title: Virologic failure in first-line human immunodeficiency virus therapy with a CCR5 entry inhibitor, aplaviroc, plus a fixed-dose combination of lamivudine-zidovudine: nucleoside reverse transcriptase inhibitor resistance regardless of envelope tropism.
abstract: The CCR102881 (ASCENT) study evaluated the antiviral activity of the novel CCR5 entry inhibitor aplaviroc plus a fixed-dose combination of lamivudine-zidovudine (Combivir) in drug-naïve human immunodeficiency virus type 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. Clonal analyses of the viral envelope tropism, aplaviroc susceptibility, and env sequencing were performed on plasma at baseline and at the time of virologic failure. Molecular evolutionary analyses were also performed. The majority of the subjects with virologic failure (six of eight) acquired the lamivudine resistance-associated mutation M184V, and none had evidence of reduced susceptibility to aplaviroc at the time of virologic failure, even at the clonal level. Six subjects with virologic failure 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 evolutionary patterns were observed: five subjects had no evidence of population turnover, while three subjects had multiple lines of evidence for env population turnover. The acquisition of the M184V mutation is the primary characteristic of virologic failure in first-line therapy with aplaviroc plus lamivudine-zidovudine, regardless of the envelope tropism.
authors.affiliation: GlaxoSmithKline Virology, Research Triangle Park, North Carolina 27709, USA. james.f.demarest@gsk.com
authors.forename: James F
authors.initials: JF
authors.lastname: Demarest
authors.forename: Heather
authors.initials: H
authors.lastname: Amrine-Madsen
authors.forename: David M
authors.initials: DM
authors.lastname: Irlbeck
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Kitrinos
mesh_terms: D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D001565:Benzoates / Q000627:therapeutic use*; D054659:Diketopiperazines; D004338:Drug Combinations; D024882:Drug Resistance, Viral / Q000235:genetics; D015658:HIV Infections / Q000188:drug therapy* / Q000235:genetics / Q000821:virology; D015497:HIV-1 / Q000235:genetics; D006801:Humans; D019259:Lamivudine / Q000008:administration & dosage / Q000627:therapeutic use*; D010802:Phylogeny; D010879:Piperazines / Q000627:therapeutic use*; D019713:Receptors, CCR5 / Q000235:genetics / Q000627:therapeutic use; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use; D013141:Spiro Compounds / Q000627:therapeutic use*; D017211:Treatment Failure; D018523:Tropism / Q000235:genetics; D015215:Zidovudine / Q000008:administration & dosage / Q000627:therapeutic use*; D054299:env Gene Products, Human Immunodeficiency Virus / Q000235:genetics
chemical_list: D019380:Anti-HIV Agents; D001565:Benzoates; D054659:Diketopiperazines; D004338:Drug Combinations; D010879:Piperazines; D019713:Receptors, CCR5; D018894:Reverse Transcriptase Inhibitors; D013141:Spiro Compounds; D054299:env Gene Products, Human Immunodeficiency Virus; C109078:lamivudine, zidovudine drug combination; D019259:Lamivudine; D015215:Zidovudine; C499671:aplaviroc