak associated with a homeless shelter - Kane County, Illinois, 2007-2011. | MMWR Morb Mortal Wkly Rep | Despite the overall decline in tuberculosis (TB) incidence in the United States to a record low, outbreaks of TB among homeless persons continue to challenge TB control efforts. In January 2010, public health officials recognized an outbreak of TB after three overnight guests at a homeless shelter in Illinois received diagnoses of TB disease caused by Mycobacterium tuberculosis isolates with matching genotype patterns. As of September 2011, a total of 28 outbreak-associated cases involving shelter guests, dating back to 2007, had been recognized, indicating ongoing M. tuberculosis transmission. The subsequent investigation found that all patients were homeless and had been overnight shelter guests. Excess alcohol use was common (82%), and two bars emerged as additional sites of potential transmission. Patients with outbreak-associated TB were treated successfully for TB disease. To prevent future cases of TB, public health officials are implementing a program to offer 12 once-weekly doses of Isoniazid and rifapentine under direct observation for treatment of latent tuberculosis infection (LTBI) in this high-risk population. Although the United States has made progress toward TB elimination, this outbreak demonstrates the vulnerability of homeless persons to outbreaks of TB, highlighting the need for aggressive and sustained TB control efforts. |
| [Present and future in the use of anti-tubercular drugs]. | Pneumologia | After several decades without any notable progress, there are encouraging results in research and development of anti-TB drugs, the result of a large number of projects now in competition. Along with developing new drugs to treat tuberculosis (TMC207, SQ109, LL3858) are being reassessed others to optimize their effectiveness in order to shorten and simplify therapy (rifampin and rifapentine) and three other drugs, currently used for other indications, were forwarded towards TB (gatifloxacin and moxifloxacin, linezolid). Time to approval as a antiTB drug is 10-15 years, consisting of phases of preclinical and clinical research. Substitution of moxifloxacin for Isoniazid during intensive phase treatment of pulmonary tuberculosis resulted in a small but statistically nonsignificant increase in 8th- week culture negativity. TMC207, a diarylquinoline with a unique way to address Mycobacterial ATP synthetase, shows high activity in vitro against Mycobacterial strains sensitive or resistant to all drugs in the first and second line, including fluoroquinolones, demonstrating exceptional qualities in vivo against several species of mycobacteria, in various animal models. TMC207 was added to a basic standard regimen in a study of MDR-TB patients. After two months and satisfactory tolerability, sputum conversion rate in culture was 48% (versus 9% in the placebo group). Two nitroimidazole (PA-824 and OPC-67683) are currently in clinical development. PA-824 demonstrated good safety and tolerability in adult patients with pulmonary TB in South Africa, when given once daily for 7 days. Associating Isoniazid, would prevent the selection of mutants resistant to Isoniazid. Linezolid 600 mg is currently being tested in a Phase II for treatment of XDR-TB in the Republic of Korea. PNU-100480, analogous to the previous one, has the potential to significantly shorten the treatment in cases where there is sensitivity and in those with resistance to drugs. 300 mg dose is under investigation in a phase II pilot study in MDR-TB in South Africa. With this interest and commitment, it appears that there is a chance of having a new drug available soon. |
| 2011 | Recommendations for use of an isoniazid-rifapentine regimen with direct observation to treat latent Mycobacterium tuberculosis infection. | MMWR Morb Mortal Wkly Rep | Preventing tuberculosis (TB) by treating latent Mycobacterium tuberculosis infection (LTBI) is a cornerstone of the U.S. strategy for TB elimination. Three randomized controlled trials have shown that a new combination regimen of Isoniazid (INH) and rifapentine (RPT) administered weekly for 12 weeks as directly observed therapy (DOT) is as effective for preventing TB as other regimens and is more likely to be completed than the U.S. standard regimen of 9 months of INH daily without DOT. This report provides CDC recommendations for using the INH-RPT regimen. The new regimen is recommended as an equal alternative to the 9-month INH regimen for otherwise healthy patients aged≥12 years who have LTBI and factors that are predictive of TB developing (e.g., recent exposure to contagious TB). The new regimen also can be considered for other categories of patients when it offers practical advantages. Although the INH-RPT regimen was well tolerated in treatment trials, monitoring for adverse effects is recommended. Severe adverse effects should be reported to the Food and Drug Administration (FDA) and CDC. |
| 2011 | Three months of rifapentine and isoniazid for latent tuberculosis infection. | N Engl J Med | Treatment of latent Mycobacterium tuberculosis infection is an essential component of tuberculosis control and elimination. The current standard regimen of Isoniazid for 9 months is efficacious but is limited by toxicity and low rates of treatment completion.We conducted an open-label, randomized noninferiority trial comparing 3 months of directly observed once-weekly therapy with rifapentine (900 mg) plus Isoniazid (900 mg) (combination-therapy group) with 9 months of self-administered daily Isoniazid (300 mg) (Isoniazid-only group) in subjects at high risk for tuberculosis. Subjects were enrolled from the United States, Canada, Brazil, and Spain and followed for 33 months. The primary end point was confirmed tuberculosis, and the noninferiority margin was 0.75%.In the modified intention-to-treat analysis, tuberculosis developed in 7 of 3986 subjects in the combination-therapy group (cumulative rate, 0.19%) and in 15 of 3745 subjects in the Isoniazid-only group (cumulative rate, 0.43%), for a difference of 0.24 percentage points. Rates of treatment completion were 82.1% in the combination-therapy group and 69.0% in the Isoniazid-only group (P<0.001). Rates of permanent drug discontinuation owing to an adverse event were 4.9% in the combination-therapy group and 3.7% in the Isoniazid-only group (P=0.009). Rates of investigator-assessed drug-related hepatotoxicity were 0.4% and 2.7%, respectively (P<0.001).The use of rifapentine plus Isoniazid for 3 months was as effective as 9 months of Isoniazid alone in preventing tuberculosis and had a higher treatment-completion rate. Long-term safety monitoring will be important. (Funded by the Centers for Disease Control and Prevention; PREVENT TB ClinicalTrials.gov number, NCT00023452.). |
| 2011 | Penetration of anti-infective agents into pulmonary epithelial lining fluid: focus on antifungal, antitubercular and miscellaneous anti-infective agents. | Clin Pharmacokinet | Epithelial lining fluid (ELF) is often considered to be the site of extracellular pulmonary infections. During the past 25 years, a limited number of studies have evaluated the intrapulmonary penetration of antifungal, antitubercular, antiparasitic and antiviral agents. For antifungal agents, differences in drug concentrations in ELF or bronchoalveolar lavage (BAL) fluid were observed among various formulations or routes of administration, and between agents within the same class. Aerosolized doses of deoxycholate amphotericin B, liposomal amphotericin B and amphotericin B lipid complex resulted in higher concentrations in ELF or BAL fluid than after intravenous administration. The mean concentrations in ELF following intravenous administration of both anidulafungin and micafungin ranged between 0.04 and 1.38 μg/mL, and the ELF to plasma concentration ratios (based on the area under the concentration-time curve for total drug concentrations) were between 0.18 and 0.22 during the first 3 days of therapy. Among the azole agents, intravenous administration of voriconazole resulted in the highest mean ELF concentrations (range 10.1-48.3 μg/mL) and ratio of penetration (7.1). The range of mean ELF concentrations of itraconazole and posaconazole following oral administration was 0.2-1.9 μg/mL, and the ELF to plasma concentration ratios were <1. A series of studies have evaluated the intrapulmonary penetration of first- and second-line oral antitubercular agents in healthy adult subjects and patients with AIDS. The ELF to plasma concentration ratio was >1 for Isoniazid, ethambutol, pyrazinamide and ethionamide. For rifampicin (rifampin) and rifapentine, the ELF to plasma concentration ratio ranged between 0.2 and 0.32, but in alveolar macrophages the concentration of rifampicin was much higher (145-738 μg/mL compared with 3.3-7.5 μg/mL in ELF). No intrapulmonary studies have been conducted for rifabutin. Sex, AIDS status or smoking history had no significant effects on the magnitude of ELF concentrations of antitubercular agents. Subjects who were slow acetylators had higher plasma and ELF concentrations of Isoniazid than those who were fast acetylators. Penetration of dapsone into ELF was very good, with the range of mean ELF to plasma concentration ratios being 0.65-2.91 at individual sampling times over 48 hours. Once-daily dosing of aerosolized pentamidine resulted in higher concentrations in BAL fluid than after intravenous administration. The mean BAL concentrations at 15-32 days after once- or twice-monthly administration of aerosolized pentamidine 300 and 600 mg ranged from 6.5 to 28.4 ng/mL. No differences in pentamidine BAL concentrations were observed in symptomatic patients who developed Pneumocystis jirovecii pneumonia compared with patients who did not. Zanamivir concentrations in ELF were similar in magnitude (range 141-326 ng/mL) following administration by continuous intravenous infusion (3 mg/hour), oral inhalation (10 mg every 12 hours) and intravenous bolus (200 mg every 12 hours). Data from case reports have suggested that concentrations of nelfinavir and saquinavir in ELF are undetectable, whereas tipranavir and lopinavir had measureable ELF concentrations (2.20 μmol/L and 14.4 μg/mL, respectively) when these protease inhibitors were co-administrated with ritonavir. While the clinical significance of ELF or BAL concentrations remains unknown for this group of anti-infective agents, the knowledge of drug penetration into the extracellular space of the lung should assist in re-evaluating and designing specific dosing regimens for use against potential pathogens. |
| 2011 | Sterilizing activity of novel TMC207- and PA-824-containing regimens in a murine model of tuberculosis. | Antimicrob Agents Chemother | To truly transform the landscape of tuberculosis treatment, novel regimens containing at least 2 new drugs are needed to simplify the treatment of both drug-susceptible and drug-resistant forms of tuberculosis. As part of an ongoing effort to evaluate novel drug combinations for treatment-shortening potential in a murine model, we performed two long-term, relapse-based experiments. In the first experiment, TMC207 plus pyrazinamide, alone or in combination with any third drug, proved superior to the first-line regimen including rifampin, pyrazinamide, and Isoniazid. On the basis of CFU counts at 1 month, clofazimine proved to be the best third drug combined with TMC207 and pyrazinamide, whereas the addition of PA-824 was modestly antagonistic. Relapse results were inconclusive due to the low rate of relapse in all test groups. In the second experiment evaluating 3-drug combinations composed of TMC207, pyrazinamide, PA-824, moxifloxacin, and rifapentine, TMC207 plus pyrazinamide plus either rifapentine or moxifloxacin was the most effective, curing 100% and 67% of the mice treated, respectively, in 2 months of treatment. Four months of the first-line regimen did not cure any mice, whereas the combination of TMC207, PA-824, and moxifloxacin cured 50% of the mice treated. The results reveal new building blocks for novel regimens with the potential to shorten the duration of treatment for both drug-susceptible and drug-resistant tuberculosis, including the combination of TMC207, pyrazinamide, PA-824, and a potent fluoroquinolone. |
| 2011 | Potential economic viability of two proposed rifapentine-based regimens for treatment of latent tuberculosis infection. | PLoS One | Rifapentine-based regimens for treating latent tuberculosis infection (LTBI) are being considered for future clinical trials, but even if they prove effective, high drug costs may limit their economic viability.To inform clinical trial design by estimating the potential costs and effectiveness of rifapentine-based regimens for treatment of latent tuberculosis infection (LTBI).We used a Markov model to estimate cost and societal benefits for three regimens for treating LTBI: Isoniazid/rifapentine daily for one month, Isoniazid/rifapentine weekly for three months (self-administered and directly-observed), and Isoniazid daily for nine months; a strategy of "no treatment" used for comparison. Costs, quality-adjusted life-years gained, and instances of active tuberculosis averted were calculated for all arms.Both daily Isoniazid/rifapentine for one month and weekly Isoniazid/rifapentine for three months were less expensive and more effective than other strategies under a wide variety of clinically plausibly parameter estimates. Daily Isoniazid/rifapentine for one month was the least expensive and most effective regimen.Daily Isoniazid/rifapentine for one month and weekly Isoniazid/rifapentine for three months should be studied in a large-scale clinical trial for efficacy. Because both regimens performed well even if their efficacy is somewhat reduced, study designers should consider relaxing non-inferiority boundaries. |
| 2011 | New regimens to prevent tuberculosis in adults with HIV infection. | N Engl J Med | Treatment of latent tuberculosis in patients infected with the human immunodeficiency virus (HIV) is efficacious, but few patients around the world receive such treatment. We evaluated three new regimens for latent tuberculosis that may be more potent and durable than standard Isoniazid treatment.We randomly assigned South African adults with HIV infection and a positive tuberculin skin test who were not taking antiretroviral therapy to receive rifapentine (900 mg) plus Isoniazid (900 mg) weekly for 12 weeks, rifampin (600 mg) plus Isoniazid (900 mg) twice weekly for 12 weeks, Isoniazid (300 mg) daily for up to 6 years (continuous Isoniazid), or Isoniazid (300 mg) daily for 6 months (control group). The primary end point was tuberculosis-free survival.The 1148 patients had a median age of 30 years and a median CD4 cell count of 484 per cubic millimeter. Incidence rates of active tuberculosis or death were 3.1 per 100 person-years in the rifapentine-Isoniazid group, 2.9 per 100 person-years in the rifampin-Isoniazid group, and 2.7 per 100 person-years in the continuous-Isoniazid group, as compared with 3.6 per 100 person-years in the control group (P>0.05 for all comparisons). Serious adverse reactions were more common in the continuous-Isoniazid group (18.4 per 100 person-years) than in the other treatment groups (8.7 to 15.4 per 100 person-years). Two of 58 isolates of Mycobacterium tuberculosis (3.4%) were found to have multidrug resistance.On the basis of the expected rates of tuberculosis in this population of HIV-infected adults, all secondary prophylactic regimens were effective. Neither a 3-month course of intermittent rifapentine or rifampin with Isoniazid nor continuous Isoniazid was superior to 6 months of Isoniazid. (Funded by the National Institute of Allergy and Infectious Diseases and others; ClinicalTrials.gov number, NCT00057122.). |
| 2011 | Short-course chemotherapy with TMC207 and rifapentine in a murine model of latent tuberculosis infection. | Am J Respir Crit Care Med | Multidrug-resistant and extensively drug-resistant tuberculosis (MDR/XDR-TB) is an emerging global health threat. Proper management of close contacts of infectious patients is increasingly important. However, no evidence-based recommendations for treating latent TB infection (LTBI) after MDR/XDR-TB exposure (DR-LTBI) exist. An ultrashort regimen for LTBI caused by drug-susceptible strains (DS-LTBI) is also desirable. TMC207 has bactericidal and sterilizing activity in animal models of TB and improves the activity of current MDR-TB therapy in patients.The objective of this study was to determine whether TMC207 might enable short-course treatment of DR-LTBI and ultrashort treatment of DS-LTBI.Using an established experimental model of LTBI chemotherapy in which mice are aerosol-immunized with a recombinant bacillus Calmette-Guérin vaccine before low-dose aerosol infection with Mycobacterium tuberculosis, the efficacy of TMC207 alone and in combination with rifapentine was compared with currently recommended control regimens as well as once-weekly rifapentine + Isoniazid and daily rifapentine ± Isoniazid.Outcomes included monthly lung colony-forming unit counts and relapse rates.Lung colony-forming unit counts were stable at about 3.75 log(10) for up to 7.5 months postinfection in untreated mice. Rifamycin-containing regimens were superior to Isoniazid monotherapy. TMC207 exhibited sterilizing activity at least as strong as that of rifampin alone and similar to that of rifampin + Isoniazid, but daily rifapentine +/- Isoniazid was superior to TMC207. Addition of TMC207 to rifapentine did not improve the sterilizing activity of rifapentine in this model.TMC207 has substantial sterilizing activity and may enable treatment of DR-LTBI in 3-4 months. |
| 2011 | New drugs for tuberculosis treatment. | Enferm Infecc Microbiol Clin | Available data on anti-tuberculosis drug research reveal different properties of the agents and provoke speculation about future directions. Higher doses of the rifamycins are promising and are currently being evaluated in regimens of shorter duration that the Isoniazid plus rifampin-based, six-to-nine month-course therapy. Moxifloxacin and gatifloxacin might shorten tuberculosis treatment as well, possibly in combination with rifapentine, while SQ109 could enhance the activity of rifampin-containing regimens. On the other hand, co-administration of moxifloxacin and PA-824 could be active against latent tuberculosis, whereas linezolid, PA-824 and TMC207 are candidates for a rifampin-free regimen in multidrug-resistant and extensively-resistant tuberculosis. Unfortunately, shorter than existent treatment regimens based on the new agents discussed here are likely to take at least another decade to be fully developed and implemented in clinical practice. |
| 2011 | Recent developments in treatment of latent tuberculosis infection. | Indian J Med Res | Latent tuberculosis infection (LTBI) can be detected with immune based tests such as the tuberculin skin test (TST) or interferon gamma release assays (IGRA). Therapy for those with positive tests can reduce the subsequent risk of re-activation and development of active TB. Current standard therapy is Isoniazid (INH) which reduce the risk of active TB by as much as 90 per cent if taken daily for 9 months. However, this lengthy duration of therapy discourages patients, and the risk of serious adverse events such as hepatotoxicity, discourages both patients and providers. As a result completion of INH therapy is less than 50 per cent in many programmes. However, programmes that offer close follow up with supportive staff who emphasize patient education, have reported much better results. The problems with INH have stimulated development and evaluation of several shorter regimens. One alternative was two months daily rifampin and pyrazinamide; this regimen has been largely abandoned due to unacceptably high rates of hepatotoxicity and poor tolerability. The combination of INH and rifampin, taken for 3 or 4 months, has efficacy equivalent to 6 months INH albeit with somewhat increased hepatotoxicity. Four months rifampin has efficacy at least equivalent to 6 months INH but there are inadequate trial data on efficacy. The safety of this regimen has been demonstrated repeatedly. Most recently, a regimen of 3 months INH rifapentine taken once weekly under direct observation has been evaluated in a large scale trial. Results have not yet been published, but if this regimen is as effective as INH, this may be a very good alternative. However, close monitoring and surveillance is strongly suggested for the first few years after its introduction. Evidence from several randomized trials has shown that the benefits of LTBI therapy is only in individuals who are tuberculin skin test (TST) positive even among those with HIV infection. Hence, LTBI therapy should be given only to those with positive tests for LTBI. We conclude that LTBI therapy is considerably underutilized in many settings, particularly in low and middle income countries. |
| 2011 | Treatment of tuberculosis and optimal dosing schedules. | Thorax | Intermittent tuberculosis treatment regimens have been developed to facilitate treatment supervision. Their efficacy has been substantiated by clinical trials and tuberculosis control programmes, notwithstanding the lack of head-to-head comparison between daily and intermittent regimens. Recently, there has been opposing evidence from observational studies, pharmacokinetic-pharmacodynamic studies and animal models that intermittent treatment increases the risk of relapse, treatment failure or acquired rifamycin resistance, especially among HIV-infected patients. Systematic reviews have been conflicting. PubMed, Ovid MEDLINE and EMBASE were systematically searched for publications in English to evaluate the evidence about dosing schedules and treatment efficacy. Levels of evidence and grades of recommendation were assigned largely according to clinical evidence with reference to the Scottish Intercollegiate Guidelines Network guideline development handbook. A total of 32 articles were included after excluding 331 ineligible articles, 42 non-analytical studies, 22 narrative reviews or expert opinions and 44 articles embedded in systematic reviews. These included 9 systematic reviews, 8 controlled studies, 9 pharmacokinetic-pharmacodynamic studies, 5 mouse studies and 1 article about guinea pig experiments. Findings suggest high levels of evidence for using daily dosing schedules, especially during the initial phase in the presence of cavitation, Isoniazid resistance and advanced HIV co-infection, to reduce the risk of treatment failure, recurrence and acquired drug resistance including acquired rifamycin resistance. This review justifies the use of daily schedules in standard tuberculosis treatment regimens (particularly in the initial phase), corroborates prevailing understanding of pharmacokinetics-pharmacodynamics and mycobacterial persisters, and supports exploration of rifapentine-containing regimens in higher dosages and frequency. |
| 2010 | New approaches in the diagnosis and treatment of latent tuberculosis infection. | Respir Res | With nearly 9 million new active disease cases and 2 million deaths occurring worldwide every year, tuberculosis continues to remain a major public health problem. Exposure to Mycobacterium tuberculosis leads to active disease in only ~10% people. An effective immune response in remaining individuals stops M. tuberculosis multiplication. However, the pathogen is completely eradicated in ~10% people while others only succeed in containment of infection as some bacilli escape killing and remain in non-replicating (dormant) state (latent tuberculosis infection) in old lesions. The dormant bacilli can resuscitate and cause active disease if a disruption of immune response occurs. Nearly one-third of world population is latently infected with M. tuberculosis and 5%-10% of infected individuals will develop active disease during their life time. However, the risk of developing active disease is greatly increased (5%-15% every year and ~50% over lifetime) by human immunodeficiency virus-coinfection. While active transmission is a significant contributor of active disease cases in high tuberculosis burden countries, most active disease cases in low tuberculosis incidence countries arise from this pool of latently infected individuals. A positive tuberculin skin test or a more recent and specific interferon-gamma release assay in a person without overt signs of active disease indicates latent tuberculosis infection. Two commercial interferon-gamma release assays, QFT-G-IT and T-SPOT.TB have been developed. The standard treatment for latent tuberculosis infection is daily therapy with Isoniazid for nine months. Other options include therapy with rifampicin for 4 months or Isoniazid + rifampicin for 3 months or rifampicin + pyrazinamide for 2 months or Isoniazid + rifapentine for 3 months. Identification of latently infected individuals and their treatment has lowered tuberculosis incidence in rich, advanced countries. Similar approaches also hold great promise for other countries with low-intermediate rates of tuberculosis incidence. |
| 2010 | [Therapeutic efficacy of drug susceptibility test-guided individualized anti-tuberculosis chemotherapy for spinal tuberculosis]. | Zhonghua Wai Ke Za Zhi | To investigate the efficacy of individualized anti-tuberculosis chemotherapy guided by drug susceptibility testing for spinal tuberculosis through analyses on the post-operative follow-up outcomes.The diagnoses of spinal tuberculosis were established by clinical, radiological and histological evaluation in 132 patients who were admitted from August 2005 to January 2010, 62 patients (37 male and 25 female) with follow-up more than 12 months in this study. The average age was 33.6 years (ranging from 4 - 67 years). The infected samples were collected during surgery. After processed in a routine laboratory procedure, the samples were inoculated into vials of the BACT/ALERT 3D system. The drug susceptibility testing was performed using absolute concentration method, which included 11 first-line and second-line drugs. Four or five anti-tuberculosis drug regimen was chosen according to the results of drug susceptibility testing. All the patients were followed up a month later, and then once 3 months in the following 11 months, and subsequently at intervals of half a year. The clinical status, erythrocyte sedimentation rate (ESR), roentgenogram, MRI and 3D-CT were concerned to estimate the progress of tuberculosis.The culture positive rate was 45.2% (28/62). The average detection time was 42 d (ranging from 28 - 58 d). The drug susceptibility testing showed a total drug resistance level of 24.2%:12.9% for Isoniazid, 4.8% for rifampicin, 3.2% for ethambutol, 9.7% for streptomycin, 6.4% for pasiniazid, 14.5% for levofloxacin, 1.6% for rifapentine. The mean follow-up period was 21 months (ranging from 12 - 44 months). According to Bridwell criteria, grade I bony fusion was obtained in all patients in 8 - 12 months.Guided by drug susceptibility testing, individualized anti-tuberculosis chemotherapy for 12 to 18 months is effective for spinal tuberculosis. |
| 2010 | Treatment of latent tuberculosis infection: An update. | Respirology | Isoniazid (INH) has been the mainstay of treatment of latent tuberculosis infection for almost 50 years. The currently recommended preferred regimen is 9 months daily self-administered INH (9H); this has efficacy of more than 90% if completed properly. Unfortunately, INH is associated with serious adverse events, including hepatotoxicity. Although risk factors for this complication are well established, allowing for better selection of candidates for therapy, this complication still occurs, and is occasionally fatal. Hence close follow up of patients is necessary, increasing the cost and complexity of treatment. This problem, plus the lengthy duration, results in poor acceptance by patients and providers, and poor adherence by patients. As a result, many preventable cases of tuberculosis continue to occur, and the public health impact of latent tuberculosis infection treatment is suboptimal. These problems have spurred interest in finding shorter, safer and cheaper alternative regimens, with similar efficacy. Of the many regimens that have been examined, 2 months of rifampin and pyrazinamide has excellent efficacy-in experimental studies in mice and randomized trials, largely in HIV-infected persons. However, while the safety of 2 months of rifampin and pyrazinamide appears acceptable in HIV-infected persons and children, in non-HIV-infected adults this regimen is associated with an unacceptably high rate of severe liver toxicity. Three to four months of INH and rifampin has had equivalent effectiveness as 6 months INH in several randomized trials. However, completion of therapy and toxicity has been the same as with INH-possibly because two drugs are taken rather than one. The fourth commonly studied regimen is 4 months rifampin. This has been found to have significantly better completion than 9H, with significantly less toxicity, especially hepatotoxicity. However, only one trial has evaluated efficacy and effectiveness of mono-rifampin therapy. In this trial, 3 months rifampin had somewhat better efficacy than either 3 months of Isoniazid and rifampin (3HR) or 6 months Isoniazid. Two large scale trials are ongoing; one is comparing efficacy and effectiveness of 9H with 4 months rifampin (both daily and self-administered), while the second, which is nearing completion, compares daily self-administered 9H with 3 months directly observed once weekly INH combined with rifapentine. The results of these two trials will likely shape future recommendations substantially. |
| [On the way to shortening tuberculosis treatments: clinical trials of the Unitat d' Investagació en Tuberculosi de Barcelona supported by the Centers for Disease Control and Prevention]. | Gac Sanit | New treatment guidelines are required to improve the tuberculosis control strategies that have been used for 30 years. Seven centers of the Barcelona Tuberculosis Research Unit (BTRU) (Unitat d'Investigació en Tuberculosi de Barcelona) are collaborating with the Division of Tuberculosis Elimination of the United States Centers for Disease Control and Prevention in a series of clinical trials on latent tuberculosis infection and tuberculosis disease. BTRU participation began in 2004 with Study 26, an evaluation of the efficacy and tolerability of rifapentine plus Isoniazid administered once weekly for 3 months compared with the standard treatment for latent tuberculosis infection. The BTRU centers together enrolled 246 patients (3% of the total). General enrollment was completed in February, 2008. HIV-infected patient and child enrollment continues. Treatment with 12 doses instead of 270 doses is expected to be a clear success. However, the analysis will be completed in 2010. Study 28 (started in 2006), designed for the treatment of pulmonary tuberculosis, compared standard treatment with an experimental regimen substituting moxifloxacin for Isoniazid. BTRU centers together enrolled 15 patients (3.5% of the total). The provisional results (presented at the 47th Interscience Conference on Antimicrobial Agents and Chemotherapy in Chicago, 2007) showed no difference between the sputum conversion rate of each regimen at week 8 of treatment. Study 29 is currently underway, in which rifapentine was introduced in the experimental regimen for active tuberculosis treatment. |
| 2009 | Short-course therapy with daily rifapentine in a murine model of latent tuberculosis infection. | Am J Respir Crit Care Med | Regimens recommended to treat latent tuberculosis infection (LTBI) are 3 to 9 months long. A 2-month rifampin+pyrazinamide regimen is no longer recommended. Shorter regimens are highly desirable. Because substituting rifapentine for rifampin in the standard regimen for active tuberculosis halves the treatment duration needed to prevent relapse in mice, we hypothesized daily rifapentine-based regimens could shorten LTBI treatment to 2 months or less.To improve an existing model of LTBI chemotherapy and evaluate the efficacy of daily rifapentine-based regimens.Mice were immunized with a more immunogenic recombinant Bacille Calmette-Guérin strain (rBCG30) and received very low-dose aerosol infection with Mycobacterium tuberculosis to establish a stable lung bacterial burden below 10(4) CFU without drug treatment. Mice received a control (Isoniazid alone, rifampin alone, rifampin+Isoniazid, rifampin+pyrazinamide) or test (rifapentine alone, rifapentine+Isoniazid, rifapentine+pyrazinamide, rifapentine+Isoniazid+pyrazinamide) regimen for 8 weeks. Rifamycin doses were 10 mg/kg/d, analogous to the same human doses. Outcomes were biweekly lung CFU counts and relapse after 4 to 8 weeks of treatment.M. tuberculosis CFU counts remained stable around 3.65 log(10) in immunized, untreated mice. Isoniazid or rifampin left all or most mice culture-positive at week 8. Rifampin+Isoniazid cured 0 and 53% of mice and rifampin+pyrazinamide cured 47 and 100% of mice in 4 and 8 weeks, respectively. Rifapentine-based regimens were more active than rifampin+Isoniazid and indistinguishable from rifampin+pyrazinamide.In this improved murine model of LTBI chemotherapy with very low lung burden, existing regimens were well represented. Daily rifapentine-based regimens were at least as active as rifampin+pyrazinamide, suggesting they could effectively treat LTBI in 6 to 8 weeks. |
| 2009 | Costs and cost-effectiveness of four treatment regimens for latent tuberculosis infection. | Am J Respir Crit Care Med | Isoniazid given daily for 9 months is the standard treatment for latent tuberculosis infection (LTBI), but its effectiveness is limited by poor completion rates. Shorter course regimens and regimens using directly observed therapy result in improved adherence but have higher upfront costs.To evaluate the costs and cost-effectiveness of regimens for the treatment of LTBI.We used a computerized Markov model to estimate total societal costs and benefits associated with four regimens for the treatment of LTBI: self-administered Isoniazid daily for 9 months, directly observed Isoniazid twice-weekly for 9 months, directly observed Isoniazid plus rifapentine once weekly for 3 months, and self-administered rifampin daily for 4 months. In the base-case analysis, subjects were assumed to have newly positive tuberculin skin tests after recent exposure to infectious tuberculosis.We determined the costs of treatment, quality-adjusted life-years gained, and cases of active tuberculosis prevented. In the base-case analysis, rifampin dominated (less costly with increased benefits) all other regimens except Isoniazid plus rifapentine, which was more effective at a cost $48,997 per quality-adjusted life year gained. Isoniazid plus rifapentine dominated all regimens at a relative risk of disease 5.2 times the baseline estimate, or with completion rates less than 34% for Isoniazid or 37% for rifampin. Rifampin could be 17% less efficacious than self-administered Isoniazid and still be cost-saving compared with this regimen.In our model, rifampin is cost-saving compared with the standard therapy of self-administered Isoniazid. Isoniazid plus rifapentine is cost-saving for extremely high-risk patients and is cost-effective for lower-risk patients. |
| 2009 | A once-weekly R207910-containing regimen exceeds activity of the standard daily regimen in murine tuberculosis. | Am J Respir Crit Care Med | R207910 (TMC207 or J) is a member of the diarylquinolines, a new family of antituberculous drugs with high bactericidal activity when given daily in the murine model of tuberculosis. R207910 exhibits a long half-life and thus is a good candidate for once-weekly therapy of tuberculosis.To study the activity of once-weekly R207910 monotherapy and combinations of R207910 with other antituberculous agents (Isoniazid, rifapentine, moxifloxacin, and pyrazinamide).The established infection model of murine tuberculosis was used. Colony counts were determined in the lungs.Eight weeks of monotherapy reduced the bacillary load by 3 to 4 log(10) for rifapentine and by 5 to 6 log(10) for R207910 (P < 0.05). The addition of rifapentine and Isoniazid or moxifloxacin did not improve the bactericidal activity of R207910 monotherapy. In contrast, the triple combination of R207910 plus rifapentine plus pyrazinamide given once weekly for 2 months (i.e., a total of only eight administrations), was significantly (P < 0.05) more active than R207910 monotherapy or other R207910 combinations, and led to lung culture negativity in 9 of 10 mice, whereas all lungs were culture positive in the groups treated with other drug combinations. Moreover, R207910 plus rifapentine plus pyrazinamide given once weekly was more active than the current standard regimen of rifampin plus Isoniazid plus pyrazinamide given five times per week.The unprecedented activity of the triple combination of R207910 plus rifapentine plus pyrazinamide suggests that it may be feasible to develop a fully intermittent once-weekly regimen. |
| 2008 | New approaches to the treatment of latent tuberculosis. | Semin Respir Crit Care Med | It is estimated that one third of the global population is infected with MYCOBACTERIUM TUBERCULOSIS. Treatment of M. TUBERCULOSIS infection is an important strategy for tuberculosis elimination, but the effectiveness of this strategy is limited by poor adherence to therapy, which is due at least in part to the long duration of treatment. A 9-month course of Isoniazid is the currently preferred treatment regimen for M. TUBERCULOSIS infection, due to the extensive data regarding the effectiveness and tolerability of Isoniazid, and limited data on the effectiveness and tolerability of alternative shorter-course regimens. This review covers all currently available regimens, including less established alternative treatment regimens (e.g., rifampin for 4 months and Isoniazid + rifampin for 3 months), as well as regimens that are currently under investigation (e.g., Isoniazid + rifapentine for 3 months). Potential future regimens and experimental approaches are also discussed. |
| 2008 | Isoniazid or moxifloxacin in rifapentine-based regimens for experimental tuberculosis? | Am J Respir Crit Care Med | Recent studies have demonstrated that combined substitutions of rifapentine for rifampin and moxifloxacin for Isoniazid in the standard, daily, short-course regimen of rifampin, Isoniazid, and pyrazinamide produces stable cure in 12 weeks or less. This study was designed to more precisely evaluate the contribution of moxifloxacin and Isoniazid to rifapentine-based regimens.We compared bactericidal activity and treatment-shortening potential between regimens consisting of Isoniazid or moxifloxacin plus rifapentine and pyrazinamide administered either thrice-weekly or daily.Using a mouse model of tuberculosis, we assessed bactericidal activity by performing quantitative cultures of lung homogenates over the first 12 weeks of treatment. Relapse rates were assessed after completing 8, 10, and 12 weeks of treatment to determine the duration of treatment necessary for stable cure.After 4 weeks of treatment, daily and thrice-weekly therapy with rifapentine, moxifloxacin, and pyrazinamide was significantly more active than treatment with rifapentine, Isoniazid, and pyrazinamide. By 8 weeks of treatment, all mice receiving the moxifloxacin-containing regimens were lung culture negative, whereas those mice receiving the Isoniazid-containing regimens continued to be lung culture positive. However, the duration of treatment necessary to achieve stable cure was 10 weeks for daily regimens and 12 weeks for thrice-weekly regimens, regardless of whether Isoniazid or moxifloxacin was used. All mice receiving standard daily therapy with rifampin, Isoniazid, and pyrazinamide relapsed after 12 weeks of treatment.These results suggest that regimens consisting of Isoniazid or moxifloxacin plus rifapentine and pyrazinamide may dramatically shorten the duration of treatment needed to cure human tuberculosis. |
| 2007 | Daily dosing of rifapentine cures tuberculosis in three months or less in the murine model. | PLoS Med | Availability of an ultra-short-course drug regimen capable of curing patients with tuberculosis in 2 to 3 mo would significantly improve global control efforts. Because immediate prospects for novel treatment-shortening drugs remain uncertain, we examined whether better use of existing drugs could shorten the duration of treatment. Rifapentine is a long-lived rifamycin derivative currently recommended only in once-weekly continuation-phase regimens. Moxifloxacin is an 8-methoxyfluoroquinolone currently used in second-line regimens.Using a well-established mouse model with a high bacterial burden and human-equivalent drug dosing, we compared the efficacy of rifapentine- and moxifloxacin-containing regimens with that of the standard daily short-course regimen based on rifampin, Isoniazid, and pyrazinamide. Bactericidal activity was assessed by lung colony-forming unit counts, and sterilizing activity was assessed by the proportion of mice with culture-positive relapse after 2, 3, 4, and 6 mo of treatment. Here, we demonstrate that replacing rifampin with rifapentine and Isoniazid with moxifloxacin dramatically increased the activity of the standard daily regimen. After just 2 mo of treatment, mice receiving rifapentine- and moxifloxacin-containing regimens were found to have negative lung cultures, while those given the standard regimen still harbored 3.17 log10 colony-forming units in the lungs (p < 0.01). No relapse was observed after just 3 mo of treatment with daily and thrice-weekly administered rifapentine- and moxifloxacin-containing regimens, whereas the standard daily regimen required 6 mo to prevent relapse in all mice.Rifapentine should no longer be viewed solely as a rifamycin for once-weekly administration. Our results suggest that treatment regimens based on daily and thrice-weekly administration of rifapentine and moxifloxacin may permit shortening the current 6 mo duration of treatment to 3 mo or less. Such regimens warrant urgent clinical investigation. |
| 2007 | Overview of anti-tuberculosis (TB) drugs and their resistance mechanisms. | Mini Rev Med Chem | One-third of the world's population is infected with Mycobacterium (M.) tuberculosis. Tuberculosis continues to be the most common infectious cause of death and still has a serious impact, medically, socially and financially. Multidrug-resistant tuberculosis (MDR-TB), caused by tubercle bacilli that are resistant to at least Isoniazid and rifampin, is among the most worrisome elements of the pandemic of antibiotic resistance because TB patients for whom treatment has failed have a high risk of death. Drugs used to treat tuberculosis are classified into first-line and second-line agents. First-line essential anti-tuberculosis agents are the most effective, and are a necessary component of any short-course therapeutic regimen. The drugs in this category are Isoniazid, rifampin, ethambutol, pyrazinamide and streptomycin. Second-line anti-tuberculosis drugs are clinically much less effective than first-line agents and elicit severe reactions much more frequently. These drugs include para-aminosalicylic acid (PAS), ethionamide, cycloserine, amikacin and capreomycin. New drugs, which are yet to be assigned to the above categories, include rifapentine, levofloxacin, gatifloxacin and moxifloxacin. Recently there has been much development in the molecular pharmacology of anti-tuberculosis drugs. This review summarizes information for Isoniazid, rifampicin, ethambutol, pyrazinamide, and fluoroquinolones, and describes their resistance mechanisms. |
| 2006 | Rifapentine for the treatment of pulmonary tuberculosis. | Clin Infect Dis | Rifapentine is a recently approved antituberculosis drug that has not yet been widely used in clinical settings. Clinical data support intermittent use of rifapentine with Isoniazid during the continuation phase of tuberculosis treatment. Patients with culture-positive, noncavitary, pulmonary tuberculosis whose sputum smear is negative for acid-fast bacilli at the end of the 2-month intensive treatment phase are eligible for rifapentine therapy. Rifapentine should not be used in human immunodeficiency virus-infected patients, given their increased risk of developing rifampin resistance with currently recommended dosages. Rifapentine is not currently recommended for children aged <12 years, pregnant or lactating women, or individuals with culture-negative or extrapulmonary tuberculosis. Rifapentine (600 mg) is administered once weekly with Isoniazid (900 mg) during the continuation phase of treatment. This combination should only be given under direct observation. As with rifampin, drug-drug interactions are common, and regular patient monitoring is required. Ease of administration makes this regimen attractive both for tuberculosis-control programs and for patients. |
| 2006 | Antituberculosis drugs and hepatotoxicity. | Respirology | Isoniazid, pyrazinamide and rifampicin have hepatotoxic potential, and can lead to such reactions during antituberculosis chemotherapy. Most of the hepatotoxic reactions are dose-related; some are, however, caused by drug hypersensitivity. The immunogenetics of antituberculosis drug-induced hepatotoxicity, especially inclusive of acetylaor phenotype polymorphism, have been increasingly unravelled. Other principal clinical risk factors for hepatotoxicity are old age, malnutrition, alcoholism, HIV infection, as well as chronic hepatitis B and C infections. Drug-induced hepatic dysfunction usually occurs within the initial few weeks of the intensive phase of antituberculosis chemotherapy. Vigilant clinical (including patient education on symptoms of hepatitis) and biochemical monitoring are mandatory to improve the outcomes of patients with drug-induced hepatotoxicity during antituberculosis chemotherapy. Some fluoroquinolones like ofloxacin/levofloxacin may have a role in constituting non-hepatotoxic drug regimens for management of tuberculosis (TB) in the presence of hepatic dysfunction. Isoniazid administration is currently the standard therapy for latent TB infection. Rifamycins like rifampicin or rifapentine, alone or in combination with Isoniazid, may also be considered as alternatives, pending accumulation of further clinical data. During treatment of latent TB infection, regular follow up is essential to ensure adherence to therapy and facilitate clinical monitoring for hepatic dysfunction. Monitoring of liver chemistry is also required for those patients at risk of drug-induced hepatotoxicity. |
| 2006 | Study of the interaction between rifapentine and isoniazid under acid conditions. | J Pharm Biomed Anal | A well-known problem of anti-tuberculosis fixed-dose combination (FDC) products containing rifampicin (R) and Isoniazid (H) is the fall in bioavailability, in particular of R, when two or more drugs are present together. The same has been ascribed to hydrolysis of R to 3-formylrifamycin (3-RIF) under stomach acid conditions and reaction of the latter with H to form isonicotinyl hydrazone (HYD). The objective of present study was to explore whether the same reaction occurred when H was present along with rifapentine (Rp), a newer long acting rifamycin, which is structurally similar to R. Clinical trials are currently undergoing for co-administration of Rp with H in patients who had completed 2 months of standard chemotherapy. For the purpose, first a validated HPLC method was developed for the separation of Rp and H, and the same was used for the study of interaction between the two drugs. Like R, Rp was also found to convert to 3-RIF in acid conditions, which reacted further with H to form HYD. The pH-rate profile was also similar in shape to that established with the combination of R and H; maximum decomposition occurred at pH 2, where Rp loss was to an extent of approximately 30%, while corresponding decomposition of H was approximately 9%. These values were similar to those reported for the combination of R (approximately 33%) and H (approximately 10%). Hence, the study suggests that co-administration of Rp and H should be avoided, like in case of R and H, and the two drugs should not be formulated directly into a single dosage form. |
| 2006 | Potent twice-weekly rifapentine-containing regimens in murine tuberculosis. | Am J Respir Crit Care Med | Recent studies have demonstrated that intermittent administration of rifamycin-based regimens results in higher rates of tuberculosis relapse and treatment failure compared with daily therapy. Twice-weekly treatment with rifampin, Isoniazid, and pyrazinamide may be improved by increasing Mycobacterium tuberculosis exposure to rifamycin by substituting rifapentine for rifampin.To test this hypothesis, we compared the activities of standard daily and twice-weekly rifampin plus Isoniazid-based regimens to those of twice-weekly rifapentine plus Isoniazid- or moxifloxacin-containing regimens in the murine model of tuberculosis. Relapse rates were assessed after 4, 5, and 6 mo of treatment to assess stable cure. Single- and multiple-dose pharmacokinetics of rifampin and rifapentine were also determined.After 2 mo of treatment, twice-weekly therapy with rifapentine (15 or 20 mg/kg), moxifloxacin, and pyrazinamide was significantly more active than standard daily or twice-weekly therapy with rifampin, Isoniazid, and pyrazinamide. Stable cure was achieved after 4 mo of twice-weekly rifapentine plus Isoniazid- or moxifloxacin-containing therapy, but only after 6 mo of standard daily therapy. Twice-weekly rifapentine (15 mg/kg) displayed more favorable pharmacodynamics than did daily rifampin (10 mg/kg).By virtue of the enhanced rifamycin exposure, twice-weekly regimens containing rifapentine (15 or 20 mg/kg) may permit shortening the current treatment duration by 2 mo. Such regimens warrant clinical investigation. |
| 2006 | Weekly rifapentine/isoniazid or daily rifampin/pyrazinamide for latent tuberculosis in household contacts. | Am J Respir Crit Care Med | Treatment of latent tuberculosis (TB) infection with weekly rifapentine and Isoniazid is a potentially effective alternative to current therapies.To compare the efficacy of weekly rifapentine/Isoniazid to daily rifampin/pyrazinamide in preventing TB in household contacts of patients with pulmonary TB in Brazil.Contacts of patients with TB were randomized to rifapentine 900 mg/Isoniazid 900 mg once weekly for 12 wk or rifampin 450-600 mg/pyrazinamide 750-1,500 mg daily for 8 wk and followed for at least 2 yr.TB rates, adverse events, and adherence to therapy.A total of 399 household contacts were enrolled, 206 in the rifapentine/Isoniazid arm and 193 in the rifampin/pyrazinamide arm. The median age was 34 yr, median weight was 63 kg, 60% of participants were female, and only one patient was HIV infected. Rifapentine/Isoniazid was well tolerated, but the trial was halted by the investigators before completion because of unanticipated hepatotoxicity in the rifampin/pyrazinamide arm. Twenty of 193 participants (10%) receiving rifampin/pyrazinamide experienced grade 3 or 4 hepatotoxicity, compared with 2 of 206 participants (1%) on rifapentine/Isoniazid (p<0.001). There were no hospitalizations or deaths due to hepatotoxicity, and all participants' liver enzyme levels returned to normal during follow-up. During follow-up, four cases of active TB developed, three in the rifapentine/Isoniazid group and one in the rifampin/pyrazinamide group (1.46 vs. 0.52%; difference, 0.94%; 95% confidence interval, -1.6 to 3.7%).Rifapentine/Isoniazid was better tolerated than rifampin/pyrazinamide and was associated with good protection against TB. Rifapentine/Isoniazid weekly for 12 wk is likely a promising therapy for latent TB infection. |
| 2006 | Monitoring the ingestion of anti-tuberculosis drugs by simple non-invasive methods. | Int J Pharm | This investigation retrospectively assessed inexpensive non-invasive qualitative methods to monitor the ingestion of anti-tuberculosis drugs Isoniazid, rifampicin and rifapentine. Results showed that commercial test strips detected the Isoniazid metabolites isonicotinic acid and isonicotinylglycine as efficiently as the isonicotinic acid method in 150 urine samples. The presence of rifamycins in urine samples (n=1085) was detected by microbiological assay techniques and the sensitivity compared to the n-butanol extraction colour test in 91 of these specimens. The proportions detected by the two methods were significantly different and the sensitivity of the n-butanol procedure was only 63.8% (95% CL 51.2-76.4%) as compared to that of the superior microbiological method. Final validation (n=691) showed that qualitative assays measure Isoniazid and rifamycin ingestion with an efficiency similar to high-performance liquid chromatography. The qualitative procedures may therefore be valuable in clinical trials and in tuberculosis clinics to confirm drug ingestion. |
| 2005 | Population pharmacokinetics of rifapentine and its primary desacetyl metabolite in South African tuberculosis patients. | Antimicrob Agents Chemother | This study was designed to describe the population pharmacokinetics of rifapentine (RFP) and 25-desacetyl RFP in a South African pulmonary tuberculosis patient population. Special reference was made to studying the influence of previous exposure to rifampin (RIF) and the variability in pharmacokinetic parameters between patients and between occasions and the influence of different covariates. Patients were included in the study if they had been receiving first-line antimycobacterial therapy (rifampin, Isoniazid, pyrazinamide, and ethambutol) for not less than 4 weeks and not more than 6 weeks and were divided into three RFP dosage groups based on weight: 600 mg, <45 kg; 750 mg, 46 to 55 kg; and 900 mg, >55 kg. Participants received a single oral dose of RFP together with concomitant antimycobacterial agents, excluding RIF, on study days 1 and 5 after they ingested a soup-based meal. The RFP and 25-desacetyl RFP concentration-time data were analyzed by nonlinear mixed-effect modeling using NONMEM. The pharmacokinetics of the parent drug were modeled separately, and the individual pharmacokinetic parameters were used as inputs for the 25-desacetyl RFP pharmacokinetic model. A one-compartment disposition model was found to best describe the data for both the parent and the metabolite, and the metabolite was assumed to be formed only from the central compartment of the parent drug. Prior treatment with RIF did not alter the pharmacokinetics of RFP but appeared to increase the excretion of 25-desacetyl RFP in a nonlinear fashion. The RFP oral clearance and volume of distribution were found to increase by 0.049 liter/h and 0.691 liter, respectively, with a 1-kg increase from the median weight of 50 kg. The oral clearance of 25-desacetyl RFP was found to be 35% lower in female patients. The model developed here describes the population pharmacokinetics of RFP and its primary metabolite in tuberculosis patients and includes the effects of prior administration with RIF and covariate factors. |
| 2005 | Efficient intermittent rifapentine-moxifloxacin-containing short-course regimen for treatment of tuberculosis in mice. | Antimicrob Agents Chemother | Long-half-life drugs raise the hope of once-a-week administration of antituberculous treatment. In a previous study with the murine model of tuberculosis, the most active intermittent regimen which contained rifapentine (RFP), Isoniazid (INH), and moxifloxacin (MXF) given once a week during 5.5 months, preceded by 2 weeks of daily treatment with INH, rifampin (RIF), pyrazinamide (PZA), and MXF, was less active than the standard 6-month daily RIF-INH-PZA regimen. We evaluated with the same model similar regimens in which we increased the dosing of rifapentine from 10 to 15 mg/kg of body weight and of moxifloxacin from 100 to 400 mg/kg. Mice infected intravenously by 6.2 x10(6) CFU of Mycobacterium tuberculosis H37Rv were treated 2 weeks later when infection was established. After 6 months of treatment, all mice had negative lung culture. After 3 months of follow-up, no relapse occurred in the two groups that received moxifloxacin at 400 mg/kg, whatever the dosage of RFP, and in the group receiving the standard RIF-INH-PZA control regimen. In contrast, in the two groups receiving moxifloxacin at a lower dosage, the relapse rate was significantly higher (13% in mice receiving RFP at 15 mg/kg and 27% in those receiving RFP at 10 mg/kg). Finally, the fully intermittent once-a-week regimen (26 drug ingestions) of INH, RFP (15 mg/kg), and MXF (400 mg/kg) led to a relapse rate of 11%. In conclusion, when used at high dosage, rifapentine and moxifloxacin are very efficient when combined with Isoniazid in a once-a-week treatment in mouse tuberculosis. |
| 2005 | Rifapentine, moxifloxacin, or DNA vaccine improves treatment of latent tuberculosis in a mouse model. | Am J Respir Crit Care Med | Priorities for developing improved regimens for treatment of latent tuberculosis (TB) infection include (1) developing shorter and/or more intermittently administered regimens that are easier to supervise and (2) developing and evaluating regimens that are active against multidrug-resistant organisms.By using a previously validated murine model that involves immunizing mice with Mycobacterium bovis bacillus Calmette-Guérin to augment host immunity before infection with virulent Mycobacterium tuberculosis, we evaluated new treatment regimens including rifapentine and moxifloxacin, and assessed the potential of the Mycobacterium leprae heat shock protein-65 DNA vaccine to augment the activity of moxifloxacin.Quantitative spleen colony-forming unit counts, and the proportion of mice with culture-positive relapse after treatment, were determined.Three-month, once-weekly regimens of rifapentine combined with either Isoniazid or moxifloxacin were as active as daily Isoniazid for 6-9 mo. Six-month daily combinations of moxifloxacin with pyrazinamide, ethionamide, or ethambutol were more active than pyrazinamide plus ethambutol, a regimen recommended for latent TB infection after exposure to multidrug-resistant TB. The combination of moxifloxacin with the experimental nitroimidazopyran PA-824 was especially active. Finally, the heat shock protein-65 DNA vaccine had no effect on colony-forming unit counts when given alone, but augmented the bactericidal activity of moxifloxacin.Together, these findings suggest that rifapentine, moxifloxacin, and, perhaps, therapeutic DNA vaccination have the potential to improve on the current treatment of latent TB infection. |
| 2005 | Weekly moxifloxacin and rifapentine is more active than the denver regimen in murine tuberculosis. | Am J Respir Crit Care Med | Treatment of tuberculosis with an efficacious once-weekly regimen would be a significant achievement in improving patient adherence. Currently, the only recommended once-weekly continuation phase regimen of Isoniazid plus rifapentine (10 mg/kg) is inferior to standard twice-weekly therapy with Isoniazid plus rifampin and is, therefore, restricted to non-high-risk patients. The substitution of moxifloxacin, a new 8-methoxyfluoroquinolone, for Isoniazid and an increase in the dose of rifapentine could augment the activity of once-weekly regimens.To test this hypothesis we evaluated the sterilizing activity of improved once-weekly rifapentine-based continuation phase regimens in a murine model that mimics the treatment of high-risk patients with tuberculosis. The bactericidal activity of standard daily therapy and standard intermittent therapy ("Denver" regimen) was also assessed to evaluate the effect of intermittent drug administration during the initial phase of therapy.After 2 mo of treatment, lung colony-forming unit counts were 1 log(10) lower in mice treated with standard daily therapy than with the Denver regimen. During the continuation phase, the sterilizing activity of once-weekly moxifloxacin plus rifapentine (15 mg/kg) was significantly greater than that of the predominantly twice-weekly Denver regimen of Isoniazid plus rifampin. No significant difference in sterilizing activity was detected between once-weekly Isoniazid plus rifapentine (15 mg/kg) and the Denver regimen.These results suggest that the efficacy of the once-weekly Isoniazid plus rifapentine continuation phase regimen can be increased by substituting moxifloxacin for Isoniazid and by increasing the dose of rifapentine to a clinically acceptable level of 15 mg/kg. |
| 2004 | Consecutive-dose pharmacokinetics of rifapentine in patients diagnosed with pulmonary tuberculosis. | Int J Tuberc Lung Dis | To characterise the pharmacokinetics of two consecutive doses of rifapentine (RPT) in patients diagnosed with pulmonary tuberculosis at a South African hospital.Forty-five patients received RPT doses of 600, 750 and 900 mg, based on body weight, after receiving a soup-based meal. Doses were administered to each subject on study days 1 and 5. All patients had already received not less than 4 weeks and not more than 6 weeks of standard antimycobacterial therapy (including Isoniazid, rifampicin, pyrazinamide and ethambutol). Serial blood samples were collected between 0 and 72 h post-dose. RPT and 25-desacetyl-RPT concentrations were determined using validated high performance liquid chromatography methods. The plasma concentration-time data were analysed using a noncompartmental approach and compared to healthy volunteer data from a previous study.Median peak plasma concentrations for RPT in the patient cohort were 15.19 and 15.48 microg/ml on study days 1 and 5, respectively. Time to reach these concentrations was 5.00 and 5.08 h and plasma elimination half-lives were 11.63 and 12.03 h, respectively. Areas under the plasma concentration-time curve (0-72 h) were 355.81 and 371.89 microg x h/ml on the two occasions, respectively.A 15 mg/kg dose of RPT was well absorbed and well tolerated. The variability observed between individuals and between occasions was small, and similar to that seen in data from previous studies in healthy volunteers. |
| 2004 | Pharmacokinetics of rifapentine at 600, 900, and 1,200 mg during once-weekly tuberculosis therapy. | Am J Respir Crit Care Med | The pharmacokinetics of rifapentine at 600, 900, and 1,200 mg were studied during once-weekly continuation phase therapy in 35 patients with tuberculosis. Mean area under the plasma concentration-time curve (AUC(0-infinity)) increased significantly with dose (rifapentine AUC(0- infinity): 296, 410, and 477 microg.hour/ml at 600, 900, and 1,200 mg, respectively; p = 0.02 by linear regression). In multivariate stepwise regression analyses, AUC(0-infinity) values for rifapentine and the active 25-desacetyl metabolite were associated with drug dose and plasma albumin concentration, and were lower among men and among white individuals. Fifty-four percent of patients had total (free and protein-bound) plasma concentrations of rifapentine and of desacetyl rifapentine detected for more than 36 hours after clearance of concurrently administered Isoniazid. Serious adverse effects of therapy in these study patients were infrequent (1 of 35 cases; 3%) and not linked with higher rifapentine AUC(0-infinity) or peak concentration. The present pharmacokinetic study supports further trials to determine the optimal rifapentine dose for treatment of tuberculosis. |
| 2004 | In vitro postantibiotic effects of rifapentine, isoniazid, and moxifloxacin against Mycobacterium tuberculosis. | Antimicrob Agents Chemother | Postantibiotic effects (PAEs) of rifapentine, Isoniazid, and moxifloxacin against Mycobacterium tuberculosis ATCC 27294 were studied using a radiometric culture system. Rifapentine at 20 mg/liter gave the longest PAE (104 h) among the drugs used alone. The combinations of rifapentine plus Isoniazid, rifapentine plus moxifloxacin, and Isoniazid plus moxifloxacin gave PAEs of 136.5, 59.0, and 8.3 h, respectively. |
| 2003 | Low isoniazid concentrations and outcome of tuberculosis treatment with once-weekly isoniazid and rifapentine. | Am J Respir Crit Care Med | To understand why once-weekly Isoniazid/rifapentine therapy for tuberculosis was less effective than twice-weekly Isoniazid/rifampin, we studied human immunodeficiency virus-seronegative patients with either failure (n = 4), relapse (n = 35), or cure (n = 94), recruited from a comparative treatment trial. In multivariate analyses that were adjusted for severity of disease, low plasma concentrations of Isoniazid were associated with failure/relapse with once-weekly Isoniazid/rifapentine (median Isoniazid area under the concentration-time curve for 12 hours after the dose [AUC(0-12)] was 36 microg x hour/ml in failure/relapse versus 56 microg x hour/ml in control cases p = 0.005), but not with twice-weekly Isoniazid/rifampin. Furthermore, two patients who relapsed with Mycobacterium tuberculosis monoresistant to rifamycin had very low concentrations of Isoniazid. Finally, Isoniazid acetylator status determined by N-acetyltransferase type 2 genotype was associated with outcome with once-weekly Isoniazid/rifapentine (p = 0.03) but not twice-weekly Isoniazid/rifampin. No rifamycin pharmacokinetic parameter was consistently and significantly associated with outcome (p > 0.10). Because low Isoniazid concentrations were associated with failure/relapse, a drug with consistently greater area under the concentration-time curve than Isoniazid may be needed to achieve highly active once-weekly therapy with rifapentine. |
| 2002 | Therapeutic drug monitoring in the treatment of tuberculosis. | Drugs | Therapeutic drug monitoring (TDM) is a standard clinical technique used for many disease states, including many infectious diseases. As for these other conditions, the use of TDM in the setting of tuberculosis (TB) allows the clinician to make informed decisions regarding the timely adjustment of drug therapy. Such adjustments may not be required for otherwise healthy individuals who are responding to the standard, four-drug TB regimens. However, some patients are slow to respond to treatment, have drug-resistant TB, are at risk of drug-drug interactions or have concurrent disease states that significantly complicate the clinical situation. Such patients may benefit from TDM and early interventions may preclude the development of further drug resistance. It is not possible to collect multiple blood samples in the clinical setting for logistical and financial reasons. Therefore, one typically is limited to one or two time points. When only one sample can be obtained, the 2-hour post-dose concentrations of Isoniazid, rifampin, pyrazinamide and ethambutol are usually most informative. Unfortunately, low 2-hour values do not distinguish between delayed absorption (late peak, close to normal range) and malabsorption (low concentrations at all time points). A second sample, often collected at 6-hour post-dose, can differentiate between these two scenarios. The second time point can also provide some information about clearance and half-life, assuming that drug absorption was nearly completed by 2 hours. TDM requires that samples are promptly centrifuged, and that the serum is promptly harvested and frozen. Isoniazid and ethionamide, in particular, are not stable in human serum at room temperature. Rifampin is stable for more than 6 hours under these conditions. During TB treatment, Isoniazid causes the greatest early reduction in organisms and is considered to be one of the two most important TB drugs, along with rifampin. Although Isoniazid is highly active against TB, low Isoniazid concentrations were associated with poorer clinical and bacteriological outcomes in US Public Health Services (USPHS) TB Trial 22. Several earlier trials showed a clear dose-response for rifampin and pyrazinamide, so low concentrations for those two drugs also may correlate with poorer treatment outcomes. At least in USPHS TB Trial 22, the rifampin pharmacokinetic parameters were not predictive of the outcome variables. In contrast, low concentrations of unbound rifapentine may have been responsible, in part, for the worse-than-anticipated performance of this drug in clinical trials. The 'second-line' TB drugs, including p-aminosalicylic acid, cycloserine and ethionamide, are relatively weak TB drugs. Under the best conditions, treatment with these drugs takes over 2 years, as opposed to 6 to 9 months with Isoniazid- and rifampin-containing regimens. Therefore, TB centres such as National Jewish Medical and Research Center in Denver, CO, USA, measure serum concentrations of the 'second-line' TB drugs early in the course of treatment. That way, poor drug absorption can be dealt with in a timely manner. This helps to minimise the time that patients are sputum smear- and culture-positive with multidrug-resistant TB, and may prevent the need for even longer treatment durations. Patients with HIV are at particular risk for drug-drug interactions. Because the published guidelines typically reflect interactions only between two drugs, these guidelines are of limited value when the patient is treated with three or more interacting drugs. Under such complicated circumstances, TDM often is the best available tool for sorting out these interactions and placing the patient the necessary doses that they require. TDM is only one part of the care of patients with TB. In isolation, it is of limited value. However, combined with clinical and bacteriological data, it can be a decisive tool, allowing the clinician to successfully treat even the most complicated TB patients. |
| 2002 | Rifapentine and isoniazid once a week versus rifampicin and isoniazid twice a week for treatment of drug-susceptible pulmonary tuberculosis in HIV-negative patients: a randomised clinical trial. | Lancet | Rifapentine has a long half-life in serum, which suggests a possible treatment once a week for tuberculosis. We aimed to compare rifapentine and Isoniazid once a week with rifampicin and Isoniazid twice a week.We did a randomised, multicentre, open-label trial in the USA and Canada of HIV-negative people with drug-susceptible pulmonary tuberculosis who had completed 2 months of a 6-month treatment regimen. We randomly allocated patients directly observed treatment with either 600 mg rifapentine plus 900 mg Isoniazid once a week or 600 mg rifampicin plus 900 mg Isoniazid twice a week. Primary outcome was failure/relapse. Analysis was by intention to treat.1004 patients were enrolled (502 per treatment group). 928 successfully completed treatment, and 803 completed the 2-year 4-month study. Crude rates of failure/relapse were 46/502 (9.2%) in those on rifapentine once a week, and 28/502 (5.6%) in those given rifampicin twice a week (relative risk 1.64, 95% CI 1.04-2.58, p=0.04). By proportional hazards regression, five characteristics were independently associated with increased risk of failure/relapse: sputum culture positive at 2 months (hazard ratio 2.8, 95% CI 1.7-4.6); cavitation on chest radiography (3.0, 1.6-5.9); being underweight (3.0, 1.8-4.9); bilateral pulmonary involvement (1.8, 1.0-3.1); and being a non-Hispanic white person (1.8, 1.1-3.0). Adjustment for imbalances in 2-month culture and cavitation diminished the association of treatment group with outcome (1.34; 0.83-2.18; p=0.23). Of participants without cavitation, rates of failure/relapse were 6/210 (2.9%) in the once a week group and 6/241 (2.5%) in the twice a week group (relative risk 1.15; 95% CI 0.38-3.50; p=0.81). Rates of adverse events and death were similar in the two treatment groups.Rifapentine once a week is safe and effective for treatment of pulmonary tuberculosis in HIV-negative people without cavitation on chest radiography. Clinical, radiographic, and microbiological data help to identify patients with tuberculosis who are at increased risk of failure or relapse when treated with either regimen. |
| 2002 | A prospective, randomized, double-blind study of the tolerability of rifapentine 600, 900, and 1,200 mg plus isoniazid in the continuation phase of tuberculosis treatment. | Am J Respir Crit Care Med | Once-weekly rifapentine 600 mg plus Isoniazid (INH) during the continuation phase treatment of tuberculosis is associated with a relapse rate higher than that of twice-weekly rifampin plus INH. The safety and tolerability of higher rifapentine doses need to be determined. We conducted a prospective, randomized, double-blind trial of rifapentine at three doses (600, 900, and 1,200 mg) plus INH 15 mg/kg once weekly in the continuation phase treatment of culture-positive tuberculosis in 150 human immunodeficiency virus-seronegative adults. Outcome measures were discontinuation of therapy for any reason and adverse events on therapy. Treatment was discontinued in 3 of 52 (6%), 2 of 51 (4%), and 3 of 47 (6%) in the rifapentine 600-, 900-, and 1,200-mg treatment arms, respectively. Only one discontinuation, in the rifapentine 1,200-mg arm, was due to an adverse event possibly associated with study therapy. There was a trend toward more adverse events, possibly associated with study therapy, in the highest-dose arms (p = 0.051). Rifapentine 900-mg, once-weekly dosing appears to be safe and well tolerated and is being evaluated in Phase III efficacy trials of treatment of latent tuberculosis. Further evaluation of the safety and tolerability of rifapentine 1,200 mg is warranted. |
| 2002 | Rifapentine and isoniazid in the continuation phase of a 6-month regimen. Final report at 5 years: prognostic value of various measures. | Int J Tuberc Lung Dis | Clinical trial in 672 patients with newly diagnosed pulmonary tuberculosis in Hong Kong. After an initial 2 months of a four-drug intensive phase consisting of thrice-weekly streptomycin, Isoniazid, rifampicin and pyrazinamide (SHRZ), a random allocation was made to a continuation phase of once-weekly 600 mg rifapentine + 15 mg/kg Isoniazid (HRp1), HRp1 given in 2 of every 3 weeks (HRp1.2/3), or to thrice-weekly Isoniazid + rifampicin (HR3), the standard treatment in Hong Kong.Final report evaluating adverse events (46 relapses and one failure) after 5 years and the prognostic influence of various factors.Kaplan-Meier analysis of adverse events and Cox proportional hazards analysis of prognostic factors.The two rifapentine regimens, HRp1 and HRp1.2/3 had similar final rates of adverse events of 10.8% and 11.7%, respectively, compared to 4.2% for the HR3 regimen (P = 0.02 and 0.009, respectively). In the initial univariate proportional hazards analysis, adverse events were significantly related to the regimen, age, sex, pretreatment radiographic extent of disease and cavitation, and also to sputum culture at 2 months. In the final multivariate analysis, after step-wise removal of non-significant factors, adverse events were related only to the regimen, patients' sex and pretreatment radiographic extent of disease. Elderly male patients were more at risk of an adverse event, as were those with more severe disease. Adverse events occurred at life table rates of 9.0% in patients with drug-sensitive strains and in 8.9% of those with initially Isoniazid-resistant organisms at 5 years.The two rifapentine regimens were unsatisfactory because of their high incidence of adverse events. Isoniazid appeared not to contribute to preventing relapse. Further studies with increased rifapentine dosage are necessary. |
| 2001 | Effectiveness of once-weekly rifapentine and moxifloxacin regimens against Mycobacterium tuberculosis in mice. | Antimicrob Agents Chemother | Mice infected with 1.6 x 10(7) CFU of Mycobacterium tuberculosis were treated 14 days later for 6 months with a regimen of once-weekly 10 mg of rifapentine and 75 mg of Isoniazid per kg of body weight supplemented with either 150 mg of streptomycin per kg or 100 mg of moxifloxacin per kg during either both the 2-week daily initial and once-weekly continuation phases or only in the daily 2-week initial phase. On completion of treatment, all lung cultures were negative, except for three mice, each with a single colony: two whose rifapentine-Isoniazid regimen was supplemented with streptomycin during the whole course of therapy and one whose rifapentine-Isoniazid regimen had no initial daily phase, but was supplemented with streptomycin and moxifloxacin during the whole course of therapy. After 3 months of follow-up, positive lung cultures were obtained from 61 and 56% of mice supplemented with streptomycin during either the full course of therapy or only the daily 2-week initial phase, respectively, and 15 and 50% of mice supplemented with moxifloxacin during either the full course of therapy or only the daily 2-week initial phase, respectively. These results suggest that moxifloxacin has sterilizing activity against M. tuberculosis. |
| 2000 | Role of individual drugs in the chemotherapy of tuberculosis. | Int J Tuberc Lung Dis | During the course of chemotherapy, certain drugs are predominant in their bactericidal activities. Isoniazid is responsible for an initial kill of about 95% of organisms during the first 2 days of treatment. Its bactericidal role is then replaced by rifampicin and pyrazinamide during the intensive phase. In the continuation phase with an Isoniazid/rifampicin regimen, rifampicin is the only effective drug against persisters, as shown by the similarity of response by patients with initially Isoniazid-resistant or sensitive strains. If the continuation phase regimen does not contain rifampicin but does contain Isoniazid, the dominant bactericidal drug is Isoniazid. In this case, the response of patients with initial Isoniazid resistance is appreciably less good than in those with sensitive organisms. The review suggests exploration in randomised control trials of a continuation phase of rifampicin (or rifapentine) alone. It also suggests the importance of the dose size of rifampicin and the need for exploring a higher dose. Finally, it emphasises the importance of finding drugs that act on persisting organisms that are phenotypically but not genetically resistant to rifampicin. |
| 2000 | Antituberculosis activity of once-weekly rifapentine-containing regimens in mice. Long-term effectiveness with 6- and 8-month treatment regimens. | Am J Respir Crit Care Med | The effectiveness of various once-weekly 10 mg/kg rifapentine (P)- containing regimens for treatment of tuberculosis was assessed in mice infected intravenously with 4.3 x 10(6) colony-forming units (cfu) of Mycobacterium tuberculosis H37Rv, and treated 14 d later with various combinations of rifampin (R), P, Isoniazid (H), pyrazinamide (Z), ethambutol (E), or streptomycin (S). Control mice treated daily with either 2-mo HRZ + 4-mo HR or 2-mo HRZ + 6-mo HE were rendered spleen and lung culture-negative at 6 mo and 8 mo, respectively. Treatment failure with emergence of R-resistant bacilli occurred in all mice given once-weekly monotherapy with P for 6 mo. Once-weekly PH treatment was successful at 6 mo when it was preceded by a 2-mo daily phase with HRZ. When the initial daily phase was reduced to 2 wk, once-weekly PH-containing treatment was successful, at 6 mo, only if it was supplemented with S during the initial daily and the once-weekly phases, and at 8 mo if it was supplemented with daily H during the once-weekly phase. Without these supplements, once-weekly treatment failed in some mice with selection of R-resistant or H-resistant mutants. |
| 2000 | Rifapentine and isoniazid in the continuation phase of a 6-month regimen. Interim report: no activity of isoniazid in the continuation phase. | Int J Tuberc Lung Dis | Clinical trial amongst 762 patients with newly diagnosed pulmonary tuberculosis in Hong Kong. After an initial 2 months of a four-drug intensive phase consisting of streptomycin, Isoniazid, rifampicin and pyrazinamide (SHRZ), a random allocation in continuation to once-weekly rifapentine + Isoniazid (HRp1), HRp1 given in 2 of every 3 weeks (HRp1.2/3), or to three times weekly Isoniazid + rifampicin (HR3).Interim report evaluating progress of study and the role of Isoniazid in the continuation phase.Kaplan-Meier analysis and response of patients related to susceptibility of pretreatment organisms to Isoniazid and to rate of Isoniazid acetylation determined by NAT2 genotyping.In the 30-month follow-up, rates for adverse treatment events (failure and relapse) were 4.2% in the HR3, 10.2% in the HRp1 and 11.2% in the HRp1.2/3 series (P = 0.02 for HR3 vs HRp1 and P = 0.01 for HR3 vs HRp1.2/3). Occurrence of adverse events was not related to initial susceptibility to Isoniazid nor to the rate of acetylation of Isoniazid.The two rifapentine regimens had similar final rates of adverse events which were unsatisfactory. Isoniazid had little or no activity in the continuation phase, indicating that no improvement of the continuation regimen is likely to be obtained by alteration of the Isoniazid dosage. |
| 1999 | Rifapentine: its role in the treatment of tuberculosis. | Ann Pharmacother | To review the pharmacokinetics, efficacy, adverse effects, and cost of the newest antitubercular drug, rifapentine.A MEDLINE search using key terms such as rifapentine, rifampin, Isoniazid, Mycobacterium tuberculosis, and pyrazinamide was conducted for the time period 1966-November 1998.Animal data were used for basic information and human studies were selected for inclusion if they were randomized, controlled studies assessing efficacy, or if they were single- or multiple-dose studies assessing the pharmacokinetics of rifapentine. Background articles on the pathophysiology of tuberculosis and cost of care and noncontrolled studies assessing drug interactions were also included.Compared with an oral solution, the relative bioavailability of rifapentine is 70% following oral admninistration of tablets. Food increased bioavailability by 55%. Rifapentine accumulated significantly in human macrophages and its elimination half-life was longer than that of rifampin. Comparative studies of rifapentine and rifampin in humans during intensive- and continuation-phase treatment of tuberculosis suggest that at currently accepted doses, rifapentine was slightly less effective than rifampin. The most significant drug interaction with rifapentine involves indinavir: the maximum concentration and AUC of indinavir are reduced by 55% and 70%, respectively, when rifapentine is coadministered with indinavir. Adverse events of rifapentine may occur less frequently at the currently recommended 600-mg dose as compared with rifampin; however, the difference was not statistically significant. If only drug costs were evaluated during the six-month treatment of tuberculosis, rifapentine is more expensive than rifampin.Rifapentine can be administered twice weekly during the intensive phase of tuberculosis treatment and then once weekly during the continuation phase of treatment. This may improve patient adherence over some other treatments and possibly reduce costs of treatment by preventing development of resistant tubercular strains due to nonadherence. Rifapentine is well tolerated, with most patients experiencing adverse effects at a similar rate as rifampin. Rifapentine induces cytochrome P450 somewhat less than rifampin, although few drug interaction studies have been done with rifapentine. Its efficacy at the currently approved dosage of 600 mg may be slightly lower than that of rifampin. Studies are needed to determine if equal or greater efficacy can be achieved with higher doses of rifapentine. Rifampin is less expensive than rifapentine. Further pharmacoeconomic studies are needed to evaluate costs of relapse and failure in patients receiving these agents. |
| 1999 | Evaluation of rifapentine in long-term treatment regimens for tuberculosis in mice. | Antimicrob Agents Chemother | Besides direct bactericidal activity, long-term effectiveness is one of the most important features to consider when developing new drugs for chemotherapy. In this study, we evaluated the ability of rifapentine (RFP), in monotherapy and combination therapy, to completely eradicate a Mycobacterium tuberculosis infection and to prevent relapse posttreatment in a Swiss mouse model. The combination of RFP, Isoniazid (INH), and pyrazinamide (PZA) administered daily resulted in an apparent clearance of M. tuberculosis organisms in the lungs and spleens of infected mice after 10 weeks of treatment. However, 3 months after the cessation of therapy, bacterial regrowth occurred in mice treated for a 12-week period, indicating a relapse of infection. In intermittent treatment regimens of RFP in combination with INH and PZA, sterilization was achieved when mice were treated two to five times per week for 9 weeks. Bacterial growth was still observed in the once-weekly treatment group. Our results show that mouse models can predict important parameters for new drugs. We stress the necessity for long-term posttreatment observation in animal models for the routine evaluation of new drugs for antituberculosis chemotherapy. |
| 1999 | Analysis of rifapentine for preventive therapy in the Cornell mouse model of latent tuberculosis. | Antimicrob Agents Chemother | Rifapentine is a long-acting rifamycin which may be useful for intermittent drug therapy against tuberculosis. In this study we measured the efficacies of rifapentine-containing intermittent drug regimens for preventive therapy using the Cornell mouse model of latent tuberculosis. We infected groups of mice intravenously with Mycobacterium tuberculosis and then treated them with Isoniazid and pyrazinamide for 12 weeks according to the Cornell latency development protocol. After a 4-week interval of no treatment, experimental preventive therapy was administered by esophageal gavage for 12 or 18 weeks. After equilibration and dexamethasone amplification treatment, mouse organs were analyzed by quantitative colony counts to measure the effectiveness of therapy. Our results showed that once-weekly Isoniazid plus rifapentine combination therapy for 18 weeks was an effective preventive regimen with sterilizing potency and bacillary load reduction comparable to those of daily Isoniazid therapy for 18 weeks. Monotherapy with rifapentine weekly or fortnightly or with rifampin twice weekly for up to 18 weeks did not offer advantages in reducing bacillary load or in sterilizing organs compared to the effects of a placebo. These results with the Cornell mouse model indicate that once-weekly, short-course preventive therapy with Isoniazid plus rifapentine is effective and may warrant investigation in humans with latent tuberculosis infection. |
| 1999 | Acquired rifamycin monoresistance in patients with HIV-related tuberculosis treated with once-weekly rifapentine and isoniazid. Tuberculosis Trials Consortium. | Lancet | Rifapentine is a cyclopentyl-substituted rifamycin whose serum half-life is five times that of rifampin. The US Public Health Service Study 22 compared a once-weekly regimen of Isoniazid and rifapentine with twice weekly Isoniazid and rifampin in the continuation phase (the last 4 months) of treatment for pulmonary tuberculosis in HIV-seropositive and HIV-seronegative patients. This report concerns only the HIV-seropositive part of the trial, which has ended. The HIV-seronegative part will stop follow-up in 2001.Adults with culture-positive, drug-susceptible pulmonary tuberculosis who completed 2 months of four-drug (Isoniazid, rifampin, pyrazinamide, ethambutol) treatment (induction phase) were randomly assigned 900 mg Isoniazid and 600 mg rifapentine once weekly, or 900 mg Isoniazid and 600 mg rifampin twice weekly. All therapy was directly observed. Statistical analysis used univariate, Kaplan-Meier, and logistic and proportional hazards regression methods.71 HIV-seropositive patients were enrolled: 61 completed therapy and were assessed for relapse. Five of 30 patients in the once-weekly Isoniazid/rifapentine group relapsed, compared with three of 31 patients in the twice-weekly Isoniazid/rifampin group (log rank chi2=0.69, p=0.41). However, four of five relapses in the once-weekly Isoniazid/rifapentine group had monoresistance to rifamycin, compared with none of three in the rifampin group (p=0.05). Patients who relapsed with rifamycin monoresistance were younger (median age 29 vs 41 years), had lower baseline CD4 cell counts (median 16 vs 144 microL), and were more likely to have extrapulmonary involvement (75% vs 18%, p=0.03) and concomitant therapy with antifungal agents (75% vs 9%, p=0.006). No rifamycin monoresistant relapse has occurred among 1004 HIV-seronegative patients enrolled to date.Relapse with rifamycin monoresistant tuberculosis occurred among HIV-seropositive tuberculosis patients treated with a once-weekly Isoniazid/rifapentine continuation-phase regimen. Until more effective regimens have been identified and assessed in clinical trials, HIV-seropositive people with tuberculosis should not be treated with a once-weekly Isoniazid/rifapentine regimen. |
| 1999 | Determination of rifampicin and its main metabolite in plasma and urine in presence of pyrazinamide and isoniazid by HPLC method. | J Pharm Biomed Anal | A reversed phase HPLC method is described for the simultaneous estimation of rifampicin and its major metabolite desacetyl rifampicin, in the presence of Isoniazid and pyrazinamide, in human plasma and urine. The assay involves simple liquid extraction of drug, metabolite and internal standard (rifapentine) from biological specimens and their subsequent separation on a C18 reversed phase column and single wavelength UV detection. In plasma as well as in urine samples, all the three compounds of interest eluted within 17 min. Using methanol-sodium phosphate buffer (pH 5.2; 0.01 M) (65:35, v/v) as mobile phase under isocratic conditions, it was established that Isoniazid, pyrazinamide and ascorbic acid (added to prevent oxidative degradation of analytes) did not interfere with the analyte peaks. Recoveries (extraction efficiency) for drug were greater than 90% in both plasma and urine, whereas for metabolite the values were found to be 79 and 86% in plasma and urine, respectively. The plasma and urine methods were precise (total coefficient of variation ranged from 5 to 23%) and accurate (-7 to 5% of the nominal values) for both the analytes. Individual variance components, their estimates and their contribution to the total variance were also determined. Using the same method, unknown samples supplied by WHO were assayed and good correlations were obtained between the found and intended values. The method developed proved to be suitable for simultaneous estimation of rifampicin and desacetyl rifampicin in plasma and urine samples. |
| 1998 | Rifapentine. | Drugs | Rifapentine is a rifamycin antibiotic with antimycobacterial activity. Rifapentine is generally more active against Mycobacterium tuberculosis than rifampicin (rifampin), although strains resistant to rifampicin are usually cross-resistant to rifapentine. Sputum culture conversion rates were slightly higher after 6 months of rifapentine- versus rifampicin-based therapy in patients with pulmonary tuberculosis in a Western study; however, relapse rates were higher in rifapentine recipients during follow-up. The excess relapses in the rifapentine group appeared to be related to poor compliance with nonrifamycin antituberculosis drugs during the intensive phase (first 2 months) of therapy. Rifapentine- and rifampicin-containing regimens produced similar sputum culture conversion rates with low rates of relapse in 2 randomised clinical trials in patients with smear-positive tuberculosis in China. In one trial, there was no difference in sputum culture conversion rates in patients treated with rifapentine once weekly or rifampicin twice weekly in combination with Isoniazid and ethambutol during the continuation phase of treatment. Hyperuricaemia, which was reported only during the intensive phase, elevated ALT and AST levels and neutropenia were the most common treatment-related adverse events reported in patients receiving rifapentine- or rifampicin-containing regimens for tuberculosis in 1 Western study. |
| 1998 | Evaluation of once-weekly therapy for tuberculosis using isoniazid plus rifamycins in the mouse aerosol infection model. | Antimicrob Agents Chemother | Once-weekly therapy with combinations of Isoniazid plus a rifamycin was tested in the mouse low-dose aerosol infection model against two strains of Mycobacterium tuberculosis. Combinations of Isoniazid and rifalizil and Isoniazid and rifapentine were both highly effective. These animal model data thus support the evaluation of these regimens under clinical conditions. |
| 1998 | Rifapentine and isoniazid in the continuation phase of treating pulmonary tuberculosis. Initial report. | Am J Respir Crit Care Med | A randomized comparison has been made of three times weekly rifampin plus Isoniazid (HR3) with rifapentine plus Isoniazid given once weekly (HRp1) or on 2 of 3 wk (HRp1.2/3) in the continuation phase of 6-mo regimens (each starting with an initial 2 mo of 4-drug therapy) for the treatment of pulmonary tuberculosis in 672 Chinese patients in Hong Kong. Because of poor bioavailability of the rifapentine used (produced in China), its dose size was increased from 600 mg initially to about 750 mg in the last third of patients to obtain serum concentrations similar to those with rifapentine of Western origin; all doses were given after a meal promoting absorption. After initial exclusions, an intent to treat analysis, done on the remaining 592 patients, showed 45 adverse treatment events in 7 of 190 HR3 patients, in 17 of 199 HRp1 patients, and in 21 of 203 HRp1.2/3 patients; of these, 42 were bacteriological or radiographic relapses after the end of treatment (HR3 versus HRp1, p = 0.04; HR3 versus HRp1.2/3, p = 0.01). Patients with organisms initially sensitive or resistant to Isoniazid or streptomycin had similar relapse rates. The high relapse rate in the HRp1 regimen suggests that the rifapentine dose should be increased. Similarity of relapse rates, 8.9% and 10.4%, after the HRp1 and HRp1.2/3 regimens, respectively, indicates that irregularity in taking rifapentine/Isoniazid could be tolerated. The few adverse side effects in the continuation phase in the rifapentine regimens were less frequent than in the HR3 regimen. |
| 1998 | Once-weekly rifapentine-containing regimens for treatment of tuberculosis in mice. | Am J Respir Crit Care Med | The bactericidal activities of several once-weekly rifapentine (P)-containing combination regimens against Mycobacterium tuberculosis, and their ability to prevent the selection of rifampin (R)-resistant mutants, were compared with those of the standard six-times-weekly regimen consisting of R, Isoniazid (H), and pyrazinamide (Z) in a mouse experiment. Mice were infected intravenously with 1.3 x 10(7) cfu of M. tuberculosis strain H37Rv, and 8 wk of treatment began on Day 14 after infection, when mice were randomly allocated to an untreated control group and nine treatment groups of 30 mice each. At the end of 8 wk of treatment, all the tested regimens showed promising bactericidal activities. Once-weekly P alone was less bactericidal than six-times-weekly R alone; likewise, the once-weekly P-containing combined regimens were less bactericidal than the six-times-weekly standard regimen. However, the difference in killing was about 1 log10, which represented only a fraction of the overall 4 log10 to 5 log10 magnitude of killing effects. The addition of streptomycin (S) improved the bactericidal effect of once-weekly PHZ, and the effect of once-weekly PHZS was further enhanced when it was preceded by 2 wk of daily HZS. The latter regimen achieved the same level of activity as the standard six-times-weekly regimen. All of the once-weekly P-containing combined regimens were able to prevent the selection of R-resistant mutants, whereas monotherapy with R or P selected resistant mutants in approximately 50% of animals. |
| 1995 | New drugs for tuberculosis. | Eur Respir J Suppl | Since the late 1960s, tuberculosis has been successfully cured with antibiotics. With the introduction of rifampin, "short course" regimens using Isoniazid and rifampin together with either streptomycin, ethambutol or pyrazinamide, for 6-9 months, have been successfully adopted. The spread of drug resistant M. tuberculosis strains in large urban areas has made this armamentarium of drugs insufficient, calling for the development of new drugs. Among rifamycin derivatives, rifabutin is more active than rifampin in vitro and in experimental animals, and allows sputum conversion rats of 95-100%. It is effective in treating multidrug-resistant tuberculosis. Rifapentine is more active than rifampin in vitro and has a longer half-life, but it is not active against rifampin-resistant strains. Fluoroquinolones concentrate within macrophages, are effective against M. tuberculosis and act synergistically with rifampin and Isoniazid. Ofloxacin, ciprofloxacin, sparfloxacin and lomefloxacin have been evaluated as antimycobacterial agents, and no cross-resistance with major antituberculous drugs has been found. Several other drugs, including new inhibitors of beta-lactamase and new beta-lactamase-resistant antibiotics, the aminoglycoside antibiotic, paromomycin, and the new nitroimidazole, 2-ethyl-5-intro-2.3-dihydro imidazo-oxazole, have been found to be active in vitro against M. tuberculosis. |
| 1994 | Preventive therapy of tuberculosis with rifapentine in immunocompetent and nude mice. | Am J Respir Crit Care Med | The effectiveness of intermittent administration of rifapentine (RPT), with or without Isoniazid (INH), for preventive therapy of tuberculosis was evaluated in immunocompetent (normal) and nude mice. After infection with a small inoculum of Mycobacterium tuberculosis H37Rv, normal mice developed a chronic and nonfatal infection, and the bacterial population became relatively stable after an initial period of limited multiplication. On the other hand, nude mice developed an acute and fatal infection, and all untreated mice died within 5 wk, with very high colony-forming-unit (CFU) counts in their organs. Various degrees of bactericidal activity were shown in normal mice after daily treatment with rifampin (RMP) plus pyrazinamide (PZA) for 13 wk, INH daily for 26 wk, or RPT once weekly for 13 or 26 wk or once fortnightly for 26 wk. The activity of RPT was significantly enhanced when INH was added at the same dosing frequency. In nude mice the response of M. tuberculosis infection to certain regimens was less favorable than that in normal mice, suggesting that preventive therapy may be less effective in severely immunodeficient hosts even during treatment. After chemotherapy was stopped, virtually all nude mice relapsed within 12 wk regardless of the regimen administered, whereas no or very few relapses were observed in normal mice that had been treated with RMP+PZA daily for 13 wk, or RPT alone or RPT+INH once weekly for 26 wk. The latter three regimens and RPT+INH once weekly for 13 wk may be applied for fixed-duration preventive therapy in human immunodeficiency virus (HIV)-negative subjects.(ABSTRACT TRUNCATED AT 250 WORDS) |
| 1994 | Antimycobacterial drugs. | Semin Respir Infect | This review consists of the following three sections: (1) General principles in selecting antimycobacterial drugs for the treatment regimens, (2) The antimicrobial activity in vitro with an emphasis on inhibitory and bactericidal potency of various agents, and (3) Drug susceptibility testing including methodology and interpretation of the test results. Each of these sections addresses three groups of antimycobacterial agents: (1) against tuberculosis, (2) against Mycobacterium avium complex infections, and (3) against infections caused by M. fortuitum and M chelonae. The following are the drugs examined in the sections and subsections of this review: Isoniazid, ethionamide, thiacetazone, rifampin, rifabutin, rifapentine, KRM-1648, pyrazinamide, streptomycin, kanamycin, amikacin, capreomycin, gentamicin, tobramycin, ethambutol, para-aminosalicylic acid, D-cycloserine, ofloxacin, levofloxacin, ciprofloxacin, sparfloin, clofazimine, clarithromycin, azithromycin, erythromycin, cefoxitin, cefmetazole, imipenem, sulfamethoxazole, sulfisoxazole, sulfadiazine, sulfathiazole, trimethoprim, and doxycycline. |
| 1992 | Epithelial cells in culture as a model for the intestinal transport of antimicrobial agents. | Antimicrob Agents Chemother | The bioavailabilities of orally administered drugs depend to a great extent on their capability of being transported across the intestinal mucosa. In an attempt to develop an in vitro model for studying the intestinal transport of drugs, we used an intestinal epithelial cell line (Caco 2) derived from a human colon adenocarcinoma. A renal epithelial cell line (MDCK) was also used to determine the tissue specificity of drug transport. These cell lines, which were grown on filters, form a monolayer of well-polarized cells coupled by tight junctions and can be used for transcellular transport experiments. We studied the transport of nine antimicrobial agents with different physicochemical and pharmacokinetic characteristics using these epithelial cell monolayers to determine whether this model could be predictive of oral bioavailability. The transepithelial passage was assayed from the apical (AP) to the basolateral (BL) side and in the opposite direction (BL to AP) in both cell lines. Radioactively labeled mannitol was used to monitor the intactness of the cell monolayer during drug passage. The results indicated that all antimicrobial agents tested tended to behave in vitro generally according to their known in vivo absorptive characteristics. In addition, the use of epithelia from different tissues enabled us to divide the drugs into four groups according to their behaviors and suggested the existence of different transport mechanisms. In particular, two antibiotics, gentamicin and teicoplanin, showed no passage in either direction or cell line, in accordance with their very poor in vivo absorbances after oral administration. In contrast, rifapentine, rifampin, and nalidixic acid passed very efficiently at similar rates in both directions and cell lines in a concentration-dependent, nonsaturable manner, which is suggestive of passive diffusion down a concentration gradient. Of the remaining drugs, Isoniazid and novobiocin sodium showed some differences in passage between the two cell lines and, given their ionized state at the pH that was used, may use the paracellular route. Finally, trimethoprim and D-cycloserine exhibited differences in passage both with respect to polarity and cell line; in particular, trimethoprim had a faster rate of passage only in Caco 2 cells and in the BL to AP direction, while D-cycloserine was exclusively transported by Caco 2 cells in the AP to BL direction. In both cases it is possible that active transport mechanisms are involved. |
| 1992 | Activity of two long-acting rifamycins, rifapentine and FCE 22807, in experimental murine tuberculosis. | Tuber Lung Dis | The efficacy of the long-acting rifamycins, rifapentine (RPE) and FCE 22807 (FCE) in experimental murine tuberculosis was studied by counting viable bacilli in spleens. At 2 weeks after infection with Mycobacterium tuberculosis, strain H37Rv, treatment with Isoniazid 25 mg/kg, rifampicin 10 mg/kg and pyrazinamide 150 mg/kg was given daily for 6 weeks. The mice were then divided into groups given RPE or FCE at intervals of 1, 2 or 3 weeks with spleen counts after 18 and 24 weeks of chemotherapy. The first experiment showed the great effect of the size of the dose of RPE, which, in once-weekly regimens, caused rapid sterilization at 16 mg/kg, less rapid sterilization at 10 mg/kg and incomplete activity at 6.25 mg/kg. Regimens of RPE given every 2 or 3 weeks were less effective, though 16 mg/kg fortnightly was as good as 6 mg/kg once-weekly. The second experiment compared RPE and FCE each given at 12 or 8 mg/kg. The results were similar though, at 8 mg/kg every 2 or 3 weeks, FCE was slightly more effective than RPE. Serum assays showed that the levels with 8 and 12 mg/kg FCE were lower than those produced even by 6.25 mg/kg RPE, suggesting that FCE would be a better drug than RPE if its bioavailability could be improved, and that the levels following 16 mg/kg RPE were similar to those found in man after 8 mg/kg RPE taken with a fat-rich meal, suggesting good prospects for effective once-fortnightly human treatment. The potential for long-acting rifamycins in the management of pulmonary tuberculosis is discussed. |