Effects of HIV-1 entry inhibitors in combination

Inhibiting the HIV-1 entry process offer a new therapeutic target and the hope to potentialize our current treatments against wild-type or drug-resistant viruses. Several inhibitors of CD4, co-receptor CCR5 or CXCR4 and fusion are at various levels of clinical development. How best to use this class of drugs in our therapeutic arsenal remains to be defined. It is likely that these compounds will not be used as monotherapy. Therefore, it is important to evaluate how these drugs will interact among themselves as well as with antiretrovirals from other classes. Drug interactions can range from synergy to antagonism depending on factors including binding affinity, drug concentrations, and pharmacokinetics. In the case of entry inhibitors, one must also consider that the entry of HIV-1 into the cell is a multi-step process that involve cumulative events which are interdependent. Furthermore, polymorphism both in the coreceptors and in gp120, the density of coreceptors, and the binding site of the drug may also affect efficacy. Therefore it is difficult to predict how blocking one step of the process will affect the subsequent one without carefully studying interactions of each potential combination in an in vitro system. So far, studies of interactions between fusion inhibitors and coreceptor inhibitors have shown a high level of synergy. Similar studies performed with two co-receptor inhibitors have shown results varying from synergy to high antagonism depending on the viral isolate and the compounds used. In the following chapter, we will review some concepts of mechanisms that may affect these interactions.