Outcomes of WHO-conforming, longer, all-oral multidrug-resistant TB regimens and analysis implications.

BACKGROUND: Evidence of the effectiveness of the WHO-recommended design of longer individualized regimens for multidrug- or rifampicin-resistant TB (MDR/RR-TB) is limited.OBJECTIVES: To report end-of-treatment outcomes for MDR/RR-TB patients from a 2015-2018 multi-country cohort that received a regimen consistent with current 2022 WHO updated recommendations and describe the complexities of comparing regimens.METHODS: We analyzed a subset of participants from the endTB Observational Study who initiated a longer MDR/RR-TB regimen that was consistent with subsequent 2022 WHO guidance on regimen design for longer treatments. We excluded individuals who received an injectable agent or who received fewer than four likely effective drugs.RESULTS: Of the 759 participants analyzed, 607 (80.0%, 95% CI 77.0-82.7) experienced successful end-of-treatment outcomes. The frequency of success was high across groups, whether stratified on number of Group A drugs or fluoroquinolone resistance, and ranged from 72.1% to 90.0%. Regimens were highly variable regarding composition and the duration of individual drugs.CONCLUSIONS: Longer, all-oral, individualized regimens that were consistent with 2022 WHO guidance on regimen design had high frequencies of treatment success. Heterogeneous regimen compositions and drug durations precluded meaningful comparisons. Future research should examine which combinations of drugs maximize safety/tolerability and effectiveness.

Concordance of three approaches for operationalizing outcome definitions for multidrug-resistant TB.

BACKGROUND: The WHO provides standardized outcome definitions for rifampicin-resistant (RR) and multidrug-resistant (MDR) TB. However, operationalizing these definitions can be challenging in some clinical settings, and incorrect classification may generate bias in reporting and research. Outcomes calculated by algorithms can increase standardization and be adapted to suit the research question. We evaluated concordance between clinician-assigned treatment outcomes and outcomes calculated based on one of two standardized algorithms, one which identified failure at its earliest possible recurrence (i.e., failure-dominant algorithm), and one which calculated the outcome based on culture results at the end of treatment, regardless of early occurrence of failure (i.e., success-dominant algorithm).METHODS: Among 2,525 patients enrolled in the multi-country endTB observational study, we calculated the frequencies of concordance using cross-tabulations of clinician-assigned and algorithm-assigned outcomes. We summarized the common discrepancies.RESULTS: Treatment success calculated by algorithms had high concordance with treatment success assigned by clinicians (95.8 and 97.7% for failure-dominant and success-dominant algorithms, respectively). The frequency and pattern of the most common discrepancies varied by country.CONCLUSION: High concordance was found between clinician-assigned and algorithm-assigned outcomes. Heterogeneity in discrepancies across settings suggests that using algorithms to calculate outcomes may minimize bias.

Introducing new and repurposed TB drugs: the endTB experience.

In 2015, the initiative Expand New Drug Markets for TB (endTB) began, with the objective of reducing barriers to access to the new and repurposed TB drugs. Here we describe the major implementation challenges encountered in 17 endTB countries. We provide insights on how national TB programmes and other stakeholders can scale-up the programmatic use of new and repurposed TB drugs, while building scientific evidence about their safety and efficacy. For any new drug or diagnostic, multiple market barriers can slow the pace of scale-up. During 2015-2019, endTB was successful in increasing the number of patients receiving new and repurposed TB drugs in 17 countries. The endTB experience has many lessons, which are relevant to country level introduction of new TB drugs, as well as non-TB drugs and diagnostics. For example: the importation of TB drugs is possible even in the absence of registration; emphasis on good clinical monitoring is more important than pharmacovigilance reporting; national guidelines and expert committees can both facilitate and hinder innovative practice; clinicians use new and repurposed TB drugs when they are available; data collection to generate scientific evidence requires financial and human resources; pilot projects can drive national scale-up.

Early Bactericidal Activity Trial of Nitazoxanide for Pulmonary Tuberculosis.

This study was conducted in treatment-naive adults with drug-susceptible pulmonary tuberculosis in Port-au-Prince, Haiti, to assess the safety, bactericidal activity, and pharmacokinetics of nitazoxanide (NTZ). This was a prospective phase II clinical trial in 30 adults with pulmonary tuberculosis. Twenty participants received 1 g of NTZ orally twice daily for 14 days. A control group of 10 participants received standard therapy over 14 days. The primary outcome was the change in time to culture positivity (TTP) in an automated liquid culture system. The most common adverse events seen in the NTZ group were gastrointestinal complaints and headache. The mean change in TTP in sputum over 14 days in the NTZ group was 3.2 h ± 22.6 h and was not statistically significant (P = 0.56). The mean change in TTP in the standard therapy group was significantly increased, at 134 h ± 45.2 h (P < 0.0001). The mean NTZ MIC for Mycobacterium tuberculosis isolates was 12.3 µg/ml; the mean NTZ maximum concentration (Cmax) in plasma was 10.2 µg/ml. Negligible NTZ levels were measured in sputum. At the doses used, NTZ did not show bactericidal activity against M. tuberculosis Plasma concentrations of NTZ were below the MIC, and its negligible accumulation in pulmonary sites may explain the lack of bactericidal activity. (This study has been registered at ClinicalTrials.gov under identifier NCT02684240.).