The dolutegravir failure cohort:;a multi-country longitudinal cohort with a randomised clinical trial of continued dolutegravir versus switch to darunavir in people with viraemia while on dolutegravir in Sub-Saharan Africa (The Ndovu Study) protocol

BackgroundThere is insufficient data to inform the management of dolutegravir failure, with the WHO and various countries adopting different approaches, underscoring the need for an evidence-based management approach. MethodsThe Ndovu study is a large multi-country cohort, with a nested randomised controlled trial (RCT), enrolling 6,600 people living with HIV (PLWH) with viral load (VL) of [&ge;]1000 copies/ml after at least 6 months of dolutegravir. Participants aged [&ge;] 1 year, including pregnant women, will be followed up for 12 months with enhanced adherence counselling (EAC) provided monthly. Viral load (VL) testing will be conducted every 3 months and drug resistance testing conducted if VL [&ge;]200 copies/ml. Three hundred and sixty-two participants aged [&ge;]15 years and 30 participants aged 3-14 years with major dolutegravir-associated drug resistant mutations (DRMs) will be enrolled into the RCT and randomised to switch to ritonavir boosted darunavir (DRV/r) or continue with dolutegravir with follow-up for 12 months. VL will be measured at 1, 3, 6 and 12 months and tenofovir levels assessed on dried blood spots at month 1 and month 6. The primary outcome of the cohort is the proportion of participants achieving viral load <200 copies/ml by month 12 and the primary endpoint of the RCT is viral load <200copies/ml at 6 months using a modified FDA snap shot algorithm. Secondary endpoints are DRM patterns associated with non-suppression, level of adherence associated with suppression as well as participant and provider experiences of staying on DTG versus switching to DRV/r. The RCT primary efficacy analysis will be conducted on the Intent-to-Treat Exposed (ITT-E) population and will compare the difference in the proportion of participants with viral load <200 copies/ml 6 months after randomisation between the treatment arms stratified by the randomisation stratification factors. This study is registered at ClinicalTrials.gov, NCT06762054 (cohort) and NCT06747507 (RCT) and enrollment into the cohort started in March 2025. ConclusionThe Ndovu study will address critical gaps in the management of DTG failure including the emergence, determinants and implications of DTG resistance. Further, it will evaluate the optimal ART regimens to use in the setting of DTG resistance in adults and children.