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

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Antimicrob. Agents Chemother. doi:10.1128/AAC.01057-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Virologic Failure in Therapy Naïve Subjects on Aplaviroc+Lopinavir/Ritonavir (CCR100136): Detection of Aplaviroc Resistance Requires Clonal Analysis of Envelope

Kathryn M. Kitrinos, Heather Amrine-Madsen, David M. Irlbeck, J. Michael Word, James F. Demarest^*, and on behalf of the CCR100136 Study Team

GlaxoSmithKline, Research Triangle Park, North Carolina 27709, USA

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

Background: CCR100136 (EPIC) evaluated the antiviral activity of the novel CCR5 entry inhibitor aplaviroc in combination with lopinavir/ritonavir in drug-naïve HIV-1 infected subjects. Although the trial was stopped prematurely due to idiosyncratic hepatotoxicity, eleven subjects met protocol-defined virologic failure criteria.

Methods: Clonal analyses of viral envelope tropism, aplaviroc susceptibility, and env sequencing were performed on plasma from Day 1 and virologic failure. Molecular evolutionary analyses were also performed.

Results: Treatment emergent resistance to aplaviroc or lopinavir/ritonavir was not observed at the population level. However, aplaviroc resistance was detected in one virologic failure prior to therapy at both the clonal and population level and in a minority (< 50%) of clones at Day 1 or virologic failure from six subjects. Reduced aplaviroc susceptibility manifested as either an IC₅₀ curve shift and/or plateau. Sequence changes in clones with aplaviroc resistance were unique to each subject and scattered across the envelope coding region. Clones from Day 1 and virologic failure were not phylogenetically distinct. Two virologic failures had a population tropism change from CCR5- to dual/mixed-tropic on treatment.

Conclusions: Virologic failure on a regimen of aplaviroc and lopinavir/ritonavir may be associated with aplaviroc resistance, only at the clonal level, and/or, infrequently, tropism changes.