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

March 17, 2025 by
Population dynamics of HIV drug resistance during treatment scale-up in Uganda: a population-based longitudinal study
Aber Maurine

Michael A. Martin1*; Steven James Reynolds2,3,4; Brian T. Foley5; Fred Nalugoda2; Thomas C. Quinn2,3,4; Steven A. Kemp6; Margaret Nakalanzi2; Edward Nelson Kankaka2; Godfrey Kigozi2; Robert Ssekubugu2; Ravindra K. Gupta6,7; Lucie Abeler-Dörner8; Joseph Kagaayi2,9; Oliver Ratmann10; Christophe Fraser8; Ronald Moses Galiwango2; David Bonsall11†; M. Kate Grabowski1,2,12†, on behalf of the PANGEA-HIV Consortium and the Rakai Health Sciences Program

Affiliations:

1Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD, USA
2Rakai Health Sciences Program, Kalisizo, Uganda
3Division of Infectious Disease, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA
4Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
5Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, New Mexico, USA
6Department of Medicine, University of Cambridge, Cambridge, UK
7Africa Health Research Institute, KwaZulu-Natal, South Africa
8Pandemic Sciences Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK
9Makerere University School of Public Health, Kampala, Uganda
10Department of Mathematics, Imperial College London, London, England, United Kingdom
11Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK
12Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA

†These authors contributed equally

*Corresponding author: mmart108@jhmi.edu


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.

Funding

National Institutes of Health and the Gates Foundation

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