AAC Accepts, published online ahead of print on 15 December 2008

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Antimicrob. Agents Chemother. doi:10.1128/AAC.01055-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Virologic Failure in First Line HIV Therapy with a CCR5 Entry Inhibitor (Aplaviroc/Combivir, CCR102881): NRTI Resistance Regardless of Envelope Tropism

James F. Demarest^*, Heather Amrine-Madsen, David M. Irlbeck, Kathryn M. Kitrinos, and on behalf of the CCR102881 Clinical Study Team

GlaxoSmithKline, Research Triangle Park, North Carolina 27709, USA

^* To whom correspondence should be addressed. Email: james.f.demarest{at}gsk.com.

Background: CCR102881(ASCENT) evaluated the antiviral activity of the novel CCR5 entry inhibitor aplaviroc in combination with combivir in drug-naïve HIV-1 infected subjects with only CCR5-tropic virus detected in plasma. Although the trial was stopped prematurely due to idiosyncratic hepatotoxicity, eight subjects met protocol-defined virologic failure criteria.

Methods: Clonal analyses of viral envelope tropism, aplaviroc susceptibility, and env sequencing were performed on plasma from baseline and virologic failure. Molecular evolutionary analyses were also performed.

Results: The majority of virologic failures (6/8) acquired the lamivudine resistance-associated mutation M184V, and none had evidence of reduced susceptibility to aplaviroc at virologic failure, even at the clonal level. Six virologic failures maintained CCR5-tropism while two exhibited a change in population tropism readout to dual/mixed-tropic with R5X4-tropic clones detected prior to therapy. Two molecular evolutionary patterns were observed; 5 subjects had no evidence for population turnover while 3 subjects had multiple lines of evidence for env population turnover.

Conclusions: Acquisition of the M184V mutation is the primary characteristic of virologic failure in first line therapy with aplaviroc/combivir, regardless of envelope tropism.