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

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.

Acceptance and completion of rifapentine-based TB preventive therapy (3HP) among people living with HIV (PLHIV) in Kampala, Uganda-patient and health worker perspectives.

BACKGROUND: A 12-dose, once-weekly regimen of isoniazid and rifapentine (3HP) is effective in preventing tuberculosis (TB) among people living with HIV (PLHIV). We sought to identify potential barriers to and facilitators of acceptance and completion of 3HP treatment from the perspective of people living with HIV (PLHIV) and health workers in a routine HIV care setting in Kampala, Uganda. METHODS: We conducted semi-structured interviews with 25 PLHIV and 10 health workers at an HIV/AIDS clinic in Kampala, Uganda. For both groups, we explored their understanding and interpretations of TB and TB preventive therapy (TPT), and perceptions about social and contextual factors that might influence the willingness of PLHIV to initiate and complete 3HP. We analyzed the data using an inductive thematic approach and aligned the emergent themes to the Behavior Change Wheel framework to identify sources of behavior and targeted behavior change interventions. RESULTS: Facilitators of acceptance and completion of 3HP treatment among PLHIV were fear of contracting TB, awareness of being at risk of getting TB, willingness to take TPT, trust in health workers, and the perceived benefits of directly observed therapy (DOT) and self-administered therapy (SAT) 3HP delivery strategies. Barriers included inadequate understanding of TPT, fear of potential side effects, concerns about the effectiveness of 3HP, and the perceived challenges of DOT or SAT. Among health workers, perceived facilitators included knowledge that TB is a common cause of mortality for PLHIV, fear of getting TB, and trust in the health workers by PLHIV, the advantages of once-weekly 3HP dosing, and the benefits of DOT and SAT 3HP delivery strategies. Health worker-reported barriers for PLHIV included inadequate understanding of TB and benefits of TPT, TB-associated stigma, potential side effects pill burden, and challenges of DOT and SAT 3HP delivery strategies. Lack of experience in the use of digital technology to monitor patient care was identified as a health worker-specific barrier. Identified intervention functions to address the facilitators or barriers included education, persuasion, environmental restructuring, enablement, and training. CONCLUSIONS: Using a formative qualitative and comprehensive theoretical approach, we identified key barriers, facilitators, and appropriate interventions, including patient education, enhancing trust, and patient-centered treatment support that could be used to optimize the delivery of 3HP to PLHIV in our setting. These interventions are likely generalizable to other clinical interventions in similar populations in sub-Saharan Africa and other TB high-burden settings.

Protocol for the 3HP Options Trial: a hybrid type 3 implementation-effectiveness randomized trial of delivery strategies for short-course tuberculosis preventive therapy among people living with HIV in Uganda.

BACKGROUND: Recently, a 3-month (12-dose) regimen of weekly isoniazid and rifapentine (3HP) was recommended by the World Health Organization for the prevention of tuberculosis (TB) among people living with HIV (PLHIV) on common antiretroviral therapy regimens. The best approach to delivering 3HP to PLHIV remains uncertain. METHODS: We developed a three-armed randomized trial assessing optimized strategies for delivering 3HP to PLHIV. The trial will be conducted at the Mulago Immune Suppression Syndrome (i.e., HIV/AIDS) clinic in Kampala, Uganda. We plan to recruit 1656 PLHIV, randomized 1:1 to each of the three arms (552 per arm). Using a hybrid type 3 effectiveness-implementation design, this pragmatic trial aims to (1) compare the acceptance and completion of 3HP among PLHIV under three delivery strategies: directly observed therapy (DOT), self-administered therapy (SAT), and informed patient choice of either DOT or SAT (with the assistance of a decision aid); (2) to identify processes and contextual factors that influence the acceptance and completion of 3HP under each delivery strategy; and (3) to estimate the costs and compare the cost-effectiveness of three strategies for delivering 3HP. The three delivery strategies were each optimized to address key barriers to 3HP completion using a theory-informed approach. We hypothesize that high levels of treatment acceptance and completion can be achieved among PLHIV in sub-Saharan Africa and that offering PLHIV an informed choice between the optimized DOT and SAT delivery strategies will result in greater acceptance and completion of 3HP. The design and planned evaluation of the delivery strategies were guided by the use of implementation science conceptual frameworks. DISCUSSION: 3HP-one of the most promising interventions for TB prevention-will not be scaled up unless it can be delivered in a patient-centered fashion. We highlight shared decision-making as a key element of our trial design and theorize that offering PLHIV an informed choice between optimized delivery strategies will facilitate the highest levels of treatment acceptance and completion. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03934931 ; Registered 2 May 2019.