Inhibitors of HIV - Antiviral Agents

Inhibitors of HIV

Nucleoside Reverse Transcriptase Inhibitors

Azidothymidine Azidothymidine (AZT), a nucleoside analog of thymidine, inhibits thereverse transcriptase of HIV. As with other nucleosides, AZT must be phosphorylated; host cell enzymes carry out the process. The basis for the relatively selective therapeutic effect of AZT is that HIV reverse transcriptase is more than 100 times more sen-sitive to AZT than is host cell DNA polymerase. Nonetheless, toxicity frequently occurs.

AZT was the first useful treatment for HIV infection but now is recommended for use only in combination with other inhibitors of HIV replication (eg, lamivudine and protease inhibitors). Toxicity includes malaise, nausea, and bone marrow toxicity. All hematopoi-etic components may be depressed but usually reverse with discontinuation of the drug or dose reduction. Resistance is associated with one or more mutations in the HIV reverse transcriptase gene.

Didanosine and Zalcitabine Didanosine (ddI, dideoxyinosine) and zalcitabine (ddC,dideoxycytidine) are nucleoside analogs that inhibit HIV replication. Following intracel-lular phosphorylation by host enzymes to their active triphosphate form, they block viral replication by inhibiting viral reverse transcriptase, like zidovudine. Serious adverse ef-fects of treatment include peripheral neuropathy with either ddI or ddC, and pancreatitis with ddI; both conditions are dose related. Dose reduction is required for impaired renal function. As with other anti-HIV drugs, these agents should be used only in combination with one or two other anti-HIV drugs to limit the development of resistance and to en-hance antiviral effect.

Stavudine Stavudine (D4T) is another nucleoside analog that inhibits HIV replication.D4T is phosphorylated by cellular enzymes to an active triphosphate form that interferes with viral reverse transcriptase, and it also terminates the growth of the chain of viral nu-cleic acid. D4T is well absorbed and has a high bioavailability. Adverse effects include headache, nausea and vomiting, asthenia, confusion, and elevated serum transaminase and creatinine kinase. A painful sensory peripheral neuropathy that appears to be dose re-lated has also been noted. Dose reduction is required for impaired renal function. D4T should be used only in combination with other anti-HIV agents.

Lamivudine Lamivudine (3TC), another reverse transcriptase inhibitor, is a compara-tively safe and usually well-tolerated agent and is used in combination with AZT or other nucleoside analogs. AZT and 3TC have a unique interaction; 3TC suppresses the develop-ment and persistence of AZT resistance mutations. When combined with interferon alpha, 3TC is also useful for treating hepatitis B.

Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

Compounds that are not nucleoside analogs also inhibit HIV reverse transcriptase. Several compounds, e.g., nevirapine, delavirdine, and efavirenz, have been evaluated alone or in combination with other nucleosides. These compounds are very active against HIV-1, do not require cellular enzymes to be phosphorylated, and bind to essentially the same site on reverse transcriptase. They are active against both AZT-resistant and AZT-sensitive iso-lates. In addition, most of these compounds do not inhibit human DNA polymerase and are not cytotoxic at concentrations required for effective antiviral activity; therefore, they are relatively nontoxic. Unfortunately, drug resistance readily emerges with even single pas-sage of virus in the presence of drug in vitro and in vivo. Thus, NNRTIs should only be used in combination regimens with other drugs active against HIV.

Protease Inhibitors

The newest agents that inhibit HIV are the protease inhibitors. These agents block the action of the viral-encoded enzyme protease, which cleaves polyproteins to produce structural pro-teins. Inhibition of this enzyme leads to blockage of viral assembly and release. The pro-tease inhibitors are potent suppressors of HIV replication in vitro and in vivo, particularly when combined with other antiretroviral agents.

In late 1995, saquinavir was the first protease inhibitor to receive approval. Ritonavir,indinavir, and nelfinavir are other potent protease inhibitors that have since been released.These drugs may cause hepatotoxicity and all agents inhibit P450, resulting in important drug interactions. Because drug resistance develops to all protease inhibitors, they should not be used alone without other anti-HIV drugs.