Abstract & Commentary

Three Months, 27 Supervised Doses for Latent TB

By Stan Deresinski, MD, FACP, FIDSA, Clinical Professor of Medicine, Stanford University, Associate Chief of Infectious Diseases, Santa Clara Valley Medical Center, is Editor for Infectious Disease Alert.

Clinical Professor of Medicine, Stanford University

Synopsis: A 3-month weekly supervised regimen of rifapentine plus INH was non-inferior to a 9-month daily self-administered dose of isoniazid (INH) alone in the treatment of latent tuberculosis in an as-yet unpublished study.

Sources: Centers for Disease Control and Prevention. Press Release: Session B9, oral presentation: Sterling, PREVENT TB: Results of a 12-dose, once-weekly treatment of Latent Tuberculosis Infection (LTBI). Available at: http://www.cdc.gov/nchhstp/newsroom/PREVENTTBPressRelease.html; Smith M. ATS: Rapid treatment effective for latent TB. Source reference: Sterling TR, et al. "The PREVENT TB STUDY" ATS 2011. Available at: http://www.medpagetoday.com/MeetingCoverage/ATS/26508.

The number of individuals with active tuberculosis in the United States reached an all-time low of 11,181 cases in 2010. At the same time, it is estimated that approximately 11 million people, or 4% of the population, is latently infected and at risk of developing active disease due to Mycobacterium tuberculosis. A major strategy for control of tuberculosis in the United States, where BCG vaccination is not routinely recommended, includes the identification and treatment of latently infected individuals, as recognized by the presence of a positive PPD skin test and/or interferon gamma release assay (IGRA) in the absence of clinical or radiographic evidence of active tuberculosis. The standard therapeutic approach has been the daily self-administration of INH for 9 months, a regimen that, because of its duration, is often not completed in actual practice. A 3-month regimen of rifampin and pyrazinamide is associated with a generally unacceptably high risk of hepatotoxicity and a 4-month regimen of daily rifampin is of uncertain efficacy and raises concerns regarding the selection of microbial resistance.

On May 16, 2011, the results of an international, multicenter randomized clinical trial comparing supervised once-weekly rifapentine plus INH to daily self-administered INH were presented to the annual meeting of the American Thoracic Society by the principal investigator, Timothy Sterling. The trial, which was sponsored by the Centers for Disease Control and Prevention (CDC) in collaboration with the Department of Veterans Affairs and was initiated in 2002,1 was performed in countries with low or medium incidences of tuberculosis, with the majority of subjects enrolled in the United States and Canada, and others in Brazil and Spain. Enrollees were > 2 years of age; HIV-infected patients receiving antiretroviral therapy were excluded because of the interaction between rifapentine and many antiretrovirals. Pregnancy and breastfeeding were among additional reasons for exclusion.

The experimental group received 900 mg rifapentine and 900 mg INH, each given under supervision once weekly, while the control group self-administered 5-15 mg/kg INH (300 mg for most adults) daily for 9 months. A total of 8,053 participants were enrolled, 71% of which had a close contact who had active TB, while 22% had evidence of skin test conversion. None, of course, had evidence of active tuberculosis and none had previously received antituberculous therapy. This was designed as a non-inferiority trial. Non-inferiority was considered to be achieved if the upper limit of the 95% confidence interval of the difference between the outcomes in the two arms was < 0.75 percentage points.

Patients were observed for 33 months after completion of therapy. The regimen was successfully completed by 82% of those assigned the weekly regimen and by only 69% of those assigned daily INH (P = 0.0001). Among the modified intent-to-treat population of 7,731 subjects, 7 in the weekly rifapentine/INH and 15 in the daily INH arms developed active tuberculosis. Among the 5,858 subjects who successfully completed the protocol, active tuberculosis developed in 4 and 8, respectively. Non-inferiority was demonstrated in both of the analyzed populations.

Both regimens were well tolerated, but discontinuation because of an adverse event was more frequent in the weekly (4.7%) than the daily (3.6%) administration groups (P = 0.004). Hepatoxicity, both study drug-related and -unrelated, occurred significantly more commonly in the daily INH recipients (P < 0.0001).

Commentary

Rifapentine is a cyclopentyl derivative of rifampicin whose major metabolite, 25-desacetyl rifapentine, retains microbiological activity. The parent compound has a mean plasma T1/2 of 13-14 hours, while that of the metabolite is 13-24 hours.2 The bioavailability of rifapentine is significantly enhanced by its administration with a high-fat meal.3 Rifapentine is more active in vitro than rifampin or rifabutin against M. tuberculosis, although its high degree of protein binding (97%) would be expected to significantly diminish its activity in the presence of albumin.

The weekly regimen of supervised administration of INH and rifapentine reduced the number of doses required for treatment of latent tuberculosis from 270 daily doses to 12 once-weekly doses. As expected, this was associated with a significantly greater proportion of participants successfully completing the regimen and it did so without compromising efficacy. The majority of patients in this study were enrolled in the United States and Canada. Whether this weekly regimen would be applicable to countries with significantly higher incidences of tuberculosis is uncertain. Among the concerns in such settings is the risk of re-infection.

Another issue is that of cost, one element of which is the cost of the drugs themselves. One internet site sells a 150 mg rifapentine tablet for $3.63 (U.S.) and a 300 mg INH tablet for $0.10 (U.S.). Thus, the 6 weekly rifapentine tablets given 12 times would cost $392.04 while the 2 weekly INH tablets cost $3.60 for a total of $395.64 for the entire regimen. In contrast, the drug acquisition cost of the 9-month daily INH regimen would be only $27.00. However, there would likely be less laboratory monitoring costs associated with the 3-month regimen. Perhaps most importantly, the cost of weekly supervision of drug administration adds significant cost.

Also to be considered are the many drug interactions associated with administration of rifampicins, including rifapentine. These are largely the result of induction of CYP450 enzymes and affect a large number of drugs, including, as indicated above, many antiretroviral agents.

While the available results are important, it must be recognized that they have not yet gone through peer review and are subject to alteration. I look forward to their publication.

References

  1. TBTC Study 26: Weekly Rifapentine+INH for 3 mo. vs. Daily INH for 9 mo. for the Treatment of LTBI. Available at: http://clinicaltrials.gov/ct2/show.
  2. Keung A, Eller MG, McKenzie KA, et al. Single and multiple dose pharmacokinetics of rifapentine in man: Part II. Int J Tuberc Lung Dis 1999;3:437-444.
  3. Burman WJ, Gallicano K, Peloquin C. Comparative pharmacokinetics and pharmacodynamics of the rifamycin antibacterials. Clin Pharmacokinet 2001;40:327-341.