Butha Buthe

Researchers are studying viral suppression in people living with HIV who have high viral loads despite being on dolutegravir (DTG)-based antiretroviral therapy (ART) for at least six months. The study aims to fill gaps in data about viral suppression rates without changing the ART regimen and to monitor the emergence of drug-resistant mutations linked to DTG and their effects on viral control. The research is conducted across multiple countries including Kenya, Mozambique, Tanzania, and Lesotho. Participants will continue their DTG-based ART throughout the study, which lasts up to 12 months. Those with viral loads of 200 copies/mL or higher will receive enhanced adherence counseling during scheduled visits every three months. The counseling includes at least three sessions focused on improving medication adherence and managing other causes of viral load increase. For participants who achieve viral suppression below 200 copies/mL during follow-up, an additional viral load test will be done after three months, with longer-term outcome data collected up to 24 months. Throughout the study, participants will have viral load testing at enrollment and every three months if suppression is not reached. Researchers will track viral suppression rates at 6 and 12 months and analyze factors linked to success, development of DTG resistance mutations, and opportunistic infections. The study also collects routine clinical data such as loss to follow-up and mortality. Participants may be evaluated for eligibility in a nested clinical trial focused on managing those who develop drug resistance during the cohort study.

BACKGROUND: The majority of people living with HIV (PLWH) on first-line antiretroviral therapy (ART) in low- and middle-income countries are on dolutegravir (DTG)-containing regimens. Different countries have adopted different approaches in the management of people on DTG-based first-line ART with repeat HIV viral load (VL) of \> 1,000 copies/mL after 3 months of enhanced adherence counselling. For example, Kenya recommends a drug resistance test (DRT) to guide on switch and the optimal second-line regimen; Mozambique and Tanzania recommend switch to 2 nucleoside reverse transcriptase inhibitors (NRTIs) and protease inhibitors (PIs) without drug resistance testing; South Africa does not recommend switch from DTG or DRT for those who are on first-line DTG-containing regimens within the first 2 years of treatment, after which management is guided by possible DRT and expert opinion. The World Health Organization has recognised the role of drug resistance testing (DRT) in a treatment failure algorithm for people living with HIV receiving DTG-based treatment to minimise unnecessary switches from this regimen. The switch to PI has disadvantages including higher cost, higher pill burden, less convenient administration (often should be taken with food), more potential drug-drug interactions, poorer tolerability and more long-term toxicities. GOAL: To assess the efficacy and safety of remaining on DTG compared to switching to DRV/r among people failing DTG-based ART with at least one major DTG DRM. METHODS: This is a phase 3b, multi-country, open-label, two-arm, active-controlled randomized clinical trial (RCT) over 12 months describing the efficacy and safety of switching from DTG to DRV/r among PLWH age ≥ 3 years who are failing DTG-based ART with HIV-1 RNA ≥ 200 copies/mL and ≥ 1 major DTG-associated DRM (and most recent prior HIV-1 RNA ≥ 1,000 copies/mL after at least 6 months on DTG-based ART). The primary efficacy endpoint is the proportion of participants with HIV-1 RNA \< 200 copies/mL at month 6. The study will be conducted in 9 sites in Kenya, Mozambique, Tanzania and Lesotho targeting 392 participants including 30 children aged between 3 and 14 years old. The primary efficacy analysis will assess the difference in the proportion of participants with viral suppression at month 6 using the Cochran-Mantel-Haenszel method. This RCT is nested within an observational cohort study describing HIV-1 viral suppression of people with HIV-1 RNA value of ≥ 1,000 copies/mL after at least six months on DTG-based ART.