Daily vs Intermittent Antituberculosis Therapy for Pulmonary Tuberculosis in Patients With HIV: A Randomized Clinical Trial

Abstract

Importance: The benefit of daily over thrice-weekly antituberculosis therapy among HIV-positive patients with pulmonary tuberculosis (TB) who are receiving antiretroviral therapy remains unproven.

Objective: To compare the efficacy and safety of daily, part-daily, and intermittent antituberculosis therapy regimens in the treatment of HIV-associated pulmonary TB.

Design, setting, and participants: This open-label, randomized clinical trial was conducted by the National Institute for Research in Tuberculosis, south India. Adults infected with HIV with newly diagnosed, culture-positive, pulmonary TB were enrolled between September 14, 2009, and January 18, 2016.

Interventions: Patients were randomized to daily, part-daily, and intermittent antituberculosis therapy regimens, stratified by baseline CD4 lymphocyte count and sputum smear grade. Antiretroviral therapy was initiated as per national guidelines. Clinical and sputum microbiological examinations of patients were performed monthly until 18 months after randomization. Adverse events were recorded using standard criteria.

Main outcomes and measures: The primary outcome was favorable response, defined as treatment completion with all available sputum cultures negative for Mycobacterium tuberculosis during the last 2 months of treatment. Unfavorable responses included treatment failures, dropouts, deaths, and toxic effects among regimens.

Results: Of 331 patients (251 [76%] male; mean [SD] age, 39 [9] years; mean [SD] HIV viral load, 4.9 [1.2] log10 copies/mL; and median [interquartile range] CD4 lymphocyte count, 138 [69-248] cells/μL), favorable responses were experienced by 91% (89 of 98), 80% (77 of 96), and 77% (75 of 98) in the daily, part-daily, and intermittent regimens, respectively. With the difference in outcome between daily and intermittent regimens crossing the O'Brien-Fleming group sequential boundaries and acquired rifampicin resistance emergence (n = 4) confined to the intermittent group, the data safety monitoring committee halted the study. A total of 18 patients died and 18 patients dropped out during the treatment period in the 3 regimens. Six, 4, and 6 patients in the daily, part-daily, and intermittent regimens, respectively, had TB recurrence.

Conclusions and relevance: Among HIV-positive patients with pulmonary TB receiving antiretroviral therapy, a daily anti-TB regimen proved superior to a thrice-weekly regimen in terms of efficacy and emergence of rifampicin resistance.

Trial registration: clinicaltrials.gov Identifier: NCT00933790.

Figure 1.. Flow of Patients From Screening Until 18 Months After Randomization

Adults aged 18 years or older who were HIV positive and newly diagnosed with pulmonary tuberculosis (TB) were enrolled. Patients fulfilling the clinical and laboratory criteria were randomly allocated to 1 of 3 regimens. ATT indicates antituberculosis therapy; CXR, radiograph of the chest; MDR, multidrug-resistant; mITT, modified intent-to-treat analysis; NTM, nontuberculous mycobacteria; Xpert, Xpert MTB/RIF test (Cepheid).

Figure 2.. Mean Survival Estimates for Time to an Unfavorable Event Among Antituberculosis Therapy Regimens

The numbers given within parentheses reflect the number of individuals who experienced the event at that particular week after randomization (censored at 24 weeks after randomization). Event-free survival was 22.76 (95% CI, 21.91-23.61) in the daily regimen, 21.34 (95% CI, 20.11-22.57) in the part-daily regimen, and 21.07 (95% CI, 19.91-22.22) in the intermittent regimen, results that were significant according to the log-rank test (P = .03).