Background
Virological failure (VF) to DTG may occur without the selection of resistance in the integrase (IN) region, suggesting other mechanisms of resistance. Some in vitro and in vivo studies, mainly in subtypes B and C, have reported the selection of non-canonical (NC) mutations outside the IN region associated with IN inhibitor (INI) resistance, though clinical evidence remains limited. Our study aimed to investigate potential patterns of NC mutations among HIV-1 infected Cameroonians who failed a DTG-containing regimen
Methods
A cross-sectional study was conducted on individuals with DTG-VF at the Chantal Biya International Reference Centre, Cameroon. HIV-1 whole-genome sequencing (WGS) was performed using ABL DeepCheck Assay on Illumina MiSeq, covering gag (p1, p7, p17, p24), env (gp120, gp41), and 3’polypurin tract (3’PPT) to assess the prevalence of NC mutations (using the NGS cutoff of 5%) in relation to major INI resistance. Fisher’s test with P<0.05 was considered significant.
Results
WGS was successful from 33 individuals (median HIV-RNA 70,195 cps/ml [IQR 7,361–141,611] and duration of INI exposure 20 months [IQR 15–29]). Half had HIV-1 vertical transmission (51.5%), 72.7%) experienced poor adherence, and CRF02_AG recombinant was the prevailing clade (57.6%). Overall, DTG resistance rate was 11/33 (33.3%). At least one NC mutation in gag, env and 3’PPT was found in 25.9%, 100% and 9.4% of individuals, respectively. The distribution of gag and env mutations according to INI major resistance is shown in Figure 1. Among the 12 known NC major mutations observed in our population, none was significantly associated with INI resistance (Panel A). Two mutations (V13I in p7 and V181I in gp41) were however highly prevalent (>90%). Notably, we identified 17 novel mutations (3 in gag, 14 in env) prevailing in individuals harboring INI resistance, and 2 (1 in gag, 1 in env) rather prevailing in those without (Panel B). In the 3’PPT, no major mutations associated with DTG resistance was observed. NC mutations in CRF02_AG vs non CRF02_AG was similarly distributed.
Conclusions
In this non-B HIV-1 setting, NC off-target mutations are highly present in DTG-VF cases. These findings underscore the value of WGS for a broader characterization of DTG resistance. Thus, the reported off-target mutations associated with INI resistance deserve further studies to better delineate their clinical relevance.
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