HIV-1 entry inhibitors: recent development and clinical use

Purpose of reviewThis review provides an overview of HIV-1 entry inhibitors, with a focus on drugs in the later stages of clinical development.Recent findingsEntry of HIV-1 into target cells involves viral attachment, co-receptor binding, and fusion. Antiretroviral drugs that interact with each step in the entry process have been developed, but only two are currently approved for clinical use. The small molecule attachment inhibitor BMS-663068 has shown potent antiviral activity in early phase studies, and phase 2b trials are currently underway. The postattachment inhibitor ibalizumab has shown antiviral activity in phase 1 and 2 trials; further studies, including subcutaneous delivery of drug to healthy individuals, are anticipated. The CCR5 antagonist maraviroc is approved for use in treatment-naïve and treatment-experienced patients. Cenicriviroc, a small-molecule CCR5 antagonist that also has activity as a CCR2 antagonist, has entered phase 2b studies. No CXCR4 antagonists are currently in clinical trials, but once daily, next-generation injectable peptide fusion inhibitors have entered human trials. Both maraviroc and ibalizumab are being studied for prevention of HIV-1 transmission and/or for use in nucleoside reverse transcriptase inhibitor-sparing antiretroviral regimens.SummaryInhibition of HIV-1 entry continues to be a promising target for antiretroviral drug development.

► HIV-1 entry inhibitors are promising agents as antiretroviral drugs.
► The CCR5 antagonist maraviroc and the fusion inhibitor enfuvirtide are approved for clinical use.
► Novel inhibitors targeting attachment, coreceptor usage, and fusion are in development.
► Entry inhibitors may play an important role in prevention of HIV-1 transmission.