Population dynamics of HIV drug resistance among pre-treatment and treatment-experienced persons with HIV during treatment scale-up in Uganda: a population-based longitudinal study

Abstract

AbstractBackgroundLongitudinal data on the population prevalence of HIV drug resistance during scale-up of HIV treatment in Africa are extremely limited. We estimated trends in HIV drug resistance prevalence during ART program expansion from a population-based surveillance cohort in southern Uganda.MethodsWe analyzed data from Rakai Community Cohort Study participants aged 15-49 during four survey rounds conducted between 2012 (round 15) and 2019 (round 19). Consenting participants were tested for HIV and completed questionnaires. Persons living with HIV (PLHIV) provided samples for viral load quantification and virus deep-sequencing. Sequence data were used to predict resistance profiles. The prevalence of class-specific resistance and resistance-conferring substitutions were estimated using robust log-Poisson regression.Findings93,659 participant visits were contributed between 2012 and 2019, including 17,471 (18.65%) from PLHIV. Using deep-sequencing data from 3,713 pre-treatment participant-visits we estimated that the population prevalence of viremic NNRTI, NRTI, and PI resistance decreased significantly between 2012 and 2017 (PR = 0.38, 95% CI 0.25 – 0.57; 0.20, 95% CI 0.09 – 0.45; 0.19, 95% CI 0.09 – 0.39, respectively) with increasing viral suppression. Among viremic pre-treatment PLHIV, the prevalence of NNRTI resistance increased two-fold (PR = 1.96, 95% CI 1.31-2.95) to 9.77% (7.35% - 12.97%) over the same time period. We did not observe an increase in NRTI or PI resistance in this population. The 2017 prevalence of NNRTI and NRTI resistance among viremic treatment-experienced PLHIV was 47.67% (95% CI 40.94% - 55.50%) and 36.55% (95% CI 30.14% - 44.31%), respectively. Single-class resistance predominated among resistant pre-treatment PLHIV (83.05%) whereas most treatment-experienced resistance was multi-class (76.65%). In 2017, 10.13% (95% CI 7.83%-13.63%) and 9.98% (95% CI 6.43%-15.51%) of viremic pre-treatment and treatment-experienced PLHIV harbored the inT97A mutation.InterpretationPrevalence of HIV drug resistance among viremic PLHIV significantly increased with scale-up of ART programs. The prevalence of inT97A is potentially concerning considering the recent roll-out of dolutegravir-based regimens.FundingNational Institutes of Health, the Bill & Melinda Gates Foundation, and the U.S. President’s Emergence Plan for AIDS Relief through the Centers for Disease Control and Prevention.Research in contextEvidence before the studyWe searched PubMed for studies matching the keywords “hiv” “resistance” “longitudinal” “cohort” “population” published since 2004 (the beginning of antiretroviral therapy (ART) availability in sub-Saharan Africa) and identified 48 studies. We excluded 33 studies not based in sub-Saharan Africa, four studies primarily concerned with coinfection with other pathogens (e.g. HBV,M. tuberculosis), two studies concerned with insulin resistance, one sequencing-methods paper, and one paper concerned with host susceptibility to HIV infection. The remaining seven studies were not population-based meaning that the study population was not all persons but e.g. people living with HIV enrolled in care at a given clinic. We identified no previous longitudinal population-based cohort studies of HIV ART resistance in sub-Saharan Africa.Added value of this studyWe estimated the prevalence of drug resistance over four survey rounds of a population-based open-cohort study in southern Uganda between 2012 and 2019 during a period of intense treatment scale-up. We show that pre-treatment resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs) among pre-treatment PLHIV increased significantly during the scale-up of ART. We further show that among viremic treatment-experienced individuals 48% and 37% harbored resistance to NNRTIs and nucleoside-reverse transcriptase inhibitors (NRTIs), the majority of which harbored multiclass resistance. While drug resistance among people living with viremic HIV increased, the overall prevalence of viremic HIV drug resistance in the population decreased by about two-thirds due to increasing population viral load suppression. The most common resistance mutation in our population was inT97A, a known compensatory mutation for integrase strand transfer inhibitor (INSTI) resistance. In contrast to other mutations, presence of inT97A did not depend on treatment status.These results provide the first longitudinal population-based estimates of temporal trends in the prevalence of drug resistance during ART program expansion in a high-burden setting. Further, they provide critical insight into the landscape of prevalent drug resistance substitutions circulating in this population.Implications of all the available evidenceScale-up of HIV treatment has increased the prevalence of drug resistance mutations among viremic people living with HIV in sub-Saharan Africa. The relatively high prevalence of NNRTI resistance has prompted a recent shift to first-line regimens including dolutegravir (an INSTI) in combination with NRTIs. The high prevalence of an INSTI compensatory mutation in our population further warrants continuing monitoring of treatment failures and the prevalence of drug resistance in high burden settings.