In this study comparing two short-course, rifamycin-based regimens for the treatment of latent TB infection, we found that rifapentine and INH were significantly better tolerated than rifampin and pyrazinamide. We prematurely terminated our trial because of unexpectedly high rates of hepatotoxicity in the rifampin and pyrazinamide arm. Of participants assigned to this regimen, 10% developed grade 3 or 4 hepatotoxicity, compared with only 1% of individuals taking rifapentine and INH once weekly. This rate of rifampin and pyrazinamide toxicity is comparable to rates reported in recent years from several observational studies and two clinical trials in individuals without HIV infection (23
), but is substantially higher than rates reported in clinical trials of patients with HIV infection (7
The association of rifampin and pyrazinamide with liver injury during the treatment of latent TB is unexplained and puzzling. Three controlled clinical trials of rifampin and pyrazinamide in HIV-infected adults with latent TB found that this regimen was as well or better tolerated as INH, with extremely low rates of liver toxicity (7
); yet, two clinical trials in HIV-uninfected adults noted serious hepatotoxicity in 7 to 10% of patients taking this regimen (22
). Our results confirm these findings.
We found that both treatment regimens in our study afforded a high degree of protection against active TB in household contacts of infectious cases. Kritski and colleagues, in a study conducted in Rio de Janeiro, reported that 8% of contacts of patients with multidrug-resistant TB developed active disease within 2 yr without preventive treatment (19
). A more recent study in Rio de Janeiro also found that 7 to 9% of household contacts with a positive tuberculin skin test developed active disease within 2 yr in the absence of treatment (M. Conde, M.D., personal communication, June 2005). The observed event rates in this study were substantially lower than this, with only 1.46 and 0.52% of patients developing active disease after treatment with rifapentine and INH or rifampin and pyrazinamide, respectively. The incidence rates, 0.5 and 0.2 cases per 100 person-years, are also significantly lower than reported for untreated household contacts of active cases (30
). There was no significant difference between the two treatment groups, and the disease rate in the rifapentine and INH arm was well below the acceptable figure of 4%. The upper 95% CI of the difference between the regimens was 3.7%, slightly above our postulated acceptable difference of 3.2% based on a rate in the control arm of 0.8%, reflecting the smaller than planned sample size of the trial due to early discontinuation of enrollment. Without treatment, we would expect to have seen 16 TB cases among the 206 participants in the rifapentine- and INH-treated cohort, whereas only three cases occurred. In addition, rifapentine and INH were well tolerated, with 192 participants completing treatment and only 1% developing liver toxicity. Rifapentine and INH constitute an effective combination therapy for active TB in the continuation phase for patients without cavitation on chest radiographs (12
). Its activity in latent TB is therefore not unexpected.
Short-course, rifamycin-based regimens for latent TB have high effectiveness and are easier for patients to comply with than longer courses of INH. Rifapentine and INH given once weekly for 12 wk is an appealing alternative to 9 mo of INH for contacts of TB cases, as it can be incorporated into directly observed therapy programs as part of the management of the index case. A shorter course of rifapentine and INH could improve the cost-effectiveness of preventive therapy even further, as the number of visits and monitoring costs would be reduced (31
). TB control programs in developing countries could place a higher priority on treating latent infection in contacts of cases if the treatment could be integrated with curative therapy and an easily administered, short-course regimen were available. Rifapentine and INH given weekly for 12 wk would meet these requirements and could contribute to disease control efforts. Daily rifampin for 3 to 4 mo is another cost-effective option for treating latent TB, although clinical studies are limited (6
In conclusion, 12 doses of rifapentine and INH given weekly have good activity against latent TB, and are significantly less toxic than rifampin and pyrazinamide coadministration. Our phase 2 trial had limited power because of early discontinuation of enrollment, but demonstrates the potential of this new regimen. Although the overall efficacy of rifapentine and INH will be further described in several ongoing phase 3 trials, this regimen is a likely promising therapy for latent TB infection.
Rifapentine was provided by Aventis, Inc., and isoniazid and rifampin were supplied by the Brazilian Ministry of Health. The authors thank Elizabeth Higgs, M.D., of the National Institute of Allergy and Infectious Diseases (NIAID); Lawrence Moulton, Ph.D., Jonathan Golub, Ph.D., and Timothy Sterling, M.D., of Johns Hopkins University; and Giorgio Roscigno, M.D., and Mr. Paul Sullivan of Aventis, Inc., for support, advice, and assistance during the course of this study. In addition, they thank Solange Cavalcante, M.D., M.P.H., and Betina Durovni, M.D., for assistance with recruitment of participants. The Data Safety and Monitoring Board of the Division of Microbiology and Infectious Diseases of NIAID provided wise and useful oversight of the study. The authors also thank William Bishai, M.D., Ph.D., and Jacques Grosset, M.D., for inspiration and advice.