Learning From Full Characterization of HIV Proviruses in People Receiving Long-Acting Cabotegravir/Rilpivirine With a History of Replication on the Antiretroviral Classes.

Background: To better understand factors associated with virologic response, we retrospectively characterized the HIV proviruses of 7 people with HIV who received long-acting cabotegravir/rilpivirine (CAB/RPV-LA) and were selected according to the following criteria: virologic control achieved despite a history of viral replication on 1 or both corresponding antiretroviral classes (n = 6) and virologic failure (VF) after CAB/RPV-LA initiation (n = 1).

Methods: Last available blood samples before the initiation of CAB/RPV-LA were analyzed retrospectively. Near full-length HIV DNA genome haplotypes were inferred from Nanopore sequencing by the in vivo Genome Diversity Analyzer to search for archived drug resistance mutations (DRMs) and evaluate the frequency and intactness of proviruses harboring DRMs.

Results: Archived DRMs including G-to-A mutations were found in samples from 3 patients who maintained virologic control. Genomes harboring DRMs were majorly in minority variants (<20%) and were defective in all cases except for 1 participant. In this participant, intact genomes with the H221Y mutation on reverse transcriptase were detected representing 11 copies per 10⁶ peripheral blood mononuclear cells. The other mutations observed in the participants of the study resulted most likely from hypermutations. The patient with VF presented archived mutations, all associated with defects. Other factors could explain this VF.

Conclusions: Our findings highlight the difficulty in interpreting the clinical significance of DRMs when detected in proviral DNA and the need to filter out hypermutated sequences. Detected DRMs could be harbored by defective archived genomes unlikely to contribute to treatment failure.