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

CXCR4-USING VIRUS DETECTED IN PATIENTS RECEIVING MARAVIROC IN THE PHASE III STUDIES MOTIVATE 1 AND 2 ORIGINATES FROM A PRE-EXISTING MINORITY OF CXCR4-USING VIRUS

Antivir Ther. 2007; 12:S65 (abstract no. 56)

M Lewis¹, P Simpson¹, S Fransen², W Huang ², J Whitcomb², M Mosley¹, DL Robertson³, R Mansfield¹, G Ciaramella¹ and M Westby^1
1Pfizer Global Research and Development, Kent, UK; ²Monogram Biosciences, California, USA; ³University of Manchester, Greater Manchester, UK

INTRODUCTION: Maraviroc in combination with optimized background therapy (OBT) has demonstrated significantly greater virological suppression compared to OBT alone in two double-blind clinical studies of treatment- experienced patients with CCR5-tropic virus. This investigation aimed to understand whether CXCR4-using viruses detected in some patients emerged from a pre-treatment CXCR4-using reservoir, or as a result of mutation from a CCR5-tropic progenitor whilst on treatment (‘tropism switch’).

METHODS: Detailed clonal analyses were conducted on samples from 20 patients (16 on maraviroc and 4 on placebo) in whom CXCR4-using virus was detected by the Trofile^™ assay. For each patient, HIV-1 envelope (Env) clones were amplified from plasma: 192 baseline and 48 on-treatment clones were then randomly selected and phenotypically screened for tropism. Env sequences from these clones were aligned and phylogenetic trees were constructed.

RESULTS: For 14 patients, CXCR4-using env clones identical/ similar in sequence to the on-treatment CXCR4- using virus were identified in the baseline sample. The CXCR4-using clones were present at baseline at a low frequency (1–6%) in 10 of 14 patients, whilst the baseline samples of 4 patients had >10% of CXCR4-using clones; the latter being consistent with the D/M-tropic assignment of their plasma sample. For the remaining six patients, the on-treatment CXCR4-using clones were phylogenetically distinct from baseline and on-treatment CCR5-tropic clones, and contained between seven and 17 amino acid differences in the 35-amino acid V3 loop alone. The origin of on-treatment CXCR4-using virus did not differ between patients receiving maraviroc or placebo, but the clonal screening showed an almost complete loss of CCR5-tropic clones in the on-treatment samples from the patients receiving maraviroc. Of the 20 patients, six continued to respond to therapy at week 24 (4 on maraviroc and 2 on placebo).

CONCLUSIONS: This detailed clonal analysis supports a pre-existing CXCR4-using virus as the most likely origin of on-treatment CXCR4-using virus. No evidence for coreceptor switching was identified whilst on therapy. The apparent loss of CCR5-tropic clones in the on-treatment samples is consistent with their strong in vivo inhibition by maraviroc.

2007-06-12
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