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Review 2: "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"

While acknowledging the strength of the manuscript, the reviewers also provide constructive feedback for enhancing the study's accuracy, regional specificity, and clinical relevance.

Published onDec 07, 2023
Review 2: "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"
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key-enterThis Pub is a Review of
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
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 Background Longitudinal 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.Methods We 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.Findings 93,659 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.Interpretation Prevalence 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.Funding National 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 context Evidence before the study We 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 study We 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 evidence Scale-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.

RR:C19 Evidence Scale rating by reviewer:

  • Strong. The main study claims are very well-justified by the data and analytic methods used. There is little room for doubt that the study produced has very similar results and conclusions as compared with the hypothetical ideal study. The study’s main claims should be considered conclusive and actionable without reservation.



Antiretroviral therapy has scaled up enormously in recent years, both as treatment and prevention, so it is important to understand how the prevalence of ART resistance is changing at the population level. The authors of this study use longitudinal data from a population-based cohort to examine HIV ART resistance in a high-prevalence setting in Uganda to examine how HIV drug resistance has changed from 2012-2019. 

The authors provide a very detailed description of HIV drug resistance using data from the Rakai Cohort in Uganda. This is a long-running open general population cohort that is ideally placed for such analysis. The period of analysis (2012-2019) corresponds to the major scale-up of antiretroviral therapy (ART) in sub-Saharan Africa, so it is an important time period to analyze, though I trust that the authors will repeat the analysis with future rounds to see the longer-term effects of scale-up.

Overall, the analysis is thorough, at least as far as I can judge, being not an expert in HIV sequencing. The appendix provides a wealth of detail to help in understanding the results, as well as justifying the correlation structure used to deal with repeat observations of the same individual. The conclusions are supported by the analysis.

The main concern reading the manuscript was how "pre-treatment" and "treatment experienced" depend on self-reported ART status. However, the authors address this point in the discussion, having in a previous study compared ART self-report against detectable ART in the blood, and highlighting that the present results are consistent with expectations.
Two minor comments are firstly that the authors do not present p-values when comparing quantities (for example line 209) - was this a deliberate choice by the authors? If so, I am minded to ignore it as the confidence intervals are presented and are clearly non-overlapping. Secondly, the references to the figures in the main text are mostly wrong (line 229 1C should be 1D; line 293 3B,C should be 3C, D; etc). 

The overall prevalence of HIV drug resistance is decreasing, driven by the large number of people with undetectable HIV viral load. However, among people who do have detectable viral load, either because they have not started treatment, poor adherence or stopping treatment, resistance is high. Thus continued viral sequence monitoring of resistance mutations is critical as dolutegravir/NRTI -based treatment regimens are rolled out. 

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