Efficacy of a six-month versus a 36-month regimen for prevention of tuberculosis in HIV-infected persons in India: a randomized clinical trial

Soumya Swaminathan, Pradeep Aravindan Menon, Narendran Gopalan, Venkatesan Perumal, Ramesh Kumar Santhanakrishnan, Ranjani Ramachandran, Ponnuraja Chinnaiyan, Sheik Iliayas, Padmapriyadarsini Chandrasekaran, Pooranaganga Devi Navaneethapandian, Thiruvalluvan Elangovan, Mai Tuyet Pho, Fraser Wares, Narayanan Paranji Ramaiyengar, Soumya Swaminathan, Pradeep Aravindan Menon, Narendran Gopalan, Venkatesan Perumal, Ramesh Kumar Santhanakrishnan, Ranjani Ramachandran, Ponnuraja Chinnaiyan, Sheik Iliayas, Padmapriyadarsini Chandrasekaran, Pooranaganga Devi Navaneethapandian, Thiruvalluvan Elangovan, Mai Tuyet Pho, Fraser Wares, Narayanan Paranji Ramaiyengar

Abstract

Background: The optimal duration of preventive therapy for tuberculosis (TB) among HIV-infected persons in TB-endemic countries is unknown.

Methods: An open-label randomized clinical trial was performed and analyzed for equivalence. Seven hundred and twelve HIV-infected, ART-naïve patients without active TB were randomized to receive either ethambutol 800 mg and isoniazid 300 mg daily for six-months (6EH) or isoniazid 300 mg daily for 36-months (36H). Drugs were dispensed fortnightly and adherence checked by home visits. Patients had chest radiograph, sputum smear and culture performed every six months, in addition to investigations if they developed symptoms. The primary endpoint was incident TB while secondary endpoints were all-cause mortality and adverse events. Survival analysis was performed on the modified intent to treat population (m-ITT) and rates compared.

Findings: Tuberculosis developed in 22 (6.4%) of 344 subjects in the 6EH arm and 13 (3.8%) of 339 subjects in the 36H arm with incidence rates of 2.4/100 py (95%CI- 1.4-3.5) and 1.6/100 py (95% CI-0.8-3.0) with an adjusted rate ratio (aIRR) of 1.6 (0.8-3.2). Among TST-positive subjects, the aIRR of 6EH was 1.7 (0.6-4.3) compared to 36H, p = 0.8. All-cause mortality and toxicity were similar in the two arms. Among 15 patients with confirmed TB, 4 isolates were resistant to isoniazid and 2 were multidrug-resistant.

Interpretation: Both regimens were similarly effective in preventing TB, when compared to historical incidence rates. However, there was a trend to lower TB incidence with 36H. There was no increase in isoniazid resistance compared to the expected rate in HIV-infected patients. The trial is registered at ClinicalTrials.gov, NCT00351702.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1. Trial Profile of all patients.
Figure 1. Trial Profile of all patients.
Figure 2. Kaplan-Meier curves showing cumulative probability…
Figure 2. Kaplan-Meier curves showing cumulative probability of survival without TB and death over 36 months by regimen, TST status, CD4 count and sex.
The four top panels show cumulative survival without TB over 36 months by regimen (6EH versus 36H, ns), TST (5 mm, ns), CD4 count (200 cells/mm3, p5 mm, ns), CD4 count (200 cells/mm3, p

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