Effect of Non-nucleoside Resistance-Associated Mutations on the Effectiveness of Long-Acting Cabotegravir + Rilpivirine Therapy: Insights From the Real-World RELATIVITY Cohort.

Background: The impact of pre-existing non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance-associated mutations (RAMs) on the effectiveness of long-acting (LA) cabotegravir (CAB) and rilpivirine (RPV) remains poorly defined, particularly for mutations like K103N that do not directly compromise RPV susceptibility (non-RPV NNRTI RAMs). Methods: This observational substudy within the Spanish RELATIVITY cohort included people with HIV (PWH) who switched to CAB + RPV LA before 2025. We compared virologic outcomes between those with non-RPV NNRTI RAMs and a reference group without NNRTI/INSTI-RAMs or prior NNRTI-based virologic failure (VF). An additional subgroup with RPV-associated RAMs was also analyzed. Confirmed virologic failure (CVF) was defined as 2 consecutive viral loads ≥ 200 copies/mL or 1 ≥500 copies/mL. Results: Among 1358 participants, 83 (6.1%) harbored non-RPV NNRTI RAMs (47 with K103N) and 1247 served as the reference group. After a median follow-up of 16.7 months, CVF rates were similar between the non-RPV NNRTI RAMs group and the reference group (1.2% vs 0.8%; HR: 1.39; 95% CI: 0.18-10.84; Conclusions: In a real-world setting, CAB + RPV LA demonstrated high effectiveness in PWH with pre-existing NNRTI RAMs that do not compromise RPV susceptibility, including K103N. While no failures were seen in those with RPV-associated RAMs, these results should be interpreted with caution due to the small sample size.