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Background Long-acting (LA) cabotegravir (CAB) and rilpivirine (RPV) is an effective and well-tolerated antiretroviral switch option for virologically suppressed people with HIV (PWH). However, incomplete treatment history or unavailable historical Genotype Resistance Testing (hGRT) may limit access to LA therapy. We implemented Next-Generation Sequencing (NGS) on proviral DNA as an additional tool to refine eligibility, stratify virological failure (VF) risk, and tailor HIV-RNA monitoring frequency beyond current guideline recommendations.Materials and Methods In this single-center study, performed between September 2022 - January 2026, eligible PWH were stratified into low, intermediate, or high VF risk as described in table 1. LA CAB+RPV was given every 56 days with a ±7 days. HIV-RNA was monitored at 1 month after the initiation of LA therapy, then every 2, 4, or 6 months for high-, intermediate-, or low-risk PWH, differently from what is currently advised by BHIVA (British HIV Association) guidelines, recommending HIV RNA monitoring every 2 months in the first year of LA and every 4-6 months thereafter. PWH with at least 6 months of follow-up (FU) were included. VF was defined as single HIV-RNA >1000 copies/mL or repeated HIV-RNA >200 copies/mL.Results One hundred PWH with HIV-RNA <50 copies/mL started LA CAB+RPV (median FU 22 months, interquartile range [IQR] 12.8–28; median virological suppression 11 years, IQR 7–12). Seventy-four were classified as low risk, 11 intermediate, and 15 high ( table 2). hGRT on plasma RNA was available in 78 PWH (59 Sanger, 19 NGS), and 31 underwent proviral DNA NGS before LA initiation to complete resistance assessment. Proviral DNA NGS was more frequent in intermediate/high-risk groups (63.6% and 53.3%, respectively), compared with low-risk PWH (21.6%). Fourteen discontinued LA CAB+RPV, six due to adverse events. Transient detectable viremia (>50 copies/mL) occurred in four PWH (two: <200 copies/mL; two: 236 and 238 copies/mL), all classified as low risk. Repeat testing within two weeks showed <50 copies/mL in all cases. Of these, three switched to oral INSTI-based therapy, one continued LA without emergent RAMs detected on plasma RNA NGS performed at the time of HIV-RNA >50 copies/mL, and remaining thereafter with HIV-RNA <50 copies/mL. No VF occurred in any risk groups. During 20 months of follow-up, 501 HIV-RNA tests were performed, corresponding to approximately 300 fewer PCR assays than recommended by BHIVA guidelines.Conclusions Proviral DNA NGS enabled resistance assessment in PWH lacking historical genotypic data, supporting structured, risk-stratified eligibility for LA CAB+RPV. No VF occurred during FU, confirming feasibility and safety of this approach. Risk-adapted HIV-RNA monitoring reduced the number of assays without compromising virological control, supporting safe NGS-guided selection and tailored FU, while minimizing unnecessary medicalization and ensuring equitable access to LA therapy.Abstract SC20 Table 1Risk Stratification for Virological Failure in PWH Receiving LA CAB/RPVAbstract SC20 Table 2Demographics and Outcomes of PWH on LA CAB/RPV by Risk Class