Delamanid was associated with an increase in sputum-culture conversion at 2 months among patients with multidrug-resistant tuberculosis. This finding suggests that delamanid could enhance treatment options for multidrug-resistant tuberculosis. (Funded by Otsuka Pharmaceutical Development and Commercialization; ClinicalTrials.gov number, NCT00685360.).

Dick Menzies and colleagues report findings from a collaborative, individual patient-level meta-analysis of treatment outcomes among patients with multidrug-resistant tuberculosis.

Background To assess the validity of sputum culture conversion (SCC) on solid media at varying time points and the time to SCC as prognostic markers for end-of-treatment outcome in multidrug-resistant (MDR) tuberculosis (TB) patients. Methods Data on1,712 MDR-TB patients from two large cohort studies were analyzed. Measures of association were determined using random effects multivariable logistic regression. Predictive values were calculated using bivariate random-effects generalized linear mixed model. Findings Times to SCC and SCC status at 6 months were significantly associated with treatment success compared to failure or death. SCC status at 2 months was significantly associated with treatment success among patients without known HIV infection only. The overall association of SCC with a successful outcome was substantially stronger at 6 months (adjusted odds ratio [aOR]=14.07, 95% CI 10.05–19.71) than at 2 months (HIV-negative patients: aOR=4.12 [2.25–7.54]; HIV unknown: aOR=3.59 [1.96–6.58], HIV-positive: aOR=0.38 [0.12–1.18]). The 2-month SCC had low sensitivity (27%) and high specificity (90%) for predicting treatment success. Conversely, 6-month SCC status had high sensitivity (92%), but moderate specificity (58%). The maximum combined sensitivity and specificity for SCC was reached between the 6th and 10th month of treatment. Interpretation Time to SCC, SCC status at 6 months, and SCC status at 2 months among patients without known HIV infection can be considered proxy markers of end-of-treatment outcome in MDR-TB patients, but the overall association with treatment success is substantially stronger for 6-month compared to 2-month SCC. Funding USAID, the US CDC, the Division of Intramural Research of NIAID/NIH, and the Republic of Korea’s CDC.

Managing MDRTB through national programs can yield results similar to those seen in wealthier settings.

Treatment of MDR tuberculosis involves substantial risk of acquired resistance to SLDs, increasing as baseline drug resistance increases. The risk was significantly lower in programs documented by the GLC to meet specific standards.

Rationale: Cavitary disease and delayed culture conversion have been associated with relapse. Combining patient characteristics and measures of bacteriologic response might allow treatment shortening with current drugs in some patients. Objectives: To assess whether treatment could be shortened from 6 to 4 months in patients with noncavitary tuberculosis whose sputum cultures converted to negative after 2 months. Methods: This study was a randomized, open-label equivalence trial. HIV-uninfected adults with noncavitary tuberculosis were treated daily with isoniazid, rifampin, pyrazinamide, and ethambutol for 2 months, followed by 2 months of isoniazid and rifampin. After 4 months, patients with drug-susceptible TB whose sputum cultures on solid media were negative after 8 weeks of treatment were randomly assigned to continue treatment for 2 more months or to stop treatment. Patients were followed for relapse for 30 months after beginning treatment. Measurements and Main Results: Enrollment was stopped by the safety monitoring committee after 394 patients were enrolled due to apparent increased risk for relapse in the 4-month arm. A total of 370 patients were eligible for per protocol analysis. Thirteen patients in the 4-month arm relapsed, compared with three subjects in the 6-month arm (7.0 vs. 1.6%; risk difference, 0.054; 95% confidence interval with Hauck-Anderson correction, 0.01-0.10). Conclusion: Shortening treatment from 6 to 4 months in adults with noncavitary disease and culture conversion after 2 months using current drugs resulted in a greater relapse rate. The combination of noncavitary disease and 2-month culture conversion was insufficient to identify patients with decreased risk for relapse.

DST for ethambutol, pyrazinamide, and second-line tuberculosis drugs appears to provide clinically useful information to guide selection of treatment regimens for MDR and XDR tuberculosis.

Summary Background Multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis are emerging worldwide. The Green Light Committee initiative supported programmatic management of drug-resistant tuberculosis in 90 countries. We used estimates from the Preserving Effective TB Treatment Study to predict MDR and XDR tuberculosis trends in four countries with a high burden of MDR tuberculosis: India, the Philippines, Russia, and South Africa. Methods We calibrated a compartmental model to data from drug resistance surveys and WHO tuberculosis reports to forecast estimates of incident MDR and XDR tuberculosis and the percentage of incident MDR and XDR tuberculosis caused by acquired drug resistance, assuming no fitness cost of resistance from 2000 to 2040 in India, the Philippines, Russia, and South Africa. Findings The model forecasted the percentage of MDR tuberculosis among incident cases of tuberculosis to increase, reaching 12·4% (95% prediction interval 9·4–16·2) in India, 8·9% (4·5–11·7) in the Philippines, 32·5% (27·0–35·8) in Russia, and 5·7% (3·0–7·6) in South Africa in 2040. It also predicted the percentage of XDR tuberculosis among incident MDR tuberculosis to increase, reaching 8·9% (95% prediction interval 5·1–12·9) in India, 9·0% (4·0–14·7) in the Philippines, 9·0% (4·8–14·2) in Russia, and 8·5% (2·5–14·7) in South Africa in 2040. Acquired drug resistance would cause less than 30% of incident MDR tuberculosis during 2000–40. Acquired drug resistance caused 80% of incident XDR tuberculosis in 2000, but this estimate would decrease to less than 50% by 2040. Interpretation MDR and XDR tuberculosis were forecast to increase in all four countries despite improvements in acquired drug resistance shown by the Green Light Committee-supported programmatic management of drug resistant tuberculosis. Additional control efforts beyond improving acquired drug-resistance rates are needed to stop the spread of MDR and XDR tuberculosis in countries with a high burden of MDR tuberculosis. Funding US Agency for International Development and US Centers for Disease Control and Prevention, Division of Tuberculosis Elimination.