"Rifapentine and Isoniazid for 3 Months versus Isoniazid for 9 Months".

Clinical Question

Does 3 months of directly observed once-weekly therapy with rifapentine plus isoniazid compare with 9 months of self-administered daily isoniazid in preventing tuberculosis?

Bottom Line

Three months of once-weekly rifapentine plus isoniazid is as effective as a standard 9-month regimen of daily isoniazid alone in preventing tuberculosis, with a higher rate of treatment completion and a similar side-effect profile.

Major Points

Treatment of latent Mycobacterium tuberculosis infection is key in tuberculosis control. The conventional 9-month isoniazid regimen is effective but has low completion rates and potential toxicity. This study compared a shorter 3-month regimen with once-weekly rifapentine plus isoniazid, administered under direct observation, to the standard 9-month self-administered isoniazid. The shorter regimen proved to be as effective, with higher completion rates and fewer incidents of hepatotoxicity.

Guidelines

As of the last update, guidelines for treating latent Mycobacterium tuberculosis infection did not include this specific rifapentine plus isoniazid regimen.

Design

Open-label, randomized noninferiority trial conducted in the United States, Canada, Brazil, and Spain.

Population

7,731 subjects at high risk for tuberculosis, including 71% who were close contacts of patients with tuberculosis and 25% with recent conversion to positive tuberculin skin tests.

Interventions

Subjects were randomized to the combination-therapy group (3 months of once-weekly rifapentine plus isoniazid under direct observation) or the isoniazid-only group (9 months of daily self-administered isoniazid).

Outcomes

- Primary Outcome: Tuberculosis developed in 7 of 3986 subjects in the combination-therapy group (rate 0.19%) and in 15 of 3745 subjects in the isoniazid-only group (rate 0.43%).
- Secondary Outcomes: Treatment completion rates were 82.1% in the combination-therapy group and 69.0% in the isoniazid-only group.
- Permanent drug discontinuation due to adverse events was seen in 4.9% in the combination-therapy group and in 3.7% in the isoniazid-only group.
- Investigator-assessed drug-related hepatotoxicity occurred in 0.4% of combination-therapy group versus 2.7% in isoniazid-only group.

Criticisms

- Noninferiority margin may be considered high.
- Limited data on HIV-infected subjects.
- Need for long-term safety monitoring.

Funding

Funded by the Centers for Disease Control and Prevention.

Further Reading

- Result papers and additional data provided in the Supplementary Appendix available with the full text of this article at NEJM.org.