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

• Published in: Journal of acquired immune deficiency syndromes (1999) Vol. 64; no. 1; p. 7
• Main Authors: Ray, Neelanjana, Hwang, Carey, Healy, Matthew D, Whitcomb, Jeannette, Lataillade, Max, Wind-Rotolo, Megan, Krystal, Mark, Hanna, George J
• Format: Journal Article
• Language: English
• Published: United States 01.09.2013
• Subjects: Anti-HIV Agents - pharmacology; Anti-HIV Agents - therapeutic use; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes - drug effects; CD4-Positive T-Lymphocytes - immunology; Disease Susceptibility; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Resistance, Viral - drug effects; Drug Resistance, Viral - genetics; Female; HIV Envelope Protein gp120 - drug effects; HIV Fusion Inhibitors - administration & dosage; HIV Fusion Inhibitors - pharmacology; HIV Infections - drug therapy; HIV Infections - genetics; HIV Infections - immunology; HIV-1 - drug effects; HIV-1 - immunology; Humans; Male; Mutation, Missense; Organophosphates - therapeutic use; Piperazines - therapeutic use; Prodrugs - pharmacology; Prodrugs - therapeutic use; RNA, Viral - blood; Treatment Outcome; Triazoles - therapeutic use; Viral Load - drug effects
• ISSN: 1944-7884
• DOI: 10.1097/QAI.0b013e31829726f3

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.