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.
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.
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.
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.
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*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: firstname.lastname@example.org).
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.
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Received December 18, 2012
Accepted April 12, 2013