Anti-HIV-1 drug toxicity and management strategies
Department of Biochemistry, University of Allahabad, Allahabad, India
Abstract: Antihuman immunodeficiency virus type 1 (anti-HIV-1) medications have helped millions of HIV-1-infected people lead longer and healthier lives. The goal of HIV-1 treatment is to reduce the number of virions in the body of infected individuals and to prevent rapid destruction of CD4+ T-lymphocyte cells, thus protecting the immune system. Most of the anti-HIV-1 drugs in practice are designed using viral reverse transcriptase (HIV-1RT), protease, and integrase as targets. These drugs that inhibit the activities of HIV-1RT, viral protease, and integrase are therefore known as anti-HIV-1RT, antiprotease, and anti-integrase molecules, respectively. The US Food and Drug Administration has approved 22 anti-HIV-1/acquired immunodeficiency syndrome (AIDS) drugs for clinical use by HIV-1-infected individuals and AIDS patients. Among the drugs, most of the nucleoside analogs (excluding two isomers of 3TC, (-)3TC and (+)3TC, which are shown to be less toxic in cell culture) exhibit clinical complications that pose a threat to chemotherapy. The toxicity of these molecules arises due to their negative impact on the activities of human mitochondrial chromosomal DNA polymerases (a, d, ß, and e) in general and DNA polymerase γ in particular. Other anti-HIV-1 regimens are also reported to cause toxicity. The range of toxicity extends from mild to life-threatening levels. The prolonged use of zidovudine (3′-azido-3′-deoxythymidine [AZT] or Retrovir), which was first approved in 1987 as a nucleoside analog reverse transcriptase inhibitor, has been reported to cause severe hematologic toxicity, including severe anemia, granulocytopenia, and symptomatic myopathy. Many other drugs that are often used in combination with AZT have similar toxicities. The newer antiretrovirals (ARVs), such as 2′,3′-dideoxycytidine, 2′,3′-dideoxyinosine, and 2′,3′-dideoxy-2′,3′-didehydrothymidine, which exhibit analogous mechanisms of action and similar toxicities to AZT, have not been studied extensively. Acyclovir and gancyclovir can cause severe nausea and vomiting. Some of these ARVs when taken during pregnancy may generate teratogenic effects. Similarly, use of antiproteases in highly active ARV therapy causes hepatotoxicity, which poses a severe risk to the patients. In addition, application of fusion inhibitors and anti-integrases induces strong side effects in HIV-1-infected or AIDS patients. The present review illustrates a comprehensive analysis of the existing literature on the toxicity of anti-HIV-1/AIDS drugs, their mechanisms of action, and possible management strategies to combat this problem.
Keywords: HIV-1, AIDS, anti-HIV-1RT drugs, antiproteases, anti-integrases, fusion inhibitors, dosage, toxicity, management
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