Genotypic Analysis of the HIV V3 Region in Virologic Non-Responders to Maraviroc-containing Regimens Reveals Distinct Patterns of Failure

2013 | Antimicrob Agents Chemother

Program(s): Laboratory |

Abstract:

Changes in HIV tropism from R5 to non-R5 or development of drug resistance are often associated with virologic failure in patients treated with maraviroc, a CCR5 antagonist. We sought to examine changes in HIV envelope sequences and inferred tropism in patients who did not respond to maraviroc-based regimens. We selected 181 patients who experienced early virologic failure on maraviroc-containing therapy in the MOTIVATE trials. All patients had R5 HIV by the original Trofile assay before entry. We used population-based sequencing methods and the geno2pheno algorithm to examine changes in tropism and V3 sequence at the time of failure. Using deep sequencing, we assessed whether V3 sequences observed at failure emerged from pre-existing subpopulations. From population genotyping data at failure, 90 patients had R5 results and 91 had non-R5. Of the latter group, the geno2pheno false-positive rate (FPR) value fell from a median of 20 at screening to 1.1 at failure. By deep sequencing, the median percentage of non-R5 variants in these patients rose from 1.4% to 99.5% after a median of four weeks on maraviroc. In 70% of cases, deep sequencing could detect a pre-treatment CXCR4-using subpopulation, which emerged at failure. Overall, there were two distinct patterns of failure on maraviroc. Patients failing with R5 generally had few V3 substitutions, and low non-R5 prevalence by deep sequencing. Patients failing with non-R5 developed very high prevalence non-R5 HIV (median 99%), and had very low geno2pheno values.

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Swenson L

BC Centre for Excellence in HIV/AIDS

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Genotypic Analysis of the HIV V3 Region in Virologic Non-Responders to Maraviroc-containing Regimens Reveals Distinct Patterns of Failure

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