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BackgroundWe evaluated the prevalence of archived proviral drug resistance mutations (DRMs) associated with resistance to integrase strand transfer inhibitors (INSTIs) shortly before Botswana transitioned in 2016 to using dolutegravir (DTG)-based antiretroviral treatment in first-line regimens.MethodsWe used the Stanford University HIV drug resistance database to analyze INSTI-resistance associated mutations (RAMs) in a large representative population-based cohort of adults recruited in 30 geographically dispersed communities as part of the Botswana Combination Prevention Project (BCPP) cohort from 2013 to 2018. A total of 5,144 HIV-1 proviral DNA sequences were included in our analysis; 1,281 sequences were from antiretroviral therapy (ART)-naïve individuals and 3,863 sequences were from non-nucleoside reverse transcriptase inhibitor (NNRTI) ART-experienced individuals. None of the sequences were from DTG-ART experienced participants.ResultsThe overall prevalence of major INSTIs DRMs was 1.11% (95% CI 0.82–1.39%). The prevalence of INSTI DRMs in ART-naïve individuals was 1.64% (21/1,281) and 0.93% (36/3,863) in ART-experienced individuals. Major INSTI-RAMs detected in ART-naïve individuals were E138K (2/1,281; 0.16%), G140R (8/1,281;0.62%), E92G (2/1,281;0.16%), R263K (5/1,281; 0.4%), N155H (1/1,281; 0.08%), P145S (1/1,281;0.008%). Among the ART-experienced individuals, major INSTI RAMs detected were E138K (4/3,863; 0.10%), G140R (25/3,863;0.65%), G118R (2/3,863, 0.05%), R263K (4/3,863, 0.10%), T66I (1/3,863;0.03%), E138K + G140R (1/3,863, 0.03%|), G140R + R263K (1/3,863, 0.03%). High-level resistance to cabotegravir (CAB), elvitegravir (EVG), and raltegravir (RAL) was detected in 0.70, 0.16 and 0.06% of the individuals, respectively. Notably, bictegravir (BIC) and dolutegravir (DTG) showed no high-level resistance.ConclusionThe overall prevalence of archived INSTI RAMs in Botswana was low prior to transitioning to first-line DTG-based ART regimens, and did not differ between ART-naïve and ART-experienced individuals. Ongoing surveillance of INSTI DRMs in Botswana will allow for re-assessment of INSTI resistance risk following nationwide DTG rollout.

BackgroundApproximately 30,000 non-citizens are living with HIV in Botswana, all of whom as of 2020 are eligible to receive free antiretroviral treatment (ART) within the country. We assessed the prevalence of HIV-1 mutational profiles [pre-treatment drug resistance (PDR) and acquired drug resistance (ADR)] among treatment-experienced (TE) and treatment-naïve (TN) non-citizens living with HIV in Botswana.MethodsA total of 152 non-citizens living with HIV were enrolled from a migrant HIV clinic at Independence Surgery, a private practice in Botswana from 2019–2021. Viral RNA isolated from plasma samples were genotyped for HIV drug resistance (HIVDR) using Sanger sequencing. Major known HIV drug resistance mutations (DRMs) in the pol region were determined using the Stanford HIV Drug Resistance Database. The proportions of HIV DRMs amongst TE and TN non-citizens were estimated with 95% confidence intervals (95% CI) and compared between the two groups.ResultsA total of 60/152 (39.5%) participants had a detectable viral load (VL) >40 copies/mL and these were included in the subsequent analyses. The median age at enrollment was 43 years (Q1, Q3: 38–48). Among individuals with VL > 40 copies/mL, 60% (36/60) were treatment-experienced with 53% (19/36) of them on Atripla. Genotyping had a 62% (37/60) success rate – 24 were TE, and 13 were TN. A total of 29 participants (78.4, 95% CI: 0.12–0.35) had major HIV DRMs, including at least one non-nucleoside reverse transcriptase inhibitor (NNRTI) associated DRM. In TE individuals, ADR to any antiretroviral drug was 83.3% (20/24), while for PDR was 69.2% (9/13). The most frequent DRMs were nucleoside reverse transcriptase inhibitors (NRTIs) M184V (62.1%, 18/29), NNRTIs V106M (41.4%, 12/29), and K103N (34.4%, 10/29). No integrase strand transfer inhibitor-associated DRMs were reported.ConclusionWe report high rates of PDR and ADR in ART-experienced and ART-naïve non-citizens, respectively, in Botswana. Given the uncertainty of time of HIV acquisition and treatment adherence levels in this population, routine HIV-1C VL monitoring coupled with HIVDR genotyping is crucial for long-term ART success.

ABSTRACT: Objectives: There are limited data on the prevalence of doravirine (DOR)-associated drug resistance mutations in people with HIV (PWH) in Botswana. This cross-sectional, retrospective study aimed to explore the prevalence of DOR-associated resistance mutations among ART-naïve and -experienced PWH in Botswana enrolled in the population-based Botswana Combination Prevention Project (BCPP). Methods: A total of 6078 HIV-1C pol sequences were analysed for DOR-associated resistance mutations using the Stanford HIV drug resistance database, and their levels were predicted according to the Stanford DRM penalty scores and resistance interpretation. Virologic failure was defined as HIV-1 RNA load (VL) >400 copies/mL. Results: Among 6078 PWH, 5999 (99%) had known ART status, and 4529/5999 (79%) were on ART at time of sampling. The suppression rate among ART-experienced was 4517/4729 (96%). The overall prevalence of any DOR-associated resistance mutations was 181/1473 (12.3% [95% confidence interval {CI}: 10.7–14.1]); by ART status: 42/212 (19.8% [95% CI: 14.7–25.4]) among ART-failing individuals (VL ≥400 copies/mL) and 139/1261 (11.0% [95% CI: 9.3–12.9]) among ART-naïve individuals (P < 0.01). Intermediate DOR-associated resistance mutations were observed in 106/1261 (7.8% [95% CI: 6.9–10.1]) in ART-naïve individuals and 29/212 (13.7% [95% CI: 9.4–8.5]) among ART-experienced participants (P < 0.01). High-level DOR-associated resistance mutations were observed in 33/1261 (2.6% [95% CI: 1.8–3.7]) among ART-naïve and 13/212 (6.1% [95% CI: 3.6–10.8]) among ART-failing PWH (P < 0.01). PWH failing ART with at least one EFV/NVP-associated resistance mutation had high prevalence 13/67 (19.4%) of high-level DOR-associated resistance mutations. Conclusion: DOR-associated mutations were rare (11.0%) among ART-naive PWH but present in 62.7% of Botswana individuals who failed NNRTI-based ART with at least one EFV/NVP-associated resistance mutation. Testing for HIV drug resistance should underpin the use of DOR in PWH who have taken first-generation NNRTIs.