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

Abstract

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.

Figure 1

Longitudinal trends in HIV seroprevalence and population prevalence of viraemic HIV drug resistance in Rakai Community Cohort Study participants, 2012–19 Bars indicate 95% CIs. (A) Estimated prevalence of people with HIV, viraemic HIV, viraemic pretreatment HIV, and viraemic treatment-experienced HIV in each survey round. Due to missing viral load data, prevalence of viraemic HIV and viraemic treatment-experienced HIV were not estimated in the 2012 survey. Only some 95% CIs extend beyond the data point. Estimated prevalence of all people with viraemic resistance (B), viraemic pretreatment resistance (C), and viraemic treatment-experienced resistance (D) to NNRTI, NRTI, or PI. NNRTI=non-nucleoside reverse transcriptase inhibitor. NRTI=nucleoside reverse transcriptase inhibitor. PI=protease inhibitor.

Figure 2

Multiclass resistance in Rakai Community Cohort Study participants, 2017 Bars indicate 95% CIs. (A) Estimated prevalence of monoresistance and multiclass resistance. (B) Multiclass resistance profiles for 50 visits of participants with viraemic pretreatment HIV with genotype data for all NNRTIs, NRTIs, and PIs and resistance to at least one of these drug classes. (C) Multiclass resistance profiles for 87 visits of participants with viraemic treatment-experienced HIV with genotype data for all NNRTIs, NRTIs, and PIs and resistance to at least one of these drug classes. NNRTI=non-nucleoside reverse transcriptase inhibitor. NRTI=nucleoside reverse transcriptase inhibitor. PI=protease inhibitor.

Figure 3

Longitudinal trends in HIV drug resistance in Rakai Community Cohort Study participants, 2012–19 Bars indicate 95% CIs. (A) Estimated prevalence of NNRTI, NRTI, and PI resistance among people with viraemic pretreatment HIV. (B) Prevalence in the 2017 survey of the ten most frequently occurring substitutions in people with viraemic pretreatment HIV. INSTI=integrase strand transfer inhibitor. NNRTI=non-nucleoside reverse transcriptase inhibitor. NRTI=nucleoside reverse transcriptase inhibitor. PI=protease inhibitor.

Figure 4

Longitudinal trends in HIV drug resistance in the Rakai Community Cohort Study participants with viraemic treatment-experienced HIV, 2015–17 Bars indicate 95% CIs. (A) Estimated prevalence of NNRTI, NRTI, and PI resistance in treatment-experienced people with viraemic HIV. (B) Prevalence of the ten most frequently occurring drug-resistance mutations in people with viraemic treatment-experienced HIV in the 2017 survey round. INSTI=integrase strand transfer inhibitor. NNRTI=non-nucleoside reverse transcriptase inhibitor. NRTI=nucleoside reverse transcriptase inhibitor. PI=protease inhibitor.