Completion of isoniazid-rifapentine (3HP) for tuberculosis prevention among people living with HIV: Interim analysis of a hybrid type 3 effectiveness-implementation randomized trial

Abstract

Background: Scaling up shorter regimens for tuberculosis (TB) prevention such as once weekly isoniazid-rifapentine (3HP) taken for 3 months is a key priority for achieving targets set forth in the World Health Organization's (WHO) END TB Strategy. However, there are few data on 3HP patient acceptance and completion in the context of routine HIV care in sub-Saharan Africa.

Methods and findings: The 3HP Options Trial is a pragmatic, parallel type 3 effectiveness-implementation randomized trial comparing 3 optimized strategies for delivering 3HP-facilitated directly observed therapy (DOT), facilitated self-administered therapy (SAT), or informed choice between DOT and SAT using a shared decision-making aid-to people receiving care at a large urban HIV clinic in Kampala, Uganda. Participants and healthcare providers were not blinded to arm assignment due to the nature of the 3HP delivery strategies. We conducted an interim analysis of participants who were enrolled and exited the 3HP treatment period between July 13, 2020 and April 30, 2021. The primary outcome, which was aggregated across trial arms for this interim analysis, was the proportion who accepted and completed 3HP (≥11 of 12 doses within 16 weeks of randomization). We used Bayesian inference analysis to estimate the posterior probability that this proportion would exceed 80% under at least 1 of the 3HP delivery strategies, a coprimary hypothesis of the trial. Through April 2021, 684 participants have been enrolled, and 479 (70%) have exited the treatment period. Of these 479 participants, 309 (65%) were women, mean age was 41.9 years (standard deviation (SD): 9.2), and mean time on antiretroviral therapy (ART) was 7.8 years (SD: 4.3). In total, 445 of them (92.9%, 95% confidence interval (CI): [90.2 to 94.9]) accepted and completed 3HP treatment. There were no differences in treatment acceptance and completion by sex, age, or time on ART. Treatment was discontinued due to a documented adverse event (AE) in 8 (1.7%) patients. The probability that treatment acceptance and completion exceeds 80% under at least 1 of the three 3HP delivery strategies was greater than 99%. The main limitations are that the trial was conducted at a single site, and the interim analysis focused on aggregate outcome data to maintain blinding of investigators to arm-specific outcomes.

Conclusions: 3HP was widely accepted by people living with HIV (PLHIV) in Uganda, and very high levels of treatment completion were achieved in a programmatic setting. These findings show that 3HP can enable effective scale-up of tuberculosis preventive therapy (TPT) in high-burden countries, particularly when delivery strategies are tailored to target known barriers to treatment completion.

Trial registration: ClinicalTrials.gov NCT03934931.

Conflict of interest statement

I have read the journal’s policy and the authors of this manuscript have the following competing interests: AS receives research funding from Global Health Labs, California Health Care Foundation and is owner of The Empathy Studio, LLC. DP is a human-centered design consultant for The Empathy Studio, LLC. The other authors have declared that no competing interests exist.

Figures

Fig 1. CONSORT flow diagram.

3HP Options Trial screening, randomization, and allocation, July 13, 2020 to April 30, 2021 (n = 1,133). ALT, alanine aminotransferase; AST, aspartate transaminase; CONSORT, Consolidated Standards of Reporting Trials; INH, isoniazid; RPT, rifapentine; TB, tuberculosis.

Fig 2. 3HP acceptance and completion, by subgroup.

The forest plot shows the proportion and 95% CIs of participants accepting and competing 3HP treatment (took at least 11 of 12 doses of 3HP within 16 weeks of randomization) overall and by sex, age, and time on ART. ART, antiretroviral therapy; CI, confidence interval. * Accepting and completing treatment (≥11 of 12 doses within 16 weeks).