The Pharmacological Treatment of Human Immunodeficiency Virus Infection

Abstract

Treatment of human immunodeficiency virus (HIV) infection has only recently been possible with the discovery of the HIV life cycle and antiretroviral agents. Reverse transcriptase, a unique enzyme carried by retroviruses, allows viral RNA to be copied to DNA. The elucidation of the life cycle in 1984 and the discovery of zidovudine's effectiveness against HIV in 1985 has offered options for people with HIV infection. Zidovudine (Retrovir; Burroughs Wellcome; Research Triangle, NC), originally known as azidothymidine, is indicated in adult patients with symptomatic and asymptomatic HIV infection with CD4 cell counts less than 500. Doses of 200 mg every 4 hours for 1 month, then 100 mg every 4 hours are recommended. Zidovudine is also indicated for use in children older than 3 months with advance symptomatic HIV disease. A dose of 180 mg/M2 every 6 hours of zidovudine is recommended. Even at low doses, zidovudine is not without toxicity. Acute symptoms of headache or nausea may affect up to 50% of patients usually within the first 2 to 3 weeks of initiation. Other side effects that occur less frequently include fever (5% to 19%), insomnia (8%), diarrhea (12%), asthenia (20%), and myalgia (8%). Patients with late-stage disease are thought to develop resistant strains more quickly than patients with asymptomatic infection, often within a few months after zidovudine therapy begins. It has been estimated that up to 30% of patients with late-stage disease may show resistant strains after 1 year of continuous zidovudine therapy. The clinical significance of resistance has not been proven yet, because the appearance of strains resistant to zidovudine has not been clearly correlated with a worsening prognosis. Didanosine (formerly dideoxyinosine [ddI]) and zalcitabine (formerly dideoxycytidine [ddC]) are also reverse-transcriptase inhibitors and require triphosphorylation, similar to zidovudine. The purine analogs share a different adverse reaction profile, showing less bone marrow toxicity than zidovudine, a pyrimidine analog. Several other agents are under investigation. These include d4T, fluorothymidine, CD4, and interferon alfa. Combination therapy of reverse-transcriptase inhibitors and antiretroviral agents plus immune-stimulating agents may prove efficacious in the near future.