Geno- and phenotypic correlates of virologic response to the attachment inhibitor BMS-626529 in an 8-day monotherapy study of its prodrug BMS-663068

Abstract

Background : Administered as monotherapy for 8 days, BMS-663068, the prodrug of the attachment inhibitor BMS-626529, demonstrated significant reductions in plasma HIV-1 RNA. Although baseline IC 50 >100 nM to BMS 626529 correlated with a poor virologic response, BMS-663068 did not appear to select for BMS-626529 resistance on population sequencing or phenotyping. Methods : Genotypic population analyses of baseline samples from non-responders identified amino acid changes that could potentially encode for reduced susceptibility to BMS-626529. Reverse genetics of functional envelope clones confirmed changes responsible for this in phenotypic assays. Additional genotypic, phenotypic and reverse genetic assays were performed on samples from responders to probe the context dependence of the identified substitutions. Results : The gp120 M426L substitution was the major change associated with reduced virologic response (present in 5 of 6 non-responders) and high BMS-626529 IC 50 (present in virus from 6 of 7 subjects with IC 50 >100 nM). The remaining non-responder virus sample contained a S375M substitution that encoded reduced susceptibility. However, the M426L substitution was also identified in two responders, one with reduced susceptibility (IC 50 6300 nM) and another with low IC 50 (38 nM). A series of functional clones from 4 samples (including 2 responders with resistance mutations on population genotyping) were analyzed for susceptibility to BMS-626529. Variability of susceptibility of clones (37-246 fold) was higher than variability observed with other entry inhibitors (enfuvirtide, 6-9 fold; maraviroc, 3-9 fold). In the responder subject with M246L, all functional clones contained M426L and susceptibility varied by 246-fold, suggesting that susceptibility is highly context dependent. One of the responders contained viruses of either tropism. Clones of R5- or X4-tropic viruses from this individual exhibited the same variable range of susceptibility to BMS-626529. Conclusions : gp120 substitutions M426L and S375M were found to be strongly, albeit not exclusively, associated with low susceptibility to BMS-626529 and a lack of virologic response to its prodrug, BMS-663068. Functional clones derived from single individuals exhibited 2-3 log 10 variability in susceptibility to the agent, regardless of tropism, suggesting that susceptibility can be highly context-dependent. (Published: 11 November 2012) Citation: Abstracts of the Eleventh International Congress on Drug Therapy in HIV Infection Zhou N et al. Journal of the International AIDS Society 2012, 15 (Suppl 4):18270 http://www.jiasociety.org/index.php/jias/article/view/18270 | http://dx.doi.org/10.7448/IAS.15.6.18270