title: Virologic failure in therapy-naive subjects on aplaviroc plus lopinavir-ritonavir: detection of aplaviroc resistance requires clonal analysis of envelope.
abstract: The CCR100136 (EPIC) study evaluated the antiviral activity of the novel CCR5 entry inhibitor aplaviroc in combination with lopinavir-ritonavir in drug-naïve human immunodeficiency virus type 1-infected subjects. Although the trial was stopped prematurely due to idiosyncratic hepatotoxicity, 11 subjects met the protocol-defined virologic failure criteria. Clonal analyses of the viral envelope tropism, aplaviroc susceptibility, and env sequencing were performed on plasma at day 1 and at the time of virologic failure. Molecular evolutionary analyses were also performed. Treatment-emergent resistance to aplaviroc or lopinavir-ritonavir was not observed at the population level. However, aplaviroc resistance was detected prior to therapy at both the clonal and population levels in one subject with virologic failure and in six subjects in a minority (<50%) of clones at day 1 or at the time of virologic failure. Reduced aplaviroc susceptibility manifested as a 50% inhibitory concentration curve shift and/or a plateau. Sequence changes in the clones with aplaviroc resistance were unique to each subject and scattered across the envelope coding region. Clones at day 1 and at the time of virologic failure were not phylogenetically distinct. Two subjects with virologic failure had a population tropism change from CCR5- to dual/mixed-tropic during treatment. Virologic failure during a regimen of aplaviroc and lopinavir-ritonavir may be associated with aplaviroc resistance, only at the clonal level, and/or, infrequently, tropism changes.
authors.affiliation: GlaxoSmithKline Virology, Research Triangle Park, North Carolina 27709, USA.
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Kitrinos
authors.forename: Heather
authors.initials: H
authors.lastname: Amrine-Madsen
authors.forename: David M
authors.initials: DM
authors.lastname: Irlbeck
authors.forename: J Michael
authors.initials: JM
authors.lastname: Word
authors.forename: James F
authors.initials: JF
authors.lastname: Demarest
mesh_terms: D019380:Anti-HIV Agents / Q000627:therapeutic use*; D001565:Benzoates / Q000627:therapeutic use*; D002986:Clinical Trials as Topic / Q000009:adverse effects; D054659:Diketopiperazines; D004347:Drug Interactions; D024882:Drug Resistance, Viral / Q000235:genetics; D004359:Drug Therapy, Combination; D019143:Evolution, Molecular; D017320:HIV Protease Inhibitors / Q000627:therapeutic use*; D006801:Humans; D020128:Inhibitory Concentration 50; D061466:Lopinavir; D010879:Piperazines / Q000627:therapeutic use*; D011744:Pyrimidinones / Q000627:therapeutic use*; D019438:Ritonavir / Q000627:therapeutic use*; D013141:Spiro Compounds / Q000627:therapeutic use*; D017211:Treatment Failure; D018523:Tropism / Q000235:genetics; D054299:env Gene Products, Human Immunodeficiency Virus / Q000235:genetics
chemical_list: D019380:Anti-HIV Agents; D001565:Benzoates; D054659:Diketopiperazines; D017320:HIV Protease Inhibitors; D010879:Piperazines; D011744:Pyrimidinones; D013141:Spiro Compounds; D054299:env Gene Products, Human Immunodeficiency Virus; D061466:Lopinavir; C499671:aplaviroc; D019438:Ritonavir