Impact of Proviral-DNA M184V/I on 96-Week Outcomes of DTG/3TC Maintenance Therapy: Results from the VOLVER Clinical Trial.

Abstract

The effect of archived lamivudine resistance mutations in the efficacy of dolutegravir plus lamivudine (DTG/3TC) remains unclear. We evaluated whether proviral-DNA M184V/I detection is associated with virological outcomes in the VOLVER-GESIDA 11820 study. This open-label, single-arm, multicentre phase IIa trial (NCT04880785) enrolled virologically suppressed adults with documented or suspected historical lamivudine resistance if the M184V/I mutation was not detected in baseline proviral DNA population sequencing. Participants switched to DTG/3TC and were followed through week 96. Proviral-DNA M184V/I was assessed retrospectively by next-generation sequencing (NGS) of peripheral blood mononuclear cells at baseline and week 96. Of 121 participants, 94% had documented historical M184V/I. Proviral-DNA NGS detected M184V/I at ≥5% frequency in 37 (30.6%; 32 M184V, 5 M184I) at baseline and/or week 96: 12 only at baseline, 13 only at week 96, and 12 at both timepoints. Two virological failures occurred within the first 48 weeks; none were observed thereafter. No treatment-emergent resistance was detected. In the ITT-e population (Snapshot analysis), HIV-1 RNA <50 copies/mL at week 96 was maintained in 85.7% (72/84) with no detection of M184V/I, 66.7% (8/12) with detection only at baseline, and 100% with detection only at week 96 (13/13) or both time points (12/12). Among those with M184V/I at both time points, the proportion of proviral sequences carrying the mutation increased from 30% to 45% (p = 0.0037). Proviral-DNA M184V/I detection was not associated with virological outcomes in participants receiving DTG/3TC supporting its limited clinical value in this specific setting.