Daily vs intermittent antituberculosis therapy for pulmonary tuberculosis in patients with HIV. A Randomized clinical trial.
Gopalan, N.; Santhanakrishnan, R.K.; Palaniappan, A.N.; Menon, P.A.; Lakshman, S.; Padmapriyadarsini, C.; Gomathi, N.S.; Reddy, D.; Kannabiran, B.P.; Hemanth Kumar, A.K.; Krishnamoorthy, V.; Rathinam, S.; Chockalingam, C.; Manoharan, T.; Ayyamperumal, M.; Jayanthi, N.; Satagopan, K.; Narayanan, R.; Krishnaraja, R.; Sathiyavelu, S.; Kesavamurthy, B.; Suresh, C.; Selvachitiram, M.; Arasan, G.; Susaimuthu, S.; Rathinam, P.; Angamuthu, P.; Jayabal, L.; Murali, L.; Ramachandran, R.; Tripathy, S.P.; Swaminathan, S.
JAMA Internal Medicine; 2018; 178(4): 485-493.
Importance: The benefit of daily over thrice-weekly anti tuberculosis 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 September14, 2009, and January18, 2016.
Interventions: Patients were randomized to daily, part-daily, and intermittent anti tuberculosis 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 2months of treatment. Unfavorable responses included treatment failures, drop outs, 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] log 10copies/mL; and median [interquartile range] CD4 lymphocyte count, 138 [69-248]cells/µL), favorable responses were experienced by 91% (89of98), 80% (77of 96), and 77%(75of98) in the daily, part-daily, and intermittent regimens, respectively. With the difference in outcome between daily and intermittent regimens crossing the O'Brien-Fleming groups equential 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.
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