Antiretroviral agents

In 1987, zidovudine became the first approved agent in the United States for the treatment of human immunodeficiency virus type 1 (HIV-1) infection. Two decades later, 24 additional agents in six drug classes had been approved. These include nucleoside analog reverse transcriptase inhibitors (NRTIs), a nucleotide analog reverse transcriptase inhibitor, nonnucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), entry inhibitors, and an integrase inhibitor. This chapter describes the major characteristics of antiretroviral agents that are currently approved, or at a promising stage of development, and is organized according to the virus replication cycle. The current therapeutic niche of chemokine receptor 5 (CCR5) inhibitors is as one component of combination regimens for patients with multidrug-resistant R5 virus. In vitro, maraviroc demonstrates no antagonism with existing antiretroviral agents and additive or synergistic activity in combination with enfuvirtide. Vicriviroc is a potent inhibitor of most R5 viruses in vitro, with an IC₅₀ in the range of 20 nM. It demonstrates additive or synergistic activity in combination with other approved antiretroviral agents. Additive or synergistic in vitro inhibition has been reported with double or triple combinations of numerous antiretroviral agents, except for zidovudine-stavudine, which is an antagonistic combination. Stavudine enjoys relatively few drug-drug interactions compared to other antiretroviral agents. The major mechanism of clearance of raltegravir in humans is by hepatic uridine diphosphoglucuronosyl transferase (UGT)-1A1. Amprenavir is additive with a number of other antiretroviral agents (zidovudine, didanosine, abacavir, saquinavir, indinavir, and ritonavir).