Phenotypic characterization of virological failure following lopinavir/ritonavir monotherapy using full-length gag-protease genes

Katherine A. Sutherland, Jean Mbisa, Jade Ghosn, Marie Laure Chaix, Isabelle Cohen-Codar, Stephane Hue, Jean Francois Delfraissy, Constance Delaugerre, Ravindra K. Gupta*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

13 Citations (Scopus)

Abstract

Objectives: Major protease mutations are rarely observed following first-line failure with PIs and interpretation of genotyping results in this context may be difficult. We performed extensive phenotyping of viruses from five patients failing lopinavir/ritonavir monotherapy in the MONARK study without major PI mutations by standard genotyping. Methods: Phenotypic susceptibility testing and viral infectivity assessments were performed using a single-cycle assay and fold changes (FC) relative to a lopinavir-susceptible reference strain were calculated. Results: >10-fold reduced baseline susceptibility to lopinavir occurred in two of five patients and >5-fold in another two. Four of five patients exhibited phylogenetic evidence of a limited viral evolution between baseline and failure, with amino acid changes at drug resistance-associated positions in one: T81A emerged in Gag with M36I in the protease gene, correlating with a reduction in lopinavir susceptibility from FC 7 (95% CI 6-8.35) to FC 13 (95% CI 8.11-17.8). Reductions in darunavir susceptibility (>5 FC) occurred in three individuals. Discussion: This study suggests both baseline reduced susceptibility and evolution of resistance could be contributing factors to PI failure, despite the absence of classical PI resistance mutations by standard testing methods. Use of phenotyping also reveals lower darunavir susceptibility, warranting further study as this agent is commonly used following lopinavir failure.

Original languageEnglish
Pages (from-to)3340-3348
Number of pages9
JournalJournal of Antimicrobial Chemotherapy
Volume69
Issue number12
DOIs
Publication statusPublished - 1 Dec 2014

Bibliographical note

Funding Information:
This study was funded by the Wellcome Trust and supported by a grant from AbbVie Laboratories. R. K. G. is funded by a Wellcome Trust Fellowship (WT093722MA). K. A. S. was funded by Public Health England (formerly the Health Protection Agency).

Publisher Copyright:
© The Author 2014.

Keywords

  • Antiretroviral resistance
  • Gag
  • HIV
  • Monotherapy
  • Protease inhibitors

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