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

PLoS One. 2012;7(12):e47400. doi: 10.1371/journal.pone.0047400. Epub 2012 Dec 14.

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.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adult
  • Antitubercular Agents / administration & dosage
  • Antitubercular Agents / therapeutic use*
  • Drug Administration Schedule
  • Ethambutol / administration & dosage
  • Ethambutol / therapeutic use*
  • Female
  • HIV Infections / mortality*
  • Humans
  • Incidence
  • India / epidemiology
  • Isoniazid / administration & dosage
  • Isoniazid / therapeutic use*
  • Male
  • Middle Aged
  • Treatment Outcome
  • Tuberculosis / drug therapy
  • Tuberculosis / epidemiology
  • Tuberculosis / prevention & control*

Substances

  • Antitubercular Agents
  • Ethambutol
  • Isoniazid

Associated data

  • ClinicalTrials.gov/NCT00351702

Grants and funding

The study was supported in part by the World Health Organization, with financial assistance provided by the United States Agency for International Development under the WHO/TRC Collaborative Model DOTS Project. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.