Antiviral Efficacy of Abacavir in Antiretroviral Therapy-Experienced Adults Harbouring HIV-1 with Specific Patterns of Resistance to Nucleoside Reverse Transcriptase Inhibitors

Abstract

Objective

To evaluate HIV-1 reverse transcriptase genotypic and phenotypic indicators of resistance to abacavir (ABC) as predictors of ABC antiviral efficacy.

Design

The study was a retrospective, combined analysis of five multicentre trials in which ABC was added as a single agent to background antiretroviral therapy in experienced adults.

Methods

Baseline HIV-1 genotype and phenotypic susceptibility to ABC were determined and the association of genotype and phenotype with virological response after addition of ABC was analysed.

Results

Overall, 68% of these therapy-experienced subjects had a virological response (>0.5 log₁₀ or <400 copies/ml; 42% <400 copies/ml) 4 weeks after addition of ABC. Multivariable analyses revealed no significant difference in the response rate between subjects with wild-type virus and those carrying virus with 1–2 nucleoside reverse transcriptase inhibitor (NRTI)-associated mutations. At the 4-week time-point subjects harbouring virus with ≥3 mutations associated with NRTI resistance were significantly less likely to respond to ABC than were subjects harbouring wild-type virus (P=0.015). However, at the last viral RNA measurement after addition of ABC (12-28 weeks), ≥4 mutations were required to diminish virological response significantly (P=0.012). Phenotypic resistance was also predictive of antiviral response. Significant breakpoints were identified for virological responses for the PhenoSense™ HIV assay and the Antivirogram™ assay. CD4 responses generally paralleled the antiviral responses with a median increase of 55 cells/μl by weeks 12-28.

Conclusions

Virological response to ABC may be diminished significantly by multiple NRTI-associated mutations and/or by reductions in phenotypic susceptibility to ABC. However, many subjects with baseline samples showing evidence of resistance to NRTIs respond to ABC.