Abstract
Purpose
India carries the third-largest HIV-1 burden globally. The 2021 national transition to Tenofovir/Lamivudine/Dolutegravir (TLD) makes Integrase Strand Transfer Inhibitor resistance surveillance an urgent programmatic priority, yet no prior Indian study has simultaneously characterised all three pol gene regions using gene-region-corrected denominators or multi-threshold algorithmic scoring.Methods
We retrieved 4,375 HIV-1 subtype C pol sequences from LANL and NCBI GenBank (November 2024). Gene-region-specific denominators were applied (RT, n = 2,879; Protease, n = 2,373; Integrase, n = 1,084). Mutations were classified per 2022 IAS-USA criteria; drug-level resistance was scored across four Stanford HIVdb v9.4 thresholds with Benjamini-Hochberg FDR correction. Mutation co-occurrence was assessed across 231 pairs simultaneously.Results
NNRTI resistance was 36.7% (95% CI: 35.0-38.5%), NRTI resistance 25.4%, and dual-class resistance 23.0%; predominant mutations were M184V (19.2%), K103N (11.9%), and Y181C (8.7%). Composite HIVdb scoring detected TDF resistance in 12.1% (≥ Level 3) - four-fold higher than K65R-based counting alone (3.0%) - reflecting Thymidine Analogue Mutation cross-resistance. Nevirapine, Efavirenz, and Protease Inhibitor major resistance were 32.9%, 31.7%, and 4.0%, respectively. INSTI major resistance was 1.6% (95% CI: 0.9-2.4%); Q148H/K/R was entirely absent, and Dolutegravir/Bictegravir resistance was 0% at ≥Level 3. L74M prevalence was 11.3% (9.5-13.3%). Threshold sensitivity reached 9.4-fold for etravirine; co-occurrence analysis identified K65R+V106M enrichment (8.4-fold, FDR q Conclusions
Among publicly available Indian sequences enriched for treatment-failure submissions, the complete absence of Q148-pathway mutations provides a bounded baseline among available pre-/early-TLD integrase sequences. The four-fold TDF resistance underestimation by conventional mutation counting and up to 9.4-fold threshold-dependent prevalence variation support composite algorithm-scored, threshold-specified reporting as a standard for database-level HIV drug resistance analyses.