Cabotegravir and rilpivirine resistance-associated mutations among people with newly diagnosed HIV-1 in the Netherlands

OBJECTIVE: Pretreatment resistance-associated mutations (RAMs) increase the risk of virological failure during long-acting cabotegravir/rilpivirine (CAB/RPV) treatment. We determined the prevalence of baseline CAB/RPV RAMs in individuals with newly diagnosed HIV-1 infection in the Netherlands. DESIGN: We performed a retrospective analysis of ATHENA cohort participants diagnosed with HIV-1 in the Netherlands between 2015-2024 who underwent baseline genotypic resistance testing prior to antiretroviral therapy. METHODS: The Stanford HIVdb mutation analysis program and IAS-USA 2025 drug mutation chart were used to identify CAB/RPV RAMs. Mutations associated with low-level resistance or greater and the integrase substitution IN L74I in HIV-1 subtype A6 were considered clinically relevant. The primary outcome was the proportion of individuals with baseline CAB/RPV RAMs. RESULTS: Of the 2,416 participants undergoing baseline resistance testing, 188 (8%) had clinically relevant CAB/RPV RAMs. The most frequently observed RAMs were reverse transcriptase E138A in 76 (40.4%) and IN L74I in 57 (30.3%) participants. The observed prevalence of CAB/RPV RAMs increased significantly over time, from 3.6% in 2015 to 16.7% in 2024 (p < 0.00001), coinciding with a rise in HIV-1 subtype A6 infections. In 2024, the standardized prevalence of CAB, RPV, and total baseline RAMs was 3.5%, 5.6%, and 9%, respectively. CONCLUSIONS: Baseline CAB/RPV RAMs were detected in 8% of people with newly diagnosed HIV-1 infection. The prevalence of CAB/RPV RAMs increased over the past decade, driven by an increase in subtype A6 infections. Changes in HIV-1 subtype distribution and transmitted drug resistance may limit the implementation of long-acting CAB/RPV treatment in the Netherlands and comparable settings.