Baseline integrase drug resistance mutations and conserved regions across HIV-1 clades in Cameroon: implications for transition to dolutegravir in resource-limited settings

Abstract

Background Transition to dolutegravir-based regimens in resource-limited settings (RLS) requires prior understanding of HIV-1 integrase variants and conserved regions. Therefore, we evaluated integrase drug resistance mutations (DRMs) and conserved regions amongst integrase strand transfer inhibitor (INSTI)-naive patients harbouring diverse HIV-1 clades in Cameroon. Methods A cross-sectional study was conducted amongst 918 INSTI-naive patients from Cameroon (89 ART-naive and 829 ART-experienced patients). HIV-1 sequences were interpreted regarding INSTI-DRMs using the Stanford HIVdb v8.9-1 and the 2019 IAS–USA list. Amino acid positions with <1% variability were considered as highly conserved. Subtyping was performed by phylogeny. Results Overall prevalence (95% CI) of INSTI-DRMs was 0.8% (0.4–1.7), with 0.0% (0.0–4.0) amongst ART-naive versus 0.9% (0.5–1.9) amongst ART-experienced patients; P = 0.44. Accessory mutations (95% CI) were found in 33.8% (30.9–37.0), with 38.2% (28.1–49.1) amongst ART-naive versus 33.4% (30.4–36.7) amongst ART-experienced patients; P = 0.21. Of 288 HIV-1 integrase amino acid positions, 58.3% were highly conserved across subtypes in the following major regions: V75–G82, E85–P90, H114–G118, K127–W132, E138–G149, Q168–L172, T174–V180, W235–A239 and L241–D253. Wide genetic diversity was found (37 clades), including groups M (92.3%), N (1.4%), O (6.2%) and P (0.1%). Amongst group M, CRF02_AG was predominant (47.4%), with a significantly higher frequency (95% CI) of accessory mutations compared with non-AG [41.4% (36.8–46.0) versus 27.1% (23.3–31.2) respectively; P < 0.001]. Conclusions The low baseline of INSTI-DRMs (<1%) in Cameroon suggests effectiveness of dolutegravir-based regimens. In spite of high conservation across clades, the variability of accessory mutations between major circulating strains underscores the need for monitoring the selection of INSTI-DRMs while scaling up dolutegravir-based regimens in RLS.

Dolutegravir-Based Regimen Ensures High Virological Success despite Prior Exposure to Efavirenz-Based First-LINE ART in Cameroon: An Evidence of a Successful Transition Model

“…The absence of INSTI resistance therefore confirms the high genetic barrier of DTG while encouraging the use of the current genotyping approach. The predominance of CRF02_AG subtype found in this study is in agreement with several other local studies [ 29 , 51 , 52 , 53 , 54 , 55 , 56 ], thus confirming the reliability from genotyping.…”

Evaluation of Circulating and Archived HIV-1 Integrase Drug-Resistance Variants among Patients on Third-Line ART in Cameroon: Implications for Dolutegravir-Containing Regimens in Resource-Limited Settings

“…Finally, the most represented viral clade in this study was the recombinant form CRF02_AG, similar to several reports in Cameroon ( 64 – 69 ). Of note, the broad HIV diversity found in this small sample population could justify the considerable number of polymorphisms observed in viral reservoirs ( 25 , 66 ).…”

Factors associated with HIV-1 resistance to integrase strand transfer inhibitors in Spain: Implications for dolutegravir-containing regimens

“…Moreover, the most frequent INSTI resistance mutation found among these patients was the polymorphic G163K/R mutation ( Tzou et al, 2020 ), which is only associated with a low-level resistance to RAL and EVG. The low frequency of transmitted INSTIs resistance mutations has been reported in previous surveillance studies and meta-analyses ( Doyle et al, 2015 ; Hauser et al, 2018 ; Inzaule et al, 2018 ; Raffaelli et al, 2018 ; Alvarez et al, 2019 ; Liu et al, 2019 ; Casadellá et al, 2020 ; Mbisa et al, 2020 ; Tzou et al, 2020 ; Semengue et al, 2021 ). This scenario supports the use of INSTIs in first-line therapeutic regimens.…”