| 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 | 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 | 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. |
| 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 $100 000/QALY willingness-to-pay threshold for non-US born patients with no comorbidities, patients with diabetes, and patients with HIV. |
| Cost effectiveness of interferon-gamma release assay for tuberculosis screening using three months of rifapentine and isoniazid among long-term expatriates from low to high incidence countries. | Travel Med Infect Dis | Long-term expatriates from low to high tuberculosis (TB) incidence countries get high rates of active TB and latent TB infection (LTBI). TB screening for expatriates is important for occupational health. Interferon-gamma release assays are more accurate than tuberculin skin test (TST). Rifapentine plus isoniazid for 3 months (3HP) is as effective as 9 months of isoniazid (9H) with a higher treatment-completion rate.Decision trees and Markov models were constructed using a societal perspective on a lifetime horizon. The target population was a hypothetical cohort of 30 year-old expatriates. Seven strategies; TST with 3HP or 9H, QuantiFERON-TB Gold In-Tube (QFT) with 3HP or 9H, T-SPOT.TB (TSPOT) with 3HP or 9H and chest X-ray examination (CXR) were modeled. The main outcome measure of effectiveness was quality-adjusted life-years (QALYs) gained.QFT with 3HP yielded the greatest benefits with the lowest cost ($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 | 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. |
| 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 | 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. |
| 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. |