Correlation of the virological response to short-term maraviroc monotherapy with standard and deep-sequencing-based genotypic tropism prediction methods

Antimicrob Agents Chemother. 2012 Mar;56(3):1202-7. doi: 10.1128/AAC.05857-11. Epub 2011 Dec 5.

Abstract

Genotypic tropism testing methods are emerging as the first step before prescription of the CCR5 antagonist maraviroc (MVC) to HIV-infected patients in Europe. Studies validating genotypic tests have included other active drugs that could have potentially convoluted the effects of MVC. The maraviroc clinical test (MCT) is an in vivo drug sensitivity test based on the virological response to a short-term exposure to MVC monotherapy. Thus, our aim was to compare the results of genotypic tropism testing methods with the short-term virological response to MVC monotherapy. A virological response in the MCT was defined as a ≥ 1-log(10) decrease in HIV RNA or undetectability after 8 days of drug exposure. Seventy-three patients undergoing the MCT were included in this study. We used both standard genotypic methods (n = 73) and deep sequencing (n = 27) on MCT samples at baseline. For the standard methods, the most widely used genotypic algorithms for analyzing the V3 loop sequence, geno2pheno and PSSM, were used. For deep sequencing, the geno2pheno algorithm was used with a false-positive rate cutoff of 3.5. The discordance rates between the standard genotypic methods and the virological response were approximately 20% (including mostly patients without a virological response). Interestingly, these discordance rates were similar to that obtained from deep sequencing (18.5%). The discordance rates between the genotypic methods (tropism assays predictive of the use of the CCR5 coreceptor) and the MCT (in vivo MVC sensitivity assay) indicate that the algorithms used by genotypic methods are still not sufficiently optimized.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Algorithms
  • CCR5 Receptor Antagonists*
  • Chromatography, High Pressure Liquid
  • Cyclohexanes / blood
  • Cyclohexanes / pharmacokinetics*
  • Female
  • Genotype
  • HIV Fusion Inhibitors / blood
  • HIV Fusion Inhibitors / pharmacokinetics*
  • HIV Infections / blood
  • HIV Infections / drug therapy*
  • HIV Infections / virology
  • HIV-1 / drug effects*
  • HIV-1 / physiology
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Male
  • Maraviroc
  • Middle Aged
  • Molecular Typing
  • RNA, Viral / antagonists & inhibitors*
  • RNA, Viral / biosynthesis
  • Receptors, CCR5 / metabolism
  • Tandem Mass Spectrometry
  • Treatment Outcome
  • Triazoles / blood
  • Triazoles / pharmacokinetics*
  • Viral Load / drug effects
  • Viral Load / genetics
  • Viral Tropism / drug effects

Substances

  • CCR5 Receptor Antagonists
  • Cyclohexanes
  • HIV Fusion Inhibitors
  • RNA, Viral
  • Receptors, CCR5
  • Triazoles
  • Maraviroc