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The Second-Generation Maturation Inhibitor GSK3532795 Maintains Potent Activity Toward HIV Protease Inhibitor–Resistant Clinical Isolates

Ray, Neelanjana PhD*; Li, Tianbo PhD†,‡; Lin, Zeyu MSc*; Protack, Tricia BSc; van Ham, Petronella Maria BSc§; Hwang, Carey MD*,‖; Krystal, Mark PhD†,‡; Nijhuis, Monique PhD; Lataillade, Max DO, MPH†,‡; Dicker, Ira PhD†,‡

JAIDS Journal of Acquired Immune Deficiency Syndromes: May 1st, 2017 - Volume 75 - Issue 1 - p 52–60
doi: 10.1097/QAI.0000000000001304
Clinical Science

Background: Protease inhibitor (PI)-resistant HIV-1 isolates with primary substitutions in protease (PR) and secondary substitutions in Gag could potentially exhibit cross-resistance to maturation inhibitors. We evaluated the second-generation maturation inhibitor, GSK3532795, for activity toward clinical isolates with genotypic and phenotypic characteristics associated with PI resistance (longitudinal).

Methods: Longitudinal clinical isolates from 15 PI-treated patients and 7 highly PI-resistant (nonlongitudinal) viruses containing major and minor PI resistance-associated mutations were evaluated for GSK3532795 sensitivity. Phenotypic sensitivity was determined using the PhenoSense Gag/PR assay (Monogram Biosciences) or in-house single- and multiple-cycle assays. Changes from baseline [CFB; ratio of post- to pre-treatment FC-IC50 (fold-change in IC50 versus wild-type virus)] <3 were considered to be within the no-effect level.

Results: All nonlongitudinal viruses tested were sensitive to GSK3532795 (FC-IC50 range 0.16–0.68). Among longitudinal isolates, all post-PI treatment samples had major PI resistance-associated mutations in PR and 17/21 had PI resistance-associated changes in Gag. Nineteen of the 21 post-PI treatment samples had GSK3532795 CFB <3. Median (range) CFB was 0.83 (0.05–27.4) [Monogram (11 patients)] and 1.5 (1.0–2.2) [single-cycle (4 patients)]. The 2 post-PI treatment samples showing GSK3532795 CFB >3 (Monogram) were retested using single- and multiple-cycle assays. Neither sample had meaningful sensitivity changes in the multiple-cycle assay. Gag changes were not associated with an increased GSK3532795 CFB.

Conclusions: GSK3532795 maintained antiviral activity against PI-resistant isolates with emergent PR and/or Gag mutations. This finding supports continued development of GSK3532795 in treatment-experienced patients with or without previous PI therapy.

*Bristol-Myers Squibb, Research & Development, Princeton, NJ;

Bristol-Myers Squibb Virology, Wallingford, CT;

Currently, Tianbo Li, Genentech, South San Francisco, CA; Mark Krystal, Max Lataillade, and Ira Dicker, ViiV Healthcare, Wallingford, CT;

§Department of Medical Microbiology, Virology, UMC Utrecht, Utrecht, the Netherlands; and

Currently, Carey Hwang, Global Clinical Development, Infectious Diseases, Merck, Kenilworth, NJ.

Correspondence to: Ira Dicker, PhD, ViiV Healthcare, 5 Research Parkway, Wallingford, CT 06492 (e-mail:

Supported by Bristol-Myers Squibb.

N.R., T.L., Z.L., T.P., C.H., M.K., M.L., and I.D. were employees and held stock or stock options at Bristol-Myers Squibb during the conduct of the study. C.H. is currently an employee at Merck. M.K., M.L., and I.D. are currently employees at ViiV Healthcare. M.N. and P.H. report research grants from GSK and Shanghai De Novo Pharmatech Co., Ltd.

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Received August 24, 2016

Accepted January 02, 2017

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