Clearance of archived integrase strand transfer inhibitors resistance mutations in people with virologically suppressed HIV infection.

Introduction: We assessed the kinetics of the clearance of integrase strand transfer inhibitors resistance mutations (INSTIs-RMs) and associated factors from people living with HIV (PWH) displaying suppressed viral replication after virological failure (VF) on an INSTI regimen.

Patients and methods: We included PWH with HIV-RNA viral loads ≤20 copies/mL for at least 5 years in whom INSTIs-RM had been identified at least once in a prior RNA resistance genotyping test. HIV DNAs were sequenced by Sanger sequencing (SS) and ultra-deep sequencing (UDS; detection threshold: 5%) every year over the preceding 5 years.

Results: We included 39 PWH in the study. Most (95%) had experienced VF on a raltegravir-containing regimen. The past INSTIs-RMs were not detected in the peripheral blood mononuclear cells of 35 of the 39 (90%) PWH by SS at the end of follow-up. In a longitudinal analysis (2017-21) based on UDS, the previously detected INSTIs-RMs were not detected in 29 of the 35 (83%) PWH. In multivariable analysis, the duration of viral replication and the level of HIV-RNA during prior VF were significantly associated with the persistence of INSTIs-RM, with odds ratios of 1.05 per week of replication (95% CI, 1.00-1.11; P = 0.024) and 8.26 per log₁₀ copies/mL (95% CI, 1.46-46.59; P = 0.017).

Conclusions: We observed a clear trend towards the clearance of archived INSTIs-RM after a long period of virological control leading to changes in the resistance profile in cellular DNA, raising the possibility of studies assessing the recycling of INSTI classes even in the presence of a history of resistance.