Patterns of HIV-1 viral load suppression and drug resistance during the dolutegravir transition: a population-based longitudinal study

BackgroundData on the population-scale impact of dolutegravir (DTG)-based HIV regimens in sub-Saharan Africa are extremely limited. We used data from a surveillance cohort in southern Uganda to assess viral suppression and antiretroviral (ART) resistance over 10-years alongside DTG scale-up. MethodsConsenting participants in the population-based Rakai Community Cohort Study between August 2011 and March 2023 aged 15-59 completed questionnaires and provided samples for HIV testing, viral load quantification, and viral deep-sequencing. We collected data on DTG-utilization at HIV care clinics. We estimated the prevalence of HIV suppression (<1,000 copies/mL) and ART resistance using robust Poisson regression. Bayesian logistic regression quantified associations between resistance and individual-level suppression across surveys. FindingsAmong 20,383 people living with HIV (PLHIV), suppression increased from 57.1% (95% confidence interval [CI]: 55.4%-58.8%) to 90.3% (95%CI: 89.2%-91.4%) between 2014 and 2022. By 2020 84.4% (95%CI: 83.7%-85.2%) and 64.6% (95%CI: 63.9%-65.3%) of men and women were on DTG regimens. Among treatment-experienced viremic PLHIV, overall resistance decreased from 51.1% (95%CI: 40.7%-64.1%, 2014) to 27.9% (95%CI: 21.3%-36.5%, 2022). Only two participants harbored intermediate/high-level DTG resistance, attributable to inQ148R, inE138K, and inG140A. Low-level INSTI resistance (inS153Y) was observed in 23/207 (7.5%) of viremic individuals, with putative evidence of transmission. By 2022, suppression was unrelated to prior history of NNRTI/NRTI resistance (risk ratios: 1.14, 95%HPD: 0.96-1.32 and 1.12, 95%HPD: 0.88 - 1.35). InterpretationViral suppression increased during the DTG-transition with minimal emerging intermediate/high-level resistance. Falling resistance among treatment-experienced PLHIV underscores the role of ART adherence in reducing viremia. The emergence of inS153Y justifies continued genomic surveillance of ART resistance. FundingNational Institutes of Health and the Gates Foundation. Research in contextO_ST_ABSEvidence before the studyC_ST_ABSWe searched PubMed for studies matching the keywords "HIV" "resistance" "cohort" "dolutegravir" published after 2018, when dolutegravir (DTG) was first recommended for first-line use globally, and identified 108 studies. We excluded 78 studies, one for being a pure modeling study, one for being about HIV-2, two for being duplicates, two for being study protocols, five for evaluating DTG efficacy as a second, not first, line regimen, 11 for not including any data on individuals on DTG, 17 for focusing on a single sub-population (e.g. children or seniors), 18 for evaluating DTG two (as opposed to three)-drug regimens, and 21 for not having relevant outcomes (e.g. insulin sensitivity). While not indexed on PubMed, we analyzed the World Health Organization HIV Drug Resistance Brief Report 2024 along with the 30 studies from our targeted search. Among the remaining 30 studies, 27 were primary research articles and the remainder reviews in addition to the WHO report. Among the primary research articles, DTG-based first-line regimens were shown to be associated with high-levels of viral suppression among both ART initiators (e.g. 83.0% in South Africa and 84.6% in Tanzania) and those transitioning to DTG from other regimens (e.g. 90.5% in South Africa, 93.8% in Uganda, and 98.4% in Lesotho). Among the four countries in the Africa region reporting to the WHO, all reported levels of viral load suppression among adults receiving ART of >90% between 2019 and 2022, however, levels were not systematically higher among those on DTG, as opposed to NNRTI-based regimens. Among two studies reporting on pre-treatment non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance in the DTG-era, it continued to increase and reached 14.3% (n=14) and 15.3% (n=137) in Tanzania and Zimbabwe, respectively. Pre-existing nucleoside reverse transcriptase inhibitor (NRTI) resistance, particularly rtM184V, was associated with DTG failure in 3/4 studies in which it was reported. Among 14 studies evaluating persons failing DTG therapy, emergent DTG resistance was generally rare, on the order of 0-10%, depending on setting. Among treatment-experienced individuals who failed DTG treatment in Mozambique, however, DTG resistance was more common (19.6%, 36/183). Further, another study based in South Africa reported that 60.3% (41/68) of people failing DTG therapy harbored intermediate/high-level resistance. Across studies, the most commonly reported emergent DTG-resistance conferring mutations were, E138K, G190A, Q148H/K/R, N155H/D, and R263K. Added value of this studyAmong existing real-world studies, all were clinic-based in design, meaning they enrolled PLHIV reporting to care clinics. As not all PLHIV are engaged or retained in care, the results of these studies may not be generalizable to the broader population of PLHIV. Further, in the absence of accurate denominators on the total number of people living with and without HIV, clinic-based studies are unable to accurately assess the real-world population-scale impact of interventions such as changes to first-line treatment regimens. Further, the reviewed studies focused solely on data collected during the transition to DTG-based regimens and are therefore unable to evaluate changes in population-scale virological outcomes during DTG scale-up in light of ongoing trends towards increasing rates of treatment initiation and suppression due to scale-up of global treatment and prevention programs. In the current study, we address these limitations by evaluating population-scale real-world virological outcomes during DTG scale-up in southern Uganda using data from the population-based Rakai Community Cohort Study. We found that the population-prevalence of viral load suppression among PLHIV increased from 86.1% to 89.4% concurrent with the DTG transition. We further observe a trend towards lower rates of NNRTI and NRTI resistance among those who remain viremic despite self-reporting being on treatment alongside increased rates of suppression among those with resistance. This suggests a shift in the population of viremic treatment-experienced PLHIV away from those who remain viremic because of resistance and towards those who are disengaged from care, which is not apparent from sampling only care-seeking PLHIV. Only two viremic individuals harbored intermediate/high-level DTG resistance. We also show a continued increase in pre-treatment NNRTI resistance despite discontinuation of NNRTI-based regimens, reaching 14.8% by 2022. Encouragingly, no pretreatment intermediate/high-level DTG resistance was observed and only two people with treatment experience harbored such resistance. However, a low-level INSTI resistance mutation, inS153Y, was identified in 7.5% (23/307) of sequenced PLHIV and genetic clustering indicates potential transmission of this mutation among 5 of these individuals. Implications of the available evidenceThe transition to DTG-based first-line regimens has supported continued increases in the population prevalence of HIV viral load suppression with limited evidence of emergent intermediate or high-level drug resistance thus far. Given minimal resistance, initiating pretreatment PLHIV on therapy and engaging disengaged treatment-experienced PLHIV are critical for continued progress towards HIV treatment milestones. Continued surveillance for resistance mutations is needed in light of increasing rates of resistance to NNRTIs, which are used in long-lasting injectable ART regimens, and for emerging novel INSTI resistance mutations.