Shorter treatment regimen found to be noninferior for patients with multidrug resistant tuberculosis

1. A randomized control trial of patients with multidrug resistant tuberculosis found that shorter treatment regimens were noninferior to longer treatment regimens currently recommended by the WHO.

2. Severe adverse events were noted in both arms including death, QT interval prolongation and increases in alanine transaminase (ALT) levels.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Multidrug resistant tuberculosis requires aggressive treatment as it is resistant to two mainstay tuberculosis drugs – isoniazid and rifampin. In 2011, the World Health Organization (WHO) published a report indicating that long-term treatment lasting 20 months in duration was needed for disease management, however this report was not rooted in high quality analysis. New research has suggested that shorter length, aggressive treatment regimens may prove to be as beneficial in treating resistant tuberculosis as compared to the longer regimen. This current analysis strives to add to the current literature on the comparative effects of short-regimen therapy versus long-regimen therapy for patients with multidrug resistant tuberculosis. Researchers analyzed results from patients across sites in Ethiopia, Mongolia, South Africa and Vietnam, finding that short regimens of 9 to 11 months long were noninferior to longer regimens based on the number of participants in each arm that had negative M. tuberculosis cultures after 132 weeks post-randomization. Researchers also found that both arms were associated with adverse events, including QT interval changes and elevation in liver function test results. Overall, while these results suggest that shorter regimens of treatment may be as effective as longer treatment regimens, additional research is required to ensure the overall safety and efficacy of this treatment plan.

Click to read the study in NEJM

Click to read an accompanying editorial in NEJM

In-Depth [randomized control trial]: This multicenter, open-label, phase 3 randomized control trial randomized 707 patients between 2012-2015. Patients were assigned in a 2:1 ratio to receive either a short-regimen (9-11 months; n=282) or the WHO recommended long-regimen of tuberculosis medications (20 months; n=142). The short regimen consisted of moxifloxacin, clofazimine, ethambutol, pyrazinamide with supplemental kanamycin, isoniazid and protionamide. The primary endpoint of this study was evidence of favorable status at 132 weeks, defined by having negative cultures for M. tuberculosis at 132 weeks. Secondary outcomes included time to smear and culture conversions, and evidence of any acquired resistance to antibiotics. Safety profiles of each treatment arm were also compared and included an analysis of any death rates, severe adverse events, evidence of QT interval prolongation, and changes in liver function test results. Study participants were followed weekly for the first four weeks of treatment, and monthly thereafter through week 132. Of the initially randomized participants, 245 of the short-regimen group and 124 of the long-regimen group were included in the intention-to-treat analyses, and 227 of the short-regimen group and 83 of the long-regimen group were included in the per-protocol efficacy analysis. Favorable status in the intention-to treat population was noted among 193 of 245 patients (78.8%) of the short-regimen group and 99 of 124 participants (79.8%) in the long-regimen group (difference 1.0 percent; 95% CI -7.5 to 9.5; p=0.02 for noninferiority). Time to unfavorable outcomes were not significantly different between groups (HR 1.06; 95% CI 0.65-1.72). In the per protocol efficacy analysis, favorable status was noted in 67 of 83 participants (80.7%) in the long- regimen arm as compared to 186 of 227 participants in the short-regimen arm (81.9%; difference 0.7 percent; 95% CI -10.5-9.1; p=0.02 for noninferiority). Median conversion times to a negative smear or resistance rates to antibiotics did not differ significantly between groups. Severe adverse events occurred in 136 of 282 participants (48.2%) in the short-regimen group and in 64 of 141 participants (45.4%) in the long-regimen group. There were 24 deaths in the short-regimen group (8.5%) compared to 9 deaths (6.4%) in the long regimen group (HR 1.38; 95% CI 0.64 to 2.96). Increased QT intervals were noted among 11% of patients in the short-regimen group compared to 6.4% of patients in the long-regimen group (p=0.14). Increases in alanine transaminase levels were noted in 18 of 272 participants (6.6%) in the short-regimen group and in 2 of 139 participants (1.4%) in the long regimen group (HR 5.64; 95% CI 1.30 to 24.38; p=0.03).

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