16th International HIV Drug Resistance Workshop 12-16 June 2007, Barbados

IN VIVO EMERGENCE OF HIV-1 RESISTANCE TO THE CCR5 ANTAGONIST VICRIVIROC: FINDINGS FROM ACTG A5211

Antivir Ther. 2007; 12:S15 (abstract no. 13)

AMN Tsibris^1,2, RM Gulick³, Z Su⁴, MD Hughes⁴, C Flexner⁵, T Wilkin³, R Gross⁶, M Hirsch^1,2, PR Skolnick⁷, E Coakley⁸, WL Greaves⁹ and DR Kuritzkes^2,10
1Massachusetts General Hospital, Boston, MA, USA; ²Harvard Medical School, Boston, MA, USA; ³Weill Medical College of Cornell University, New York, NY, USA; ⁴Harvard School of Public Health, Boston, MA, USA; ⁵Johns Hopkins University, Baltimore, MD, USA; ⁶The University of Pennsylvania, Philadelphia, PA, USA; ⁷Boston Medical Center, Boston, MA, USA; ⁸Monogram Biosciences, South San Francisco, CA, USA; ⁹Schering-Plough, Kennilworth, NJ, USA; ¹⁰Brigham and Women’s Hospital, Boston, MA, USA

BACKGROUND: Few data are available regarding in vivo emergence of resistance to the CCR5 antagonist vicriviroc (VCV). We determined coreceptor usage, VCV susceptibility, and env sequences of HIV-1 from subjects with virological failure (VF) in ACTG A5211, a Phase IIb trial of VCV.

METHODS: Samples from eight subjects with VF at week 16 were randomly selected for clonal sequence analysis (two subjects each from the placebo, 5mg, 10mg, and 15mg VCV arms). VCV susceptibility (entry susceptibility assay), co-receptor usage (Trofile), and env cloning and sequencing, were performed on samples obtained at entry, confirmation of virological failure and week 24. Sequencing was performed on full-length molecular clones of env obtained from plasma virus by RT-PCR. Env sequencing was also performed on samples from one additional subject from the 10 mg arm after susceptibility testing showed progressive loss of inhibition by VCV.

RESULTS: No consistent increase in VCV IC₅₀ was observed in samples obtained from the eight randomly selected subjects through week 24 (maximum increase compared to control = 2.83-fold). HIV-1 variants from four of four subjects enrolled in the VCV 5 mg and 10 mg arms had changes in the V3 loop stem that became fixed in the population following VF; such changes were not found in samples from subjects in the placebo or 15 mg arms. Observed sequence changes involved different amino acid positions and substitutions in samples from each subject. Serial samples from the subject with phenotypic evidence of resistance showed emergence of multiple changes in the V3 loop sequence. Tropism assays on samples from these same time points showed a modest capacity to infect CXCR4-expressing cells, although the virus remained predominantly R5. A sample obtained 5 months after stopping VCV showed R5 virus with return towards phenotypic susceptibility and baseline V3 loop sequences.

CONCLUSIONS: VF in subjects receiving a VCVcontaining regimen was associated with changes in the V3 loop in samples from five of nine subjects tested. In the subject with phenotypic evidence of VCV resistance, discontinuation of VCV was associated with return toward genotypically wild-type, VCV-susceptible, R5-only virus, suggesting a fitness advantage of wild-type over VCV-resistant virus.

2007-06-12
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