Beyond Surveillance Mutations: Long-Term Trends and Clinical Relevance of Transmitted HIV Drug Resistance in Spain (2007–2023)

Background & Aims While surveillance drug resistance mutations (SDRMs) remain essential for monitoring transmitted drug resistance, the clinical impact of transmitted resistance for current first-line regimens has become increasingly important. We aimed to update estimates of transmitted drug resistance (TDR) in Spain and assess its clinical impact over time. Methods Nationwide observational study within the CoRIS cohort. We estimated the prevalence of SDRMs and clinically meaningful resistance (CMR) among ART-naïve individuals with baseline genotypic resistance testing in 2022–2023 and evaluated annual trends in CMR to first-line regimens from 2007 to 2023. CMR was defined as Stanford HIVDB resistance level ≥3. Results In 2022–2023, 1,028 individuals were included; 82.8% were male, 63.2% MSM, and 72.2% subtype B. SDRM prevalence was 14.4% (95% CI 12.2-16.9%), driven mainly by NNRTI-SDRMs, while INSTI-SDRMs remained rare [0.5% (95% CI 0.1-1.5%)]; CMR to recommended first-line regimens was very low. Over 2007–2023, CMR declined markedly, coinciding with adoption of second-generation integrase inhibitors. Rilpivirine-associated resistance mutations were detected in 7.0%, largely due to E138A (4.8%). M184V was detected in 0.8%; 6 of 8 cases occurred in persons with current or prior oral pre-exposure prophylaxis (PrEP), although numbers were small. Conclusions In Spain, TDR remains stable, but its clinical impact on first-line regimens has markedly declined. These findings support Test & Treat strategies and immediate ART initiation with contemporary triple- or dual-drug regimens, while highlighting the need for targeted resistance assessment for rilpivirine-containing regimens and further research on prior PrEP exposure and selected NRTI resistance patterns.