Next generation sequencing of HIV-1 protease in the PIVOT trial of protease inhibitor monotherapy

or the Protease Inhibitor Monotherapy Versus Ongoing Triple Therapy PIVOT Trial Team

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

Abstract

Background: The PIVOT trial examined whether patients with suppressed viral load on combination antiretroviral therapy could be safely switched long-term to ritonavir-boosted protease inhibitor (PI) monotherapy. The main trial publication reported that only one of 296 patients allocated to PI monotherapy experienced a loss of drug options due to protease mutations (identified by local Sanger sequencing resistance tests) likely selected by study drug. Objectives: To assess if we had missed low frequency mutations, using a more sensitive methodology. Study design: We performed next generation sequencing (NGS) on all available frozen plasma samples with VL >1000 copies/ml from patients who were randomised to PI monotherapy. Assays were performed at Public Health England laboratories using a previously described method. Median coverage depth was 76,000 and the threshold for detection of minority variants was 2%. Drug susceptibility was predicted using the Stanford HIVdb algorithm. Results: 17 of 26 potential samples, all from different patients, were identified and successfully tested. The median viral load was 6780 copies/ml and the median time since randomisation was 43 weeks. NGS revealed previously unidentified minority variant protease mutations (G73D, I54T, L89V) in three samples, at frequencies ranging between 2% and 10%. None of these mutations predicted intermediate or high level resistance, the trial primary outcome. Discussion: This report adds to the body of evidence that ritonavir-boosted PI monotherapy, when used as a switch strategy with prompt detection of viral load rebound and early re-introduction of combination therapy, rarely leads to the development of clinically important protease resistance mutations.

Original languageEnglish
Pages (from-to)63-65
Number of pages3
JournalJournal of Clinical Virology
Volume101
DOIs
Publication statusPublished - Apr 2018

Bibliographical note

Funding Information:
NP, WS, DTD, and AA-P report grants from the National Institute of Health Research Health Technology Assessment programme during the conduct of this study. NP reports grants, personal fees, and non-financial support from AbbVie and Janssen; personal fees and non-financial support from Merck and Roche; grants and non-financial support from GlaxoSmithKline; and non-financial support from Gilead Sciences, all outside the submitted work. AA-P reports grants from Janssen and ViiV Healthcare outside the submitted work.

Funding Information:
This work was supported by the National Institute for Health Research Health Technology Assessment programme (project number 06/403/90) and the Medical Research Council (grant MC_UU_12023/23 ). The views and opinions expressed herein are those of the authors and do not necessarily reflect those of the HTA programme, NIHR, NHS or the Department of Health.

Publisher Copyright:
© 2018 The Authors

Keywords

  • HIV
  • NGS
  • Protease inhibitor
  • Resistance

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