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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.

Publication ,  Journal Article
Demarest, JF; Amrine-Madsen, H; Irlbeck, DM; Kitrinos, KM; CCR102881 Clinical Study Team,
Published in: Antimicrob Agents Chemother
March 2009

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.

Duke Scholars

Published In

Antimicrob Agents Chemother

DOI

EISSN

1098-6596

Publication Date

March 2009

Volume

53

Issue

3

Start / End Page

1116 / 1123

Location

United States

Related Subject Headings

  • env Gene Products, Human Immunodeficiency Virus
  • Zidovudine
  • Tropism
  • Treatment Failure
  • Spiro Compounds
  • Reverse Transcriptase Inhibitors
  • Receptors, CCR5
  • Piperazines
  • Phylogeny
  • Microbiology
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Demarest, J. F., Amrine-Madsen, H., Irlbeck, D. M., Kitrinos, K. M., & CCR102881 Clinical Study Team, . (2009). 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. Antimicrob Agents Chemother, 53(3), 1116–1123. https://doi.org/10.1128/AAC.01055-08
Demarest, James F., Heather Amrine-Madsen, David M. Irlbeck, Kathryn M. Kitrinos, and Kathryn M. CCR102881 Clinical Study Team. “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.Antimicrob Agents Chemother 53, no. 3 (March 2009): 1116–23. https://doi.org/10.1128/AAC.01055-08.

Published In

Antimicrob Agents Chemother

DOI

EISSN

1098-6596

Publication Date

March 2009

Volume

53

Issue

3

Start / End Page

1116 / 1123

Location

United States

Related Subject Headings

  • env Gene Products, Human Immunodeficiency Virus
  • Zidovudine
  • Tropism
  • Treatment Failure
  • Spiro Compounds
  • Reverse Transcriptase Inhibitors
  • Receptors, CCR5
  • Piperazines
  • Phylogeny
  • Microbiology