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Genotypic and Phenotypic Characterization of HIV-1 Isolates Obtained From Patients on Rilpivirine Therapy Experiencing Virologic Failure in the Phase 3 ECHO and THRIVE Studies: 48-Week Analysis

Rimsky, Laurence PhD*; Vingerhoets, Johan PhD*; Van Eygen, Veerle MSc*; Eron, Joseph MD; Clotet, Bonaventura MD; Hoogstoel, Annemie MSc*; Boven, Katia MD§; Picchio, Gaston PhD§

JAIDS Journal of Acquired Immune Deficiency Syndromes: 1 January 2012 - Volume 59 - Issue 1 - p 39–46
doi: 10.1097/QAI.0b013e31823df4da
Clinical Science

Abstract: Genotypic and phenotypic characterization was performed of HIV-1 isolates from treatment-naive HIV-1–infected patients experiencing virologic failure (VF) during treatment with the nonnucleoside reverse transcriptase inhibitor (NNRTIs) rilpivirine or efavirenz in the pooled phase 3 studies ECHO and THRIVE. Among 686 patients receiving rilpivirine, 72 (10%) experienced VF versus 39 of 682 (6%) receiving efavirenz. In patients with low baseline viral load (VL) ≤100,000 copies per milliliter, the proportions of rilpivirine VFs (19 of 368) and efavirenz VFs (16 of 330) were the same (5%). In patients with high baseline VL >100,000 copies per milliliter, the proportion of VFs was higher with rilpivirine (53 of 318; 17%) than efavirenz (23 of 352; 7%). The rate of rilpivirine VF was comparable between HIV-1 subtype B–infected (11%) and nonsubtype B–infected (8%) patients. The absolute number of VFs with treatment-emergent NNRTI resistance-associated mutations (RAMs) was higher for rilpivirine (most commonly E138K or K101E) than efavirenz (most commonly K103N), but relative proportions were similar [63% (39 of 62) vs. 54% (15 of 28), respectively]. More rilpivirine VFs had treatment-emergent nucleoside/nucleotide reverse transcriptase inhibitor RAMs than efavirenz VFs [68% (42 of 62) versus 32% (9 of 28), respectively], most commonly M184I and M184V. The proportion of rilpivirine VFs with RAMs in patients with low baseline VL was lower than in those with high baseline VL [38% (6 of 16) versus 72% (33 of 46) for NNRTI RAMs and 44% (7 of 16) versus 76% (35 of 46) for nucleoside/nucleotide reverse transcriptase inhibitor RAMs, respectively]. In summary, VF and treatment-emergent reverse transcriptase RAMs were similar at low baseline VL but more frequent at high baseline VL in rilpivirine-treated than in efavirenz-treated patients. The frequent emergence of E138K, especially in combination with M184I, in rilpivirine VFs is a unique finding of these trials.

*Tibotec BVBA, Beerse, Belgium

The University of North Carolina School of Medicine, Chapel Hill, NC

Hospital Universitari Germans Trias i Pujol and irsiCaixa Foundation, Barcelona, Spain

§Tibotec, Titusville, NJ

Correspondence to: Laurence Rimsky, PhD, Tibotec BVBA, Turnhoutseweg, 30, Beerse, 2340 Belgium (e-mail: lrimsky@its.jnj.com).

Supported by funding by Tibotec. Editorial support was provided by I Woolveridge of Gardiner-Caldwell Communications, Macclesfield, United Kingdom; this support was funded by Tibotec.

Meetings at which parts of the data were presented are as follows: “Cohen C, Molina JM, Cahn P, et al. Pooled week 48 efficacy and safety results from ECHO and THRIVE, two double-blind, randomised, phase III trials comparing TMC278 versus efavirenz in treatment-naïve, HIV-1-infected patients” at the 18th International AIDS Conference, July 18–23, 2010, Vienna, Austria. Abstract THLBB206; “Rimsky L, Eron J, Clotet B, et al. Characterization of the resistance profile of TMC278: 48-week analysis of the Phase III studies ECHO and THRIVE” at the 50th Interscience Conference on Antimicrobial Agents and Chemotherapy, September 12–15, 2010, Boston, MA. Abstract H-1810; “Rimsky L, Vingerhoets J, Van Eygen V, et al. Genotypic and phenotypic characterization of HIV-1 isolates obtained from patients failing rilpivirine (RPV, TMC278) in the Phase III studies ECHO and THRIVE: 48 week analysis” at the 20th International Workshop on HIV and Hepatitis Virus Drug Resistance and Curative Strategies, June 7–11, 2011, Los Cabos, Mexico. Antivir Ther. 2011; 16(suppl 1): A17.

L.R., J.V., V.V.E., K.B., A.H. and G.P. are full-time employees of Tibotec. J.E. received research grants from Boehringer Ingelheim (BI), GlaxoSmithKline (GSK), and Merck Sharp and Dohme (MSD); served as a consultant to Avexa Ltd, Bristol Myers Squibb (BMS), Chimerix Inc, GSK, MSD, Pfizer, Tibotec Therapeutics, Tobira Therapeutics, and Virco Lab; and was on speakers' bureaus of BMS, MSD, Roche, Tibotec Therapeutics, and Virco. B.C. has received research funding, consultancy fees, or lecture sponsorships from or has served on advisory boards for Abbott Laboratories, BI, Gilead Sciences, GSK, Janssen-Cilag, MSD, Pfizer, and Tibotec.

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Received August 8, 2011

Accepted October 13, 2011

© 2012 Lippincott Williams & Wilkins, Inc.