A Randomized Clinical Trial to Evaluate Solutions for the Management of Virologic Failure for Individuals on TLD in Sub-Saharan Africa

Significance: Tenofovir, lamivudine, and dolutegravir (TLD) has become the predominant first-line antiretroviral therapy (ART) regimen in sub-Saharan Africa (SSA). While virologic failure on TLD is relatively rare currently, rates will inevitably increase over time, threatening epidemic control in the region. The optimal management of virologic failure on TLD is currently unknown, and policies vary widely in SSA. Innovation: We propose the first randomized clinical trial to determine the optimal management strategy for virologic failure on TLD in SSA. The trial will evaluate a novel individualized care strategy, which seeks to address diverse patient- level determinants of virologic failure, including adherence challenges, pill burden, patient preference, regimen tolerability, and drug resistance. The individualized care strategy incorporates a point-of-care urine tenofovir assay, as well as genotypic resistance tests, with a goal of salvaging once-daily regimens among individuals with virologic failure on TLD. Investigators: Our expert team of clinical epidemiologists (Suzanne McCluskey), implementation scientists and clinical trialists (Mark Siedner, Monica Gandhi), global partners (Winnie Muyindike, Richard Lessells, Mahomed Yunus Moosa), biostatisticians (Susanne Hoeppner), and decision scientists (Emily Hyle), led by an early-stage investigator (McCluskey), is uniquely positioned to provide policy- guiding data in response to this question of great public health significance. Approach: We will leverage an established pragmatic clinical trial infrastructure which recently completed an NIH R01-funded randomized trial in Mbarara, Uganda and Durban, South Africa to complete the following Specific Aims: Aim 1) We will conduct the RESOLVE trial, an open, parallel arm, randomized clinical trial in six public sector clinics to determine the optimal strategy for management of virologic failure on first-line TLD in SSA. We will randomize participants to one of the following strategies: a) Maintenance on TLD with switch to protease inhibitor (PI)- based second-line ART if virologic failure persists past six months, similar to current guidelines in South Africa; b) Individualized Care, with regimen choice based on results of genotypic resistance tests and urine tenofovir assays; or c) Immediate Switch to PI-based second-line ART, similar to current guidelines in Uganda. The primary outcome will be viral suppression (<50 copies/mL) at 48-weeks post-enrollment. Aim 2) We will populate the Cost-Effectiveness of Preventing AIDS Complications-International model with the clinical trial data from Aim 1 to project long-term clinical outcomes and cumulative lifetime costs. We will use simulation modeling to examine the clinical impact, costs, and cost-effectiveness of strategies to improve viral suppression after virologic failure on TLD. Impact: We will respond to this priority research gap with data to guide global HIV policy by determining the most clinically effective and cost-effective strategy for management of virologic failure on TLD. In doing so, this proposal directly responds to NIH HIV research priorities to improve viral suppression and to ensure that optimal treatment responses are achieved. Project Number: 3R01AI167699-04S1 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: Suzanne McCluskey | Institution: MASSACHUSETTS GENERAL HOSPITAL, BOSTON, MA | Award Amount: $278,479 | Activity Code: R01 | Study Section: Population and Public Health Approaches to HIV/AIDS Study Section[PPAH] View on NIH RePORTER: https://reporter.nih.gov/project-details/3R01AI16769904S1