The current standard treatment of latent Mycobacterium tuberculosis infection using isoniazid for 9 months is efficacious but is limited by toxicity and low rates of treatment completion. Rifapentine, a rifamycin derivative with a long half-life and greater potency against M. tuberculosis than rifampin, has shown promise for treating latent tuberculosis in animal models. Since weekly rifapentine and isoniazid are effective in the continuation phase of tuberculosis treatment in patients with a low bacillary burden, it was postulated that a 3-month course of these agents would be effective for treating latent M. tuberculosis and would also be more convenient for both patients and public health programs responsible for ensuring treatment completion. The latest in a series of investigations of shorter preventive regimens in the New England Journal of Medicine compared 3 months of directly observed once-weekly therapy with rifapentine (900 mg) plus isoniazid (900 mg) (combination-therapy group) with 9 months of self-administered daily isoniazid (300 mg) (isoniazid-only group) in subjects at high risk for tuberculosis.
The open-label, randomised non-inferiority trial was conducted in Brazil, Canada, Spain, and the United States,and involved 3986 subjects in the combination-therapy group and 3745 subjects in the isoniazid-only group who were followed for 33 months. The primary end point was confirmed tuberculosis, and the non-inferiority margin was 0.75%.
• In the modified intention-to-treat analysis, tuberculosis developed in 7 of 3986 subjects in the combination-therapy group (cumulative rate, 0.19%) and in 15 of 3745 subjects in the isoniazid-only group (cumulative rate, 0.43%), for a difference of 0.24 percentage points.
• Rates of treatment completion were 82.1% in the combination- therapy group and 69.0% in the isoniazid-only group (p<0.001).
• Rates of permanent drug discontinuation due to an adverse event were 4.9% in the combination- therapy group and 3.7% in the isoniazid-only group (p= 0.009).
• Rates of investigator-assessed drug-related hepatotoxicity were 0.4% and 2.7%, respectively (p<0.001).
The researchers conclude from these findings that “use of rifapentine plus isoniazid for 3 months was as effective as 9 months of isoniazid alone in preventing tuberculosis and had a higher treatment-completion rate. Long-term safety monitoring will be important.”
An accompanying editorial notes that the findings of this trial, performed in low-incidence countries, suggest that isoniazid plus rifapentine is as good as the principal competing regimens — notably, 3 months of isoniazid plus rifampin or 4 months of rifampin monotherapy in places where the use of isoniazid is not recommended. However, a head-to-head comparison of these three options remains to be performed. Furthermore, preventive therapy has the potential to deliver greater health benefits in high-incidence countries, and in this context, a critical question for the isoniazid-plus-rifapentine regimen is whether 3 months of treatment will provide protection for longer than 2 to 3 years. In addition, would combination therapy with isoniazid plus rifapentine have to be given continuously and under supervision to protect HIV-positive or HIV-negative persons from reactivation or reinfection? A long-term study in a high-incidence setting is needed to find out.
New U.S. guidelines on the use of an isoniazid-rifapentine regimen with direct observation to treat latent mycobacterium tuberculosis has reduced the amount of time needed to treat the infection from 9 to 3 months in otherwise healthy patients aged ≥12 years who have a predictive factor for greater likelihood of TB developing, which includes recent exposure to contagious TB, conversion from negative to positive on an indirect test for infection, and radiographic findings of healed pulmonary TB. HIV-infected patients who are otherwise healthy and are not taking antiretroviral medications also are included in this category (see link to MMWR).