Virological success despite archived INSTI drug resistance mutations on INSTI-based antiretroviral regimens.

Objectives: The clinical relevance of archived drug resistance mutations (DRMs) detected by HIV-1 proviral genotypic resistance testing (GRT) in virologically suppressed (VS) people with HIV (PWH) remains unclear, especially since these mutations may reside in defective proviruses. We assessed the impact of archived full-class integrase strand transfer inhibitor (INSTI) DRMs in a real-life setting.

Design: This was a retrospective study conducted in Paris, France, evaluating archived INSTI DRMs in VS PWH receiving INSTI-based regimens.

Methods: We included VS PWH receiving INSTI-based regimens with archived full-class INSTI DRMs. We assessed mutational load and inferred proviral defectiveness based on the presence of stop codons or G-to-A hypermutations.

Results: Among 883 PWH with INSTI proviral GRT since March 2022, 30 INSTI DRMs were identified in 26 VS PWH on INSTI-based regimens (69% male, median age 53). Median total HIV-1 DNA was 2.36 log10 copies/106 leukocytes (IQR: 2.24-2.65, n = 17), and median mutational load was 1.94 log10 copies/106 leukocytes (IQR: 1.34-2.39). Mutational load did not differ significantly between presumed defective and intact proviruses (p = 0.786). DRMs were found in presumed defective proviruses in 18/26 (69%) individuals. No virologic failure occurred on INSTI-based therapy during a median follow-up of 202 days (IQR: 105-366).

Conclusion: In this study, virological control was not compromised by archived INSTI DRMs in VS PWH on INSTI-based therapy. Prospective studies evaluating INSTI-based regimen switching despite these archived DRMs, using advanced sequencing methods to better link DRMs to proviral genome integrity, are needed to accurately assess their impact and refine clinical practices.