The production of guidelines for the management of drug-resistant tuberculosis (TB) fits the mandate of the World Health Organization (WHO) to support countries in the reinforcement of patient care.WHO commissioned external reviews to summarise evidence on priority questions regarding casefinding, treatment regimens for multidrug-resistant TB (MDR-TB), monitoring the response to MDR-TB treatment, and models of care. A multidisciplinary expert panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to develop recommendations.The recommendations support the wider use of rapid drug susceptibility testing for isoniazid and rifampicin or rifampicin alone using molecular techniques. Monitoring by sputum culture is important for early detection of failure during treatment. Regimens lasting o20 months and containing pyrazinamide, a fluoroquinolone, a second-line injectable drug, ethionamide (or prothionamide), and either cycloserine or p-aminosalicylic acid are recommended. The guidelines promote the early use of antiretroviral agents for TB patients with HIV on second-line drug regimens. Systems that primarily employ ambulatory models of care are recommended over others based mainly on hospitalisation.Scientific and medical associations should promote the recommendations among practitioners and public health decision makers involved in MDR-TB care. Controlled trials are needed to improve the quality of existing evidence, particularly on the optimal composition and duration of MDR-TB treatment regimens.
fIn an effort to update and clarify policies on tuberculosis drug susceptibility testing (DST), the World Health Organization (WHO) commissioned a systematic review evaluating WHO-endorsed diagnostic tests. We report the results of this systematic review and meta-analysis of the diagnostic accuracy and reproducibility of phenotypic DST for first-line and second-line antituberculosis drugs. This review provides support for recommended critical concentrations for isoniazid and rifampin in commercial broth-based systems. Further studies are needed to evaluate critical concentrations for ethambutol and streptomycin that accurately detect susceptibility to these drugs. Evidence is limited on the performance of DST for pyrazinamide and second-line drugs.T he global epidemic of drug-resistant tuberculosis (DR-TB), particularly multidrug-resistant TB (MDR-TB, defined as resistance to at least isoniazid and rifampin), is one of the most serious problems facing TB care and control efforts. In their most recent worldwide survey, the World Health Organization (WHO) documented the highest rates of MDR-TB ever reported (1). Effective management of drug-resistant TB relies on multiple components, including detection, treatment, prevention, surveillance, and continuous program evaluation (2). Expanding the capacity to diagnose cases of drug-resistant TB is a priority for global TB control, requiring clear policies on the use of diagnostic tests and strengthened laboratories in which testing can be safely and effectively carried out (3).Conventional phenotypic drug susceptibility testing (DST) using the proportion method (PM) on solid media has been well studied for isoniazid and rifampin, with a general consensus achieved regarding methodology, critical concentrations, and expected performance (4). However, the diagnostic accuracy and reproducibility of DST for other first-line and second-line drugs are inadequate (5). DST for second-line anti-TB drugs has not been standardized internationally, which is reflected in the wide variability of practices among supranational reference laboratories, underscoring the need for standardization of the methods and interpretive criteria for second-line DST (4, 6). Further complicating the lack of consensus is the increasing number of different DST methods that are available. In 2008, the WHO Stop TB Department published interim laboratory policy guidance for DST of second-line anti-TB drugs (4). Guideline recommendations for a specific DST method should ideally be based on the diagnostic test accuracy, reproducibility, ease of use, cost, and rapidity of result availability.In an attempt to address gaps in the evidence base, WHO initiated an update to the 2008 interim guidelines with an expanded scope to include DST for all first-line and second-line drugs. As part of the update, we conducted a systematic review to determine the diagnostic accuracy and reproducibility of WHO-endorsed phenotypic DST methods and commercial genotypic DST methods for first-line and second-line anti-TB drugs. Whi...
BackgroundEvidence of an association between cigarette smoking and latent tuberculosis infection (LTBI) is based on studies in special populations and/or from high prevalence settings. We sought to evaluate the association between LTBI and smoking in a low prevalence TB setting using population-based data from the National Health and Nutrition Examination Survey (NHANES).MethodsIn 1999–2000, NHANES assessed LTBI (defined as a tuberculin skin test measurement ≥10 mm) in participants, and those ≥20 years of age were queried regarding their tobacco use and serum cotinine was measured. We evaluated the association of LTBI with self-reported smoking history and smoking intensity in multivariable logistic regression models that adjusted for known confounders (gender, age, birthplace, race/ethnicity, poverty, education, history of BCG vaccination, and history of household exposure to tuberculosis disease).ResultsEstimated LTBI prevalence was 5.3% among those ≥20 years of age. The LTBI prevalence among never smokers, current smokers, and former smokers was 4.1%, 6.6%, and 6.2%, respectively. In a multivariable model, current smoking was associated with LTBI (OR 1.8; 95% CI, 1.1–2.9). The association between smoking and LTBI was strongest for Mexican-American and black individuals. In multivariate analysis stratified by race/ethnicity, cigarette packs per day among Mexican-American smokers and cotinine levels among black smokers, were significantly associated with LTBI.ConclusionsIn the large, representative, population-based NHANES sample, smoking was independently associated with significantly increased risks of LTBI. In certain populations, a greater risk of LTBI corresponded with increased smoking exposure.
IntroductionUse of antiretroviral therapy (ART) during treatment of drug susceptible tuberculosis (TB) improves survival. However, data from HIV infected individuals with drug resistant TB are lacking. Second line TB drugs when combined with ART may increase drug interactions and lead to higher rates of toxicity and greater noncompliance. This systematic review sought to determine the benefit of ART in the setting of second line drug therapy for drug resistant TB.MethodsWe included individual patient data from studies that evaluated treatment of drug-resistant tuberculosis in HIV-1 infected individuals published between January 1980 and December of 2009. We evaluated the effect of ART on treatment outcomes, time to smear and culture conversion, and adverse events.ResultsTen observational studies, including data from 217 subjects, were analyzed. Patients using ART during TB treatment had increased likelihood of cure (hazard ratio (HR) 3.4, 95% CI 1.6–7.4) and decreased likelihood of death (HR 0.4, 95% CI 0.3–0.6) during treatment for drug resistant TB. These associations remained significant in patients with a CD4 less than 200 cells/mm3 and less than 50 cells/mm3, and when correcting for drug resistance pattern.LimitationsWe identified only observational studies from which individual patient data could be drawn. Limitations in study design, and heterogeneity in a number of the outcomes of interest had the potential to introduce bias.DiscussionWhile there are insufficient data to determine if ART use increases adverse drug interactions when used with second line TB drugs, ART use during treatment of drug resistant TB appears to improve cure rates and decrease risk of death. All individuals with HIV appear to benefit from ART use during treatment for TB.
Summary Humans exposed to Mycobacterium tuberculosis (Mtb) show variation in susceptibility to infection and differences in tuberculosis (TB) disease outcome. Toll-like receptor 9 (TLR9) is a pattern recognition receptor that mediates recognition of Mtb and modulates Mtb-specific T-cell responses. Using a case-population design, we evaluated whether single nucleotide polymorphisms (SNPs) in the TLR9 gene region are associated with susceptibility to pulmonary or meningeal TB as well as neurologic presentation and mortality in the meningeal TB group. In a discovery cohort (n = 352 cases, 382 controls), three SNPs were associated with TB (all forms, p<0.05) while three additional SNPs neared significance (0.05
IntroductionRapid tests for rifampicin resistance may be useful for identifying isolates at high risk of drug resistance, including multidrug-resistant TB (MDR-TB). However, choice of diagnostic test and prevalence of rifampicin resistance may both impact a diagnostic strategy for identifying drug resistant-TB. We performed a systematic review to evaluate the performance of WHO-endorsed rapid tests for rifampicin resistance detection.MethodsWe searched MEDLINE, Embase and the Cochrane Library through January 1, 2012. For each rapid test, we determined pooled sensitivity and specificity estimates using a hierarchical random effects model. Predictive values of the tests were determined at different prevalence rates of rifampicin resistance and MDR-TB.ResultsWe identified 60 publications involving six different tests (INNO-LiPA Rif. TB assay, Genotype MTBDR assay, Genotype MTBDRplus assay, Colorimetric Redox Indicator (CRI) assay, Nitrate Reductase Assay (NRA) and MODS tests): for all tests, negative predictive values were high when rifampicin resistance prevalence was ≤ 30%. However, positive predictive values were considerably reduced for the INNO-LiPA Rif. TB assay, the MTBDRplus assay and MODS when rifampicin resistance prevalence was < 5%.LimitationsIn many studies, it was unclear whether patient selection or index test performance could have introduced bias. In addition, we were unable to evaluate critical concentration thresholds for the colorimetric tests.DiscussionRapid tests for rifampicin resistance alone cannot accurately predict rifampicin resistance or MDR-TB in areas with a low prevalence of rifampicin resistance. However, in areas with a high prevalence of rifampicin resistance and MDR-TB, these tests may be a valuable component of an MDR-TB management strategy.
Background Tuberculosis (TB) is a major cause of death globally. India carries the highest share of the global TB burden. The COVID-19 pandemic has severely impacted diagnosis of TB in India, yet there is limited data on how TB case reporting has changed since the pandemic began and which factors determine differences in case notification. Methods We utilized publicly available data on TB case reporting through the Indian Central TB Division from January 2017 through April of 2021 (prior to the first COVID-19 related lockdown). Using a Poisson model, we estimated seasonal and yearly patterns in TB case notification in India from January 2017 through February 2020 and extended this estimate as the counterfactual expected TB cases notified from March 2020 through April 2021. We characterized the differences in case notification observed and those expected in the absence of the pandemic by State and Territory. We then performed a linear regression to examine the relationship between the logit ratio of reported TB to counterfactual cases and mask use, mobility, daily hospitalizations/100,000 population, and public/total TB case reporting. Results We found 1,320,203 expected cases of TB (95% uncertainty interval (UI) 1,309,612 to 1,330,693) were not reported during the period from March 2020 through April 2021. This represents a 63.3% difference (95% UI 62.8 to 63.8) in reporting. We found that mobility data and average hospital admissions per month per population were correlated with differences in TB case notification, compared to the counterfactual in the absence of the pandemic (p > 0.001). Conclusion There was a large difference between reported TB cases in India and those expected in the absence of the pandemic. This information can help inform the Indian TB program as they consider interventions to accelerate case finding and notification once the pandemic related TB service disruptions improve. Mobility data and hospital admissions are surrogate measures that correlate with a greater difference in reported/expected TB cases and may correlate with a disruption in TB diagnostic services. However, further research is needed to clarify this association and identify other key contributors to gaps in TB case notifications in India.
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