Population dynamics of HIV drug resistance during treatment scale-up in Uganda: a population-based longitudinal study

Abstract

Background: Clinical studies have reported rising pre-treatment HIV drug resistance during antiretroviral treatment (ART) scale-up in Africa, but representative data are limited. We estimated population-level drug resistance trends during ART expansion in Uganda.

Methods: We analyzed data from the population-based open Rakai Community Cohort Study conducted at agrarian, trading, and fishing communities in southern Uganda between 2012 and 2019. Consenting participants aged 15-49 were HIV tested 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. Population prevalence of class-specific resistance and resistance-conferring substitutions were estimated using robust log-Poisson regression.

Findings: Data from 93,622 participant-visits, including 4,702 deep-sequencing measurements, showed that the prevalence of NNRTI resistance among pre-treatment viremic PLHIV doubled between 2012 and 2017 (PR:1.98, 95%CI:1.34-2.91), rising to 9.61% (7.27-12.7%). The overall population prevalence of pre-treatment viremic NNRTI and NRTI resistance among all participants decreased during the same period, reaching 0.25% (0.18% - 0.33%) and 0.05% (0.02% - 0.10%), respectively (p-values for trend = 0.00015, 0.002), coincident with increasing treatment coverage and viral suppression. By the final survey, population prevalence of resistance contributed by treatment-experienced PLHIV exceeded that from pre-treatment PLHIV, with NNRTI resistance at 0.54% (0.44%-0.66%) and NRTI resistance at 0.42% (0.33%-0.53%). Overall, NNRTI and NRTI resistance was predominantly attributable to rtK103N and rtM184V. While 10.52% (7.97%-13.87%) and 9.95% (6.41%-15.43%) of viremic pre-treatment and treatment-experienced PLHIV harbored the inT97A mutation, no major dolutegravir resistance mutations were observed.

Interpretation: Despite rising NNRTI resistance among pre-treatment PLHIV, overall population prevalence of pre-treatment resistance decreased due to treatment uptake. Most NNRTI and NRTI resistance is now contributed by treatment-experienced PLHIV. The high prevalence of mutations conferring resistance to components of current first-line ART regimens among PLHIV with viremia is potentially concerning.

Figure 1:. Longitudinal trends in HIV seroprevalence and population prevalence of viremic HIV drug resistance among Rakai Community Cohort Study participants, 2012–2019.

(A) Estimated prevalence of all HIV, viremic HIV, viremic pre-treatment HIV, and viremic treatment-experienced HIV in each round. Due to missing viral load data, prevalence of viremic HIV and viremic treatment-experienced HIV were not estimated in the 2012 survey. For some estimates confidence bands do not extend beyond point. (B-D) Estimated population prevalence of all viremic (B), pre-treatment viremic (C), and treatment-experienced viremic (D) NNRTI, NRTI, and PI resistance among all study participants. Estimates were generated using Poisson regression with robust standard errors with survey round as a predictor variable. Generalized estimating equations with correlation structure selection by Quasi Information Criterion value (A: independent, B: independent, C: independent, D: exchangeable (NNRTI and PI), independent (NRTI)) were used to account for repeat participants across study rounds. Error bars indicate the Wald 95% confidence interval for the mean value. For clarity, points are jittered along the x-axis. PLHIV = people living with HIV. NNRTI = non-nucleoside reverse transcriptase inhibitors (blue upwards facing triangles). NRTI = nucleoside reverse transcriptase inhibitors (green downwards facing triangles). PI = integrase inhibitors (pink squares).

Figure 2:. Patterns of multi-class resistance in Rakai Community Cohort Study, 2017.

(A) Estimating population prevalence of NNRTI, NRTI, and PI mono-resistance and NNRTI/NRTI, NNRTI/PI, NRTI/PI, and NNRTI/NRTI/PI multi-class resistance among all RCCS study participants. Estimates were generated using Poisson regression with robust standard errors with survey round as a predictor variable. General estimating equations with the best fit correlation structure by QIC value (NNRTI, NRTI, PI mono-resistance and NNRTI/NRTI and NNRTI/PI multi-class resistance: independent, NRTI/PI and NNRTI/NRTI/PI: exchangeable) were used to account for repeated measures from the same participant Error bars indicate the Wald 95% confidence interval for the mean value. (B) Multi-class resistance profiles among 50 pre-treatment viremic 2017 participant-visits with genotype data for all NNRTIs, NRTIs, PIs, and resistance to at least one of these drug classes. (C) Multi-class resistance profiles among 87 treatment-experienced viremic 2017 participant-visits with genotype data for all NNRTIs, NRTIs, PIs, and resistance to at least one of these drug classes. NNRTI = non-nucleoside reverse transcriptase inhibitors. NRTI = nucleoside reverse transcriptase inhibitors. PI = integrase inhibitors.

Figure 3:. Longitudinal trends in HIV drug resistance among pre-treatment viremic Rakai Community Cohort Study participants, 2012–2019.

(A) Estimated prevalence of NNRTI, NRTI, and PI resistance among pre-treatment viremic PLHIV. For visual clarity, points are jittered along the x-axis. (B) Prevalence in the 2017 survey of the 10 most prevalent substitutions in pre-treatment viremic PLHIV sorted by prevalence. Estimates were generated using Poisson regression with robust standard errors with survey round as a predictor variable. General estimating equations with the best fit correlation structure by QIC value (NNRTI: exchangeable, NRTI: exchangeable, PI: AR1, substitutions: independent to ensure convergence) were used to account for repeated measures from the same participant Error bars indicate the Wald 95% confidence interval for the mean value within each category. PLHIV = people living with HIV. NNRTI = non-nucleoside reverse transcriptase inhibitors. NRTI = nucleoside reverse transcriptase inhibitors. PI = integrase inhibitors.

Figure 4:. Longitudinal trends in HIV drug resistance among treatment-experienced viremic Rakai Community Cohort Study participants, 2015–2017.

(A) Estimated prevalence of NNRTI, NRTI, and PI resistance among treatment-experienced viremic PLHIV. For visual clarity, points are jittered along the x-axis. (C) Prevalence of the 10 most prevalent drug resistance mutations in treatment-experienced viremic PLHIV in the 2017 survey round, sorted by prevalence. Estimates were generated using Poisson regression with robust standard errors with survey round as a predictor variable. General estimating equations with the best fit correlation structure by QIC value (NNRTI and PI: exchangeable, NRTI: independent, mutations: independent to ensure convergence) were used to account for repeated measures from the same participant Error bars indicate the Wald 95% confidence interval for the mean value within each category. PLHIV = people living with HIV. NNRTI = non-nucleoside reverse transcriptase inhibitors. NRTI = nucleoside reverse transcriptase inhibitors. PI = integrase inhibitors.