Background

Many people living with HIV in low- and middle-income countries take a medication called dolutegravir (DTG) as part of their first treatment plan. However, if the amount of HIV virus in their blood (viral load) remains high even after three months of counseling to improve medication adherence, different countries handle the situation in different ways: Kenya does a special test to check for drug resistance before deciding whether to change the medication; Mozambique and Tanzania automatically switch the patient to a different set of drugs without testing for resistance; and South Africa does not recommend switching from DTG within the first two years, unless drug resistance testing and expert advice suggest otherwise. The World Health Organization (WHO) recognizes the importance of drug resistance testing before switching medications, as switching too soon could cause unnecessary problems. The alternative drugs (protease inhibitors) come with drawbacks like higher costs, needing to be taken with food, more side effects, and potential long-term health risks.

What the Study is Trying to Find Out

The study aims to compare two approaches for people whose HIV is not well controlled on DTG and have developed resistance to it: staying on DTG or switching to a different drug called darunavir (DRV/r). The goal is to see which approach is safer and more effective.

How the Study Works

This study is a 12-month clinical trial in four countries: Kenya, Mozambique, Tanzania, and Lesotho. It will involve 392 participants, including 30 children (ages 3–14). Researchers will measure how many people have low HIV viral load (below 200 copies/mL) after six months.

To be part of the study, a personshould have been taking DTG for at least six months, still have high HIV viral load, and have at least one major drug resistance to DTG.

Why This Study Matters

Right now, there is inadequate information on how well people with DTG resistance respond to treatment. This study will help doctors make better decisions about treating HIV in the future.

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 counseling. 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 drug resistance mutation (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 proportion of participants with viral suppression at month 6 using 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 (Ndovu Cohort Study, submitted as a separate protocol).

Study Utility

This RCT will address the gap in published data on the effect of DTG-associated DRMs on viral suppression among people remaining on DTG-based ART while using current NRTI options, as well as the gap on the optimal management strategy for this population.