Impact of DNA-stored mutations on virological response in virologically suppressed PWH in the switch to modern regimens

Background: The clinical relevance of genotypic resistance testing (GRT) performed on proviral DNA is still debated. Here, we investigate the role of archived resistance on the virological rebound (VR) after switching treatment. Methods: This retrospective study enrolled virologically suppressed people with HIV (PWH) included in the ARCA database with one proviral GRT performed in the six months prior to the switch of modern regimen. Baseline genotypic susceptibility scores (GSS) from HIV-1 DNA GRT (DNA-GSS) and, for a sub-group, from historical plasma GRT (hRNA-GSS) were calculated based on the switch regimen. Survival analysis was used to assess the probability and predictors of VR. Results: A total of 300 PWH were analyzed; 23% of them showed a fully or intermediate resistance (DNA-GSS<2). After the therapy switch, the overall probability of experiencing VR was 13.7%, with PWH with DNA-GSS<2 showing a higher adjusted hazard risk of VR (aHR 2.15, 95%CI, 1.08-4.27, p=0.028). Shorter time under suppression pre-switch was a negative predictor of VR (per 1-year increase, aHR 0.84 95%CI, 0.75-0.93, p=0.001). In the sub-group of PWH with historical plasma GRT (n=129), hRNA-GSS was not associated with VR, while PWH with an intermediate or full resistance found in both DNA-GSS and hRNA-GSS had the highest probability of experiencing VR. Conclusions: Our findings evidenced the role of archived resistance in predicting VR after switch therapy in suppressed PWH. Thus, proviral GRT could be a useful tool to optimize treatment switch strategies, especially if paired with information on previous historical resistance and the duration under suppression.