Adverse events in adults with latent tuberculosis infection receiving daily rifampicin or isoniazid: post-hoc safety analysis of two randomised controlled trials.

BACKGROUND: An important problem limiting treatment of latent tuberculosis infection is the occurrence of adverse events with isoniazid. We combined populations from phase 2 and phase 3 open-label, randomised controlled trials, to establish risk factors for adverse events during latent tuberculosis infection treatment.

METHODS: We did a post-hoc safety analysis based on data from two open-label, randomised controlled trials done in health-care facilities in Australia, Benin, Brazil, Canada, Ghana, Guinea, Indonesia, Saudi Arabia, and South Korea. Participants were consenting adults (aged ≥18 years) with a positive latent tuberculosis infection diagnostic test, indication for treatment, and without contraindications to rifampicin or isoniazid. Patients were centrally randomly assigned 1:1 to 4 months of daily 10 mg/kg rifampicin or 9 months of daily 5 mg/kg isoniazid. The primary outcome evaluated was adverse events (including grade 1-2 rash and all events of grade 3-5) resulting in permanent discontinuation of study medication and judged possibly or probably related to study drug by a masked, independent, three-member adjudication panel (trial registration: NCT00170209; NCT00931736).

FINDINGS: Participants were recruited from April 27, 2004, up until Jan 31, 2007 (phase 2), and Oct 1, 2009, up until Dec 31, 2014 (phase 3). The safety populations for each group comprised 3205 individuals receiving isoniazid and 3280 receiving rifampicin. Among those receiving isoniazid, 86 (2·7%) of 3205 had grade 1-2 rash or any grade 3-5 adverse events, more than the 50 (1·5%) of 3280 who had these events with rifampicin (risk difference -1·2%, 95% CI -1·9 to -0·5). Age was associated with adverse events in adults receiving isoniazid. Compared with individuals aged 18-34 years, the adjusted odds ratio (OR) for adverse events was 1·8 (95% CI 1·1-3·0) for individuals aged 35-64 years and 3·0 (1·2-6·8) for individuals aged 65-90 years. With rifampicin, adverse events were associated with inconsistent medication adherence (adjusted OR 2·0, 1·1-3·6) and concomitant medication use (2·8, 1·5-5·2), but not age, with an adjusted OR of 1·1 (0·6-2·1) for individuals aged 35-64 years and 1·7 (0·5-4·7) for individuals aged 65-90 years. One treatment-related death occurred in the isoniazid group.

INTERPRETATION: In patients without a contraindication, rifampicin is likely to be the safest latent tuberculosis infection treatment option. With more widespread use of rifampicin, rare, but serious adverse events might be seen. However, within these randomised trials, rifampicin was safer than isoniazid and adverse events were not associated with older age. Therefore, rifampicin should become a primary treatment option for latent tuberculosis infection based on its safety.

FUNDING: Canadian Institutes of Health Research.