Share this article on:

Prediction of Virological Response and Assessment of Resistance Emergence to the HIV-1 Attachment Inhibitor BMS-626529 During 8-Day Monotherapy With Its Prodrug BMS-663068

Ray, Neelanjana PhD*; Hwang, Carey MD, PhD*; Healy, Matthew D. PhD; Whitcomb, Jeannette PhD; Lataillade, Max DO, MPH; Wind-Rotolo, Megan PhD*; Krystal, Mark PhD; Hanna, George J. MD*

JAIDS Journal of Acquired Immune Deficiency Syndromes: September 1st, 2013 - Volume 64 - Issue 1 - p 7–15
doi: 10.1097/QAI.0b013e31829726f3
Basic and Translational Science

Background: BMS-663068 is the phosphonooxymethyl prodrug of BMS-626529, a small-molecule attachment inhibitor that targets the HIV-1 envelope glycoprotein gp120 preventing it from binding to CD4+ T cells. In vitro investigations have demonstrated considerable variation in susceptibility of different HIV-1 isolates to BMS-626529. BMS-663068 monotherapy in HIV-1–infected subjects produced a mean maximum change from baseline of −1.64 log10 copies per milliliter, but the response was variable.

Methods: In this analysis, baseline and day 8 samples were analyzed for susceptibility to BMS-626529 and the presence of known HIV-1 attachment inhibitor resistance mutations. In addition, predictors of virological response (maximal HIV-1 RNA decline ≥1 log10 copies per milliliter) and resistance selection were investigated.

Results: The only factor associated with reduced virological response was low baseline susceptibility to BMS-626529. There was no apparent relationship between virological response and baseline treatment experience, coreceptor tropism, plasma HIV-1 RNA level, or CD4+ T-cell count. Examination of all positions with known BMS-626529 resistance mutations based on in vitro selection studies showed that gp120 M426L was the primary substitution most clearly associated with nonresponse to BMS-663068. There was minimal change in susceptibility to BMS-626529 over the course of the study and no clear evidence of emergence of a known HIV-1 attachment inhibitor resistance mutation in the majority of subjects as measured by standard population-based phenotypic and genotypic approaches.

Conclusions: Nonresponse to BMS-663068 was associated with low baseline susceptibility to BMS-626529 and the presence of M426L. In this short-term trial, there was minimal evidence of selection for BMS-626529 high-level resistance over 8 days of monotherapy with BMS-663068 by population-based approaches.

Supplemental Digital Content is Available in the Text.

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

Research and Development, Bristol-Myers Squibb, Wallingford, CT; and

Monogram Biosciences Inc., South San Francisco, CA.

Correspondence to: Neelanjana Ray, PhD, Research and Development, Bristol-Myers Squibb, Princeton, NJ 08543-4000 (e-mail:

Supported by Bristol-Myers Squibb.

Presented in part at the 19th Annual Conference on Retroviruses and Opportunistic Infections, March 5–8, 2012, Seattle, WA (poster 725), and the International Workshop on HIV & Hepatitis Virus Drug Resistance, June 5–9, 2012, Sitges, Spain (poster 6).

N.R., C.H., M.D.H., M.L., M.W-R., M.K., and G.J.H. are employees of and shareholders in Bristol-Myers Squibb. J.W. is an employee of Monogram Biosciences/Laboratory Corporation of America, who received fees for some of the work included within this publication, and is a shareholder in the Laboratory Corporation of America.

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 (

Received December 18, 2012

Accepted April 12, 2013

© 2013 by Lippincott Williams & Wilkins