By Richard R. Watkins, MD, MS, FACP, FIDSA

Associate Professor of Internal Medicine, Northeast Ohio Medical University; Division of Infectious Diseases, Cleveland Clinic Akron General, Akron, OH

Dr. Watkins reports that he has received research support from Allergan.

SYNOPSIS: A randomized clinical trial conducted in the United States and three other countries compared self-administered isoniazid and rifapentine with and without weekly reminders to directly observed therapy (DOT). Self-administered therapy without reminders was non-inferior to DOT in the United States; no other comparisons met non-inferiority criteria.

SOURCE: Belknap R, Holland D, Feng PJ, et al. Self-administered versus directly observed once-weekly isoniazid and rifapentine treatment of latent tuberculosis infection: A randomized trial. Ann Intern Med 2017;167:689-697.

Reducing the duration of treatment for latent tuberculosis has several potential benefits, including less risk for drug toxicities, better compliance, and lower costs. One regimen, isoniazid (INH) and rifapentine, is safe and effective when given once weekly for 12 doses, but is limited by the need for directly observed therapy (DOT). Belknap and colleagues compared the safety and completion rate of this regimen when given by DOT vs. self-administration.

The iAdhere study was a randomized clinical trial conducted at nine sites in the United States and one each in Spain, Hong Kong, and South Africa. Patients were included if they were at least 18 years of age, males or nonpregnant females, and weighed at least 45 kg. Exclusion criteria included known or suspected active tuberculosis, known contact with someone who had drug-resistant tuberculosis, prior intolerance to either INH or rifapentine, prior treatment of active or latent tuberculosis for at least one week, baseline elevation of alanine aminotransferase more than five times the upper limit of normal, and antiretroviral therapy for HIV. The latter was because of potential drug-drug interactions with rifapentine.

Participants were assigned randomly to one of three groups: once-weekly INH and rifapentine by DOT; once-weekly therapy by self-administration; and once-weekly therapy along with weekly text message reminders. They were evaluated monthly for toxicity and therapy adherence. The primary endpoint was treatment completion, which was defined as receiving at least 11 doses within 16 weeks. Participants were followed for 28 days after receiving their last dose to assess for adverse events.

Of 2,177 patients screened, 1,002 were enrolled in the iAdhere study. The completion rate was 87.2% (95% confidence interval [CI], 83.1-90.5%) in the DOT group, 74.0% (95% CI, 68.9-78.6%) in the self-administered group, and 76.4% (95% CI, 71.3-80.8%) in the self-administered group with reminders. In the United States, the completion rate for DOT was 85.4% (95% CI, 80.4-89.4%), 77.9% (95% CI, 72.7-82.6%) in the self-administered group, and 76.7% (95% CI, 70.9-81.7%) in the self-administered group with reminders.

Factors associated with noncompletion by multivariate logistic regression included enrollment in South Africa compared to other locations, smoking, and female sex. There were 208 adverse events reported by 174 participants, with similar proportions among the three groups. Of these, 78 participants experienced drug-related adverse events, five of which were serious, and 45 participants discontinued treatment because of an adverse event. One death occurred among the participants (a suicide), but the death was determined to be unrelated to the study drugs.

COMMENTARY

Approximately 10% of individuals with latent tuberculosis progress to active tuberculosis during their lifetimes, which represents a major hurdle for controlling the global tuberculosis epidemic. The study by Belknap and colleagues offers new hope in the efforts to combat latent tuberculosis, with some important caveats. The researchers found similar completion rates for DOT and self-administered therapy from the clinical sites in the United States, but not from the site in South Africa. The high completion rate for INH and rifapentine was comparable to a recently published observational study.1 Compared to participants from the other sites, those from South Africa were younger, more likely to be unemployed, more likely to abuse alcohol, and were mostly HIV-negative household contacts of someone with active tuberculosis. These factors likely contributed to the lower completion rate, which has potentially important implications for the role of self-administered therapy in global tuberculosis control.

If the results from South Africa are excluded, treatment completion of three months of INH and rifapentine by self-administration was higher in iAdhere than has been reported previously with nine months of INH, and is similar to four months of rifampin. Safety and tolerability are important concerns when treating latent tuberculosis since many of these individuals are healthy and do not take medications routinely, which may cause them to be especially intolerant of medicine-related side effects. Therefore, the results from iAdhere that the total, drug-related, and severe adverse events were comparable in the DOT and self-administered groups are encouraging. The finding from the United States that weekly reminders did not improve compliance and that this group actually showed lower compliance compared to the self-administered group that did not receive reminders is surprising and should be evaluated further in future studies.

There were a few limitations to the study. Of the 12 study sites, only one was in a resource-limited setting (South Africa), so the results might not be generalizable to these regions. Also, the effectiveness of the weekly reminders is questionable because not all of the participants assigned to this group had access to text messages, and the investigators did not require confirmation that a message had been received.

The iAdhere study provides evidence that self-administered rifapentine and INH seems to be a viable option for treatment of latent tuberculosis in the United States. The authors of tuberculosis guidelines will need to consider the results of iAdhere carefully when deciding about future recommendations.

REFERENCE

  1. Sandul AL, Nwana N, Holcombe JM, et al. High rate of treatment completion in program settings with 12-dose weekly isoniazid and rifapentine (3HP) for latent Mycobacterium tuberculosis infection. Clin Infect Dis 2017 May 30. doi: 10.1093/cid/cix505. [Epub ahead of print].