Treatment exposure drives a profound shift toward complex multi-class HIV-1 drug resistance

The long-term success of antiretroviral therapy (ART) is increasingly jeopardized by the emergence of HIV-1 drug resistance (HIVDR). Characterizing the resistance landscape is paramount for maintaining treatment durability, particularly in regions transitioning toward new therapeutic standards. A province-wide cross-sectional study was conducted among HIV-1-infected individuals across Jiangxi Province, China. Participants were systematically selected from the provincial HIV-positive surveillance repository based on standardized sample submission criteria: (1) treatment-naïve individuals with baseline viral load (VL) tested before or within 30 days of ART initiation (evaluating pretreatment drug resistance [PDR], n = 104); and (2) treatment-experienced individuals receiving standardized ART for a minimum of six months with virological failure (VL > 400 copies/mL, n = 307). Genotypic resistance profiles for the pol and integrase genes were characterized and interpreted using the Stanford HIV Drug Resistance Database. A profound shift in the resistance landscape was observed following treatment exposure. The prevalence of multidrug resistance (MDR; ≥2 classes) nearly tripled from 10.58% at treatment-naïve group to 28.01% in the VF group ( p < 0.001). NNRTI-associated mutations predominated, with K103N/R reaching 28.66% in the VF cohort compared to 9.61% in the treatment-naïve cohort. Furthermore, the M184V/I mutation was markedly enriched in the VF group (25.73%), severely compromising the NRTI backbone. While protease inhibitors and integrase strand transfer inhibitors demonstrated high durability exceeding 93% susceptibility, the detection of the polymorphic accessory mutation L74I or M (2.93% in the virological failure cohort) highlights the necessity of establishing baseline integrase surveillance as second-generation integrase inhibitors are scaled up. These findings delineate a critical transition from transmitted to complex, multi-class acquired resistance. These findings delineate a critical transition from pretreatment/baseline drug resistance (PDR) to complex, multi-class acquired resistance (ADR). Our data advocate for an urgent clinical pivot toward robust, INSTI-containing salvage regimens and intensified molecular surveillance in high-burden regions.