In Vivo Patterns of Resistance to the HIV Attachment Inhibitor BMS-488043

Abstract

Attachment inhibitors (AI) are a novel class of HIV-1 antivirals, with little information available on clinical resistance. BMS-488043 is an orally bioavailable AI that binds to gp120 of HIV-1 and abrogates its binding to CD4 ؉ lymphocytes. A clinical proof-of-concept study of the AI BMS-488043, administered as monotherapy for 8 days, demonstrated significant viral load reductions. In order to examine the effects of AI monotherapy on HIV-1 sensitivity, phenotypic sensitivity assessment of baseline and postdosing (day 8) samples was performed. These analyses revealed that four subjects had emergent phenotypic resistance (a 50% effective concentration [EC 50 ] >10-fold greater than the baseline value) and four had high baseline EC 50 s (>200 nM). Population sequencing and sequence determination of cloned envelope genes uncovered five gp120 mutations at four loci (V68A, L116I, S375I/N, and M426L) associated with BMS-488043 resistance. Substitution at the 375 locus, located near the CD4 binding pocket, was the most common (maintained in 5/8 subjects at day 8). The five substitutions were evaluated for their effects on AI sensitivity through reverse genetics in functional envelopes, confirming their role in decreasing sensitivity to the drug. Additional analyses revealed that these substitutions did not alter sensitivity to other HIV-1 entry inhibitors. Thus, our studies demonstrate that although the majority of the subjects' viruses maintained sensitivity to BMS-488043, substitutions can be selected that decrease HIV-1 susceptibility to the AI. Most importantly, the substitutions described here are not associated with resistance to other approved antiretrovirals, and therefore, attachment inhibitors could complement the current arsenal of anti-HIV agents.

In VitroAntiviral Characteristics of HIV-1 Attachment Inhibitor BMS-626529, the Active Component of the Prodrug BMS-663068

“…Interestingly, there was no evidence of emerging resistance to BMS-626529 after 8 days of monotherapy in the only in vivo study completed to date of subjects with HIV-1 infection (34). This is in contrast to an earlier study of BMS-488043, in which viruses from 4/30 subjects were considered to have emergent resistance (defined as a Ͼ10-fold change in susceptibility from baseline) (41). This difference may indicate that the increased inhibitory potency of BMS-626529 over BMS-488043 translated into higher inhibitory quotients for BMS-626529, which in turn increased the barrier for selecting resistance to BMS-626529.…”

“…However, while BMS-488043 demonstrated potent antiviral activity in this study, significant variability in individual half-maximal effective concentration (EC 50 ) values was observed (14,41).…”

“…Additionally, this class of compounds may also form a ternary complex with gp120 and CD4 and interfere with gp41 unmasking (28). While the CD4 binding site of gp120 has shown little propensity for polymorphic substitution, heterogeneity in gp120 sequences and hence structure is believed to be the underlying reason for the broad range of EC 50 s observed with BMS-488043 (41). In addition, BMS-488043 displayed limited oral bioavailability attributed to issues with dissolution and suboptimal pharmacokinetics, properties that ultimately resulted in discontinuation of its development.…”

The emergence of drug resistant HIV variants and novel anti–retroviral therapy

“…Nevertheless, more recently developed agents have targeted new viral proteins involved in other functions of the viral replicative cycle [65] . Enfuvitide (T20) was introduced about ten years ago and inhibits the viral fusion that is necessary for the intra-cytoplasmic insertion of the HIV viral core [66,67] . In addition, new drugs in development (BMS 488043 and PRO 542) act as phase I attachment inhibitors.…”

Identification of anti-HIV and anti-Reverse Transcriptase activity from Tetracera scandens

“…Currently, therapeutic treatment of AIDS has mainly relied on the four types of anti-HIV/AIDS drugs: the viral reverse transcriptase (RTase) inhibitors that include nucleoside and non-nucleoside type RTase inhibitors (1,2), protease inhibitors (3), integrase inhibitors (4), and entry inhibitors (5). However, as the current drugs encounter problems such as the emergence of drug-resistant viruses and unexpected side effects, new types of antiviral inhibitors are being developed such as attachment inhibitors (6), a virion maturation inhibitor (7,8), and CCR5 inhibitors (9). An alternative effort to solve these problems has also been to actively seek novel antiviral agents from various natural sources such as traditionally used medicinal herbs and plants (10).…”