Review 1: "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"

Alash'le Abimiku; James Onyemata

doi:doi:10.1162/2e3983f5.91143540

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

by Michael A. Martin, Steven James Reynolds, Charles Ssuuna, Brian T. Foley, Fred Nalugoda, Thomas C. Quinn, Steven A. Kemp, Margaret Nakalanzi, Edward Nelson Kankaka, Godfrey Kigozi, Robert Ssekubugu, Ravindra K. Gupta, Lucie Abeler-Dörner, Joseph Kagaayi, Oliver Ratmann, Christophe Fraser, Ronald Moses Galiwango, David Bonsall, M. Kate Grabowski, and the PANGEA-HIV Consortium and the Rakai Health Sciences Program

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Published on Oct 15, 2023
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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.

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Review:

As we introduce new treatment drugs for HIV/AIDS, it is important to continue to monitor the virus to ensure that it does not have additional changes to evade the drugs.

This study reported a general decrease in population prevalence of NNRTI, NRTI and PI HIVDR over the course of the study (surveillance studies spanning 7 years) due to increased viral suppression which is encouraging for most countries grabbling with ending the HIV epidemic. Perhaps a worrying feature is the report of a two-fold increase in NNRTI resistance seen in pre-treatment PLHIV, although there seems to be a high prevalence of NNRTI (47.67%) and NRTI (36.55%) HIVDR in treatment experienced patients. While the report points out the common reverse transcriptase inhibitor mutations known - K103N (NNRTI) and M184V (NRTI); very interesting is the presence of Integrase compensatory inhibitor (T79A) as the most common (10%) mutation found regardless of treatment status of the participants.

The manuscript is important for the field as it describes pre-treatment and treatment experience NNRTI, NRTI and PI mutations in samples of the population in Uganda collected over 7 years; so this is a robust sample size to study the trend of HIV mutations using deep sequencing techniques in the study population without the bias of only clinic based samples which most of report in the literature use. However the manuscript could be strengthened further by considering the following comments:

Overall, data provided from this study provides a good insight into population based HIV mutations in the Southern region of Uganda. There is need for more similar population-based studies especially with the new WHO recommended DTG-based first-line treatment regimen to determine how generalizable the findings from this study is.
It may be helpful to revise the topic to capture the region of the study rather than the entire country “Population dynamics of HIV drug resistance among pre-treatment and treatment experienced persons with HIV during treatment scale-up in Southern Uganda: a population-based longitudinal study”.
The discussion will be enriched by comparing the findings in the manuscript to any previous population based HIVDR prevalence survey in Uganda or in other Eastern African countries with similar circulating HIV subtypes if this data is available. Also are there any clinical trends that could provide insights to their findings?
The high prevalence of NNRTI-based drug resistance in the pre-treatment exposed PLHIV (Fig 1D) may be indicative of additional treatment exposure in this population, in addition to suggestions provided by the authors based on the possibility that some patients could have been exposed to ART but discontinued the treatment. For such patients, a one point ARV level measurement may not provide a complete picture of pre ART exposure, especially in cases where there may have been completed drug wash out. Sequencing of archived viruses should be considered for future studies as that can provide additional insight into the high levels of NNRTI associated mutations as NRTI and PI-based mutations appear to be stable within the pre-treatment exposed population over the survey period (Fig 1D).

Review 1: "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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