The major approach to the medical management of HIV infection is the treatment of patients with antiviral drugs. The enzymatic processes of the HIV-1 replication cycle present unique approaches for targeted disruption by pharmacological agents. Due to the high rates of virus production and the mutation rate of the virus, treatment of HIV-1 infection generally includes administration of three agents in combination, referred to as highly active antiretroviral therapy (HAART). Sustained treatment of patients with three active drugs results in suppression of viral replication in peripheral blood to below detection limits of sensitive clinical assays (<50 RNA copies/ml). Continued virologic suppression has led to dramatic increases in the life expectancy of HIV-infected individuals and in time to diagnosis with AIDS, and decreases in HIV-associated morbidity and opportunistic infection. To date, 24 individual drugs have been approved by the United States Food and Drug Administration for the treatment of HIV infection. These drugs are distributed into six major classes:
- Nucleoside-analog reverse transcriptase inhibitors (NRTI)
- Non-nucleoside reverse transcriptase inhibitors (NNRTI)
- Protease inhibitors (PI)
- Fusion inhibitors
- Entry Inhibitors – Coreceptor Antagonists
- Integrase inhibitors
Entry inhibitors represent a new class of antiretroviral agents for the treatment of infection with HIV-1. While resistance to other HIV drug classes has been well described, resistance to this new class is still ill-defined despite considerable clinical use. Several potential mechanisms have been proposed: tropism switching (utilization of CXCR4 instead of CCR5 for entry), increased affinity for the coreceptor, increased rate of virus entry into host cells, and utilization of inhibitor-bound receptor for entry. This review addresses the development of attachment, fusion, and coreceptor entry inhibitors and explores recent studies describing potential mechanisms of resistance.