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Population-Based Sequencing of the V3-loop Can Predict the Virological Response to Maraviroc in Treatment-Naive Patients of the MERIT Trial

McGovern, Rachel A. BSc (Hons)*; Thielen, Alexander MD; Portsmouth, Simon FRCP; Mo, Theresa MSc*; Dong, Winnie BSc*; Woods, Conan K. BCS*; Zhong, Xiaoyin MSc*; Brumme, Chanson J. BSc*; Chapman, Douglass MSc; Lewis, Marilyn BSc§; James, Ian PhD§; Heera, Jayvant MD; Valdez, Hernan MD; Harrigan, P. Richard PhD*,¶

JAIDS Journal of Acquired Immune Deficiency Syndromes: November 1st, 2012 - Volume 61 - Issue 3 - p 279–286
doi: 10.1097/QAI.0b013e31826249cf
Basic and Translational Science

Background: MERIT was a randomized trial comparing maraviroc (MVC) + Combivir versus efavirenz (EFV) + Combivir in drug-naive patients screened as having R5 HIV-1 by the original Trofile assay (OTA). We retrospectively evaluated treatment response after rescreening for viral tropism using population-based V3-loop sequencing.

Methods: HIV env V3-loop was amplified in triplicate using reverse transcriptase–polymerase chain reaction from stored screening plasma and sequenced. Automated base calling was performed using custom software (RECall) and tropism inferred by geno2pheno (5.75% false-positive rate). Tropism results by genotype were compared with those of OTA and Enhanced Sensitivity Trofile assay (ESTA), where all results were available (n = 876).

Results: Approximately 8% of patients screened as having R5 virus by OTA were classified as having non-R5 virus by V3-loop genotyping. These patients were less likely to have early or sustained week-48 treatment response to MVC, but not EFV. When restricted to patients with R5 virus by genotype, reanalysis of the primary study endpoint (plasma viral load <50 copies/mL at week 48) showed noninferiority of MVC twice daily to EFV (67% vs. 68%). Rescreening by genotype and ESTA had 84% concordance; patients receiving MVC twice daily rescreened as having R5 virus had greater than 1 log10 copies per milliliter decrease in viral load over those rescreened as having non-R5 virus. Where genotype and ESTA screening results were discordant outcomes were similar.

Conclusions: The exclusion of ∼8% of patients with CXCR4-using virus by population-based sequencing would likely have resulted in noninferior responses in the MVC twice-daily and EFV arms. Rescreening by ESTA and population-based sequencing predicted similar virological response.

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*British Columbia Centre for Excellence in HIV/AIDS, St Paul's Hospital, Vancouver, British Columbia, Canada

Max-Planck Institute for Bioinformatics, Saarbrücken, Germany

Pfizer, Inc. New York, NY

§Pfizer R&D, Sandwich, United Kingdom

Pfizer R&D, New London, CT

Department of Medicine, Division of AIDS, University of British Columbia, Vancouver, British Columbia, Canada.

Correspondence to: P. Richard Harrigan, PhD, Director, Research Laboratories, British Columbia Centre for Excellence in HIV/AIDS, 603-1081 Burrard Street, Vancouver, British Columbia, Canada V6Z 1Y6 (e-mail: prharrigan@cfenet.ubc.ca).

Supported by Pfizer and the Canadian Institutes of Health Research (CIHR) and through a GlaxoSmithKline/CIHR Chair in Clinical Virology for Dr. Harrigan.

Presented at the 17th Conference on Retroviruses and Opportunistic Infections, February 16–19, 2010, San Francisco, CA.

Several authors as indicated are employees of Pfizer, which manufactures maraviroc. Dr P. R. Harrigan has received honoraria travel grants to attend conferences and research grants from pharmaceutical and diagnostic companies working in the area of HIV/AIDS, including Pfizer.

All other authors have no conflicts of interest to disclose.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.jaids.com).

Received November 5, 2011

Accepted May 29, 2012

© 2012 Lippincott Williams & Wilkins, Inc.