Ndovu RCT: Investing the Optimal Management of Dolutegravir Resistance

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.

• Proportion of participants with HIV-1 RNA of <200 copies/mL at 12 months [Time frame: 12 months]
• Superiority of switch to DRV/r [Time frame: 6 months]
• Viral suppression with cut-off of 50 copies/mL [Time frame: 6 and 12 months]
• Viral suppression with cut-off of 1,000 copies/mL [Time frame: 6 and 12 months]
• Viral suppression by age strata [Time frame: 6 and 12 months]
• Viral suppression by sex at birth [Time frame: 6 and 12 months]
• Incidence of adverse events by study arm [Time frame: 6 and 12 months]
• Association between adherence and suppression [Time frame: 6 months]
• Incidence of drug resistant mutations (DRMs) [Time frame: 6 and 12 months]
• Patterns of accumulated drug resistant mutations (DRMs) [Time frame: 6 and 12 months]
• Drug resistant mutations (DRM) patterns associated with non-suppression [Time frame: 6 and 12 months]
• Predictors of DTG-associated drug resistant mutations (DRMs) [Time frame: 6 and 12 months]