HIV drug resistance during antiretroviral therapy scale-up in Uganda, 2012-19: a population-based, longitudinal study.

BACKGROUND: With scale-up of antiretroviral therapy (ART) in sub-Saharan Africa, increasing pretreatment HIV drug resistance has been reported; however, the broader effect of ART expansion on population-level resistance patterns remains insufficiently quantified. We aimed to estimate the longitudinal prevalence of drug resistance and resistance-conferring mutations. METHODS: This study used data collected as part of the Rakai Community Cohort Study (RCCS), an open population-based census and cohort study conducted in southern Uganda. At each survey round, residents aged 15-49 years are invited to participate and receive a structured questionnaire that obtains sociodemographic, behavioural, and health information, including self-reported past and current ART use. Voluntary HIV testing is conducted using a rapid test algorithm and a venous blood sample. People with HIV provide samples for viral load quantification and deep sequencing. We analysed RCCS survey, HIV viral load, and deep sequencing (which was used to predict resistance) data from five survey rounds. The key outcomes were the population prevalence of viraemic people with HIV with non-nucleoside reverse transcriptase inhibitor (NNRTI), nucleoside reverse transcriptase inhibitor (NRTI), protease inhibitor, or multiclass resistance among all participants (regardless of HIV serostatus) in the 2015 and 2017 surveys. Prevalence of class-specific resistance and resistance-conferring substitutions were estimated using robust log-Poisson regression. FINDINGS: Between Aug 10, 2011, and Nov 4, 2020, there were 43 361 participants in the RCCS and 7923 (18·27%) people with HIV. Over five survey rounds, 93 622 participant visits occurred, among which 17 460 (18·65%) were from people with HIV. Over the analysis period, the median age of study participants remained similar (28 years [22-35] in 2012 and 29 years [21-38] in 2019). Sufficient data were available to reliably genotype 4072 (90·03%) of 4523 participant visits from 3407 people with HIV for at least one drug. Overall population prevalence of resistance contributed by viraemic pretreatment people with HIV decreased between 2012 and 2017 from 0·56% (95% CI 0·42-0·75) to 0·25% (0·18-0·33) for NNRTI and from 0·24% (0·15-0·37) to 0·05% (0·02-0·10) for NRTI (prevalence ratio 0·44 [0·29-0·68] for NNRTI and 0·21 [0·09-0·47] for NRTI). Between 2012 and 2017, NNRTI resistance among viraemic pretreatment people with HIV increased from 4·86% (3·69-6·42) to 9·61% (7·27-12·7; prevalence ratio 1·98 [1·34-2·91]). The prevalence of NNRTI and NRTI resistance was substantially higher among viraemic treatment-experienced people with HIV (51·49% [46·24-57·34] for NNRTI and 36·46% [30·06-44·22] for NRTI in 2017) than among pretreatment people with HIV. NNRTI and NRTI resistance was predominantly attributable to rtK103N and rtM184V. inT97A was observed at a similar prevalence among viraemic treatment-experienced (9·96% [6·41-15·48]) and viraemic pretreatment (10·56% [8·01-13·93]) people with HIV; no major dolutegravir resistance mutations were observed. INTERPRETATION: Despite rising NNRTI resistance among pretreatment people with HIV, overall population prevalence of pretreatment HIV drug-resistant viraemia decreased due to increasing ART uptake and viral suppression. This finding underscores the crucial role of achieving and maintaining high ART coverage in reducing transmission of drug-resistant HIV. The high prevalence of mutations conferring resistance to components of first-line ART regimens among viraemic people with HIV is potentially concerning. FUNDING: National Institutes of Health, Johns Hopkins University Center for AIDS Research, Bill & Melinda Gates Foundation, and the US Centers for Disease Control and Prevention.