Background:  Entry of HIV-1 is a multi-step process that offers a number of potential targets for drug development. Attachment to the primary receptor, CD4, is followed by binding to 1 of 2 chemokine receptors (CCR5 or CXCR4) that serve as HIV-1 co-receptors. Viruses that use CCR5 predominate in early disease, and represent the majority of transmitted HIV-1. With advancing disease and lower CD4 cell counts, as many as 50% of patients come to harbor CXCR4-using virus. Whether the emergence of CXCR4-using HIV-1 is the cause or consequence of disease progression is a major unresolved question in AIDS pathogenesis. Significant progress has been made in the development of CCR5 inhibitors as antiretroviral drugs. Two small molecule inhibitors, maraviroc and vicriviroc, are in phase 2-3 clinical trials. Both drugs show potent in vitro inhibition of CCR5-using HIV-1 isolates and reduced plasma HIV-1 RNA levels by more than 1.5 log₁₀ in pilot studies. Although a trial of vicriviroc plus fixed-dose zidovudine and lamivudine in treatment-naïve patients was halted due to inferior activity compared to an efavirenz-based regimen, 24-week data from an ACTG trial in treatment-experienced patients showed that vicriviroc added significantly to the activity of an optimized background regimen. Data are expected soon from ongoing phase 2-3 trials of maraviroc in treatment-experienced and treatment-naïve populations. Of greatest theoretical concern is the potential selection of CXCR4-using virus in response to CCR5 blockade. The evidence to date suggests that resistance appears to be mediated by changes in HIV-1 gp120 that allow the protein to interact with CCR5 in the drug-bound conformation. A phase 2 trial of maraviroc in patients with a mixture of CCR5- and CXCR4-using virus showed no significant virologic benefit, but appeared safe and was not associated with CD4 decline. Additional safety concerns are related to the unknown consequences of long-term pharmacological blockade of CCR5. Development of a third drug, aplaviroc, was discontinued because of the occurrence of significant hepatotoxicity in human trials; neither maraviroc nor vicriviroc is associated with hepatotoxicity. The finding of 5 cases of malignancy among vicriviroc-treated patients in the ACTG trial raised concerns about potential increased risk of malignancy associated with CCR5 blockade. However, a causal relationship between vicriviroc exposure and occurrence of these malignancies (2 of which were recurrent) could not be established. No increased risk of cancer has been reported among the more than 1000 subjects exposed to maraviroc in trials of that drug.

Conclusions:  On balance, small-molecule CCR5 inhibitors remain promising drugs that add significantly to the potency of ART regimens for treatment-experienced patients with CCR5-using virus. Full assessment of their therapeutic potential awaits completion of ongoing clinical trials.