Selection of drug-resistant HIV-1 mutants in response to repeated structured treatment interruptions.

Background: A new HIV-1 treatment strategy based on repeated structured treatment interruptions (STI) is currently being evaluated in clinical trials to determine whether immune cell-mediated control of viral replication can be stimulated by intermittent periods of viral replication. The potential for selection of drug-resistant quasi-species remains a major concern of such a treatment strategy.

Methods: Plasma and peripheral blood lymphocyte (PBL) samples from 12 patients who had three consecutive STIs were studied. Genotypic analysis was based on population and clonal sequencing. Drug susceptibility and their corresponding replication capacities were evaluated by a single-cycle growth assay.

Results: Consistent with a loss of phenotypic susceptibility to lamivudine, the M184V mutation was detected by genotypic analysis (direct and clonal sequencing) in plasma samples collected from two patients at the end of the second or third STI. Longitudinal analysis of patient samples revealed a step-wise increase in the M184V mutation in each patient virus population over successive STIs, despite the lower replicative capacity associated with this mutation in the absence of antiviral agents.

Conclusion: Consistent with a loss of phenotypic susceptibility to lamivudine, the M184V mutation was detected by genotypic analysis (direct and clonal sequencing) in plasma samples collected from two patients at the end of the second or third STI. Longitudinal analysis of patient samples revealed a step-wise increase in the M184V mutation in each patient virus population over successive STIs, despite the lower replicative capacity associated with this mutation in the absence of antiviral agents.