Person:

Shin, Sonya

Rationale: A better understanding of the composition of optimal treatment regimens for multidrug-resistant tuberculosis (MDR-TB) is essential for expanding universal access to effective treatment and for developing new therapies for MDR-TB. Analysis of observational data may inform the definition of an optimized regimen. Objectives: This study assessed the impact of an aggressive regimen–one containing at least five likely effective drugs, including a fluoroquinolone and injectable–on treatment outcomes in a large MDR-TB patient cohort. Methods: This was a retrospective cohort study of patients treated in a national outpatient program in Peru between 1999 and 2002. We examined the association between receiving an aggressive regimen and the rate of death. Measurements and Main Results: In total, 669 patients were treated with individualized regimens for laboratory-confirmed MDR-TB. Isolates were resistant to a mean of 5.4 (SD 1.7) drugs. Cure or completion was achieved in 66.1% (442) of patients; death occurred in 20.8% (139). Patients who received an aggressive regimen were less likely to die (crude hazard ratio [HR]: 0.62; 95% CI: 0.44,0.89), compared to those who did not receive such a regimen. This association held in analyses adjusted for comorbidities and indicators of severity (adjusted HR: 0.63; 95% CI: 0.43,0.93). Conclusions: The aggressive regimen is a robust predictor of MDR-TB treatment outcome. TB policy makers and program directors should consider this standard as they design and implement regimens for patients with drug-resistant disease. Furthermore, the aggressive regimen should be considered the standard background regimen when designing randomized trials of treatment for drug-resistant TB.

Background: Treatment of multidrug resistant tuberculosis (MDR-TB) is lengthy, toxic, expensive, and has generally poor outcomes. We undertook an individual patient data meta-analysis to assess the impact on outcomes of the type, number, and duration of drugs used to treat MDR-TB. Methods and Findings: Three recent systematic reviews were used to identify studies reporting treatment outcomes of microbiologically confirmed MDR-TB. Study authors were contacted to solicit individual patient data including clinical characteristics, treatment given, and outcomes. Random effects multivariable logistic meta-regression was used to estimate adjusted odds of treatment success. Adequate treatment and outcome data were provided for 9,153 patients with MDR-TB from 32 observational studies. Treatment success, compared to failure/relapse, was associated with use of: later generation quinolones, (adjusted odds ratio [aOR]: 2.5 [95% CI 1.1–6.0]), ofloxacin (aOR: 2.5 [1.6–3.9]), ethionamide or prothionamide (aOR: 1.7 [1.3–2.3]), use of four or more likely effective drugs in the initial intensive phase (aOR: 2.3 [1.3–3.9]), and three or more likely effective drugs in the continuation phase (aOR: 2.7 [1.7–4.1]). Similar results were seen for the association of treatment success compared to failure/relapse or death: later generation quinolones, (aOR: 2.7 [1.7–4.3]), ofloxacin (aOR: 2.3 [1.3–3.8]), ethionamide or prothionamide (aOR: 1.7 [1.4–2.1]), use of four or more likely effective drugs in the initial intensive phase (aOR: 2.7 [1.9–3.9]), and three or more likely effective drugs in the continuation phase (aOR: 4.5 [3.4–6.0]). Conclusions: In this individual patient data meta-analysis of observational data, improved MDR-TB treatment success and survival were associated with use of certain fluoroquinolones, ethionamide, or prothionamide, and greater total number of effective drugs. However, randomized trials are urgently needed to optimize MDR-TB treatment.