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.

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.

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.

Increasing drug resistance was associated in a logical stepwise manner with poor treatment outcomes. Acquired resistance was worse than initial resistance to the same drugs. Increasing numbers of effective drugs, specific drugs, and specific program characteristics were associated with better outcomes and less acquired resistance.

BackgroundFor treating multidrug-resistant tuberculosis (MDR TB), the World Health Organization (WHO) recommends a regimen of at least four second-line drugs that are likely to be effective as well as pyrazinamide. WHO guidelines indicate only marginal benefit for regimens based directly on drug susceptibility testing (DST) results. Recent evidence from isolated cohorts suggests that regimens containing more drugs may be beneficial, and that DST results are predictive of regimen effectiveness. The objective of our study was to gain insight into how regimen design affects treatment response by analyzing the association between time to sputum culture conversion and both the number of potentially effective drugs included in a regimen and the DST results of the drugs in the regimen.Methods and FindingsWe analyzed data from the Preserving Effective Tuberculosis Treatment Study (PETTS), a prospective observational study of 1,659 adults treated for MDR TB during 2005–2010 in nine countries: Estonia, Latvia, Peru, Philippines, Russian Federation, South Africa, South Korea, Thailand, and Taiwan. For all patients, monthly sputum samples were collected, and DST was performed on baseline isolates at the US Centers for Disease Control and Prevention. We included 1,137 patients in our analysis based on their having known baseline DST results for at least fluoroquinolones and second-line injectable drugs, and not having extensively drug-resistant TB. These patients were followed for a median of 20 mo (interquartile range 16–23 mo) after MDR TB treatment initiation. The primary outcome of interest was initial sputum culture conversion. We used Cox proportional hazards regression, stratifying by country to control for setting-associated confounders, and adjusting for the number of drugs to which patients’ baseline isolates were resistant, baseline resistance pattern, previous treatment history, sputum smear result, and extent of disease on chest radiograph.In multivariable analysis, receiving an average of at least six potentially effective drugs (defined as drugs without a DST result indicating resistance) per day was associated with a 36% greater likelihood of sputum culture conversion than receiving an average of at least five but fewer than six potentially effective drugs per day (adjusted hazard ratio [aHR] 1.36, 95% CI 1.09–1.69). Inclusion of pyrazinamide (aHR 2.00, 95% CI 1.65–2.41) or more drugs to which baseline DST indicated susceptibility (aHR 1.65, 95% CI 1.48–1.84, per drug) in regimens was associated with greater increases in the likelihood of sputum culture conversion than including more drugs to which baseline DST indicated resistance (aHR 1.33, 95% CI 1.18–1.51, per drug). Including in the regimen more drugs for which DST was not performed was beneficial only if a minimum of three effective drugs was present in the regimen (aHR 1.39, 95% CI 1.09–1.76, per drug when three effective drugs present in regimen).The main limitation of this analysis is that it is based on observational data, not a randomized trial, and...