Antiretroviral Drugs

Antiretroviral drugs inhibit the reproduction of retroviruses—viruses composed of RNA rather than DNA. The best known of this group is HIV, human immunodeficiency virus, the causative agent of AIDS.

Purpose

Antiretroviral agents are virustatic agents which block steps in the replication of the virus. The drugs are not curative; however continued use of drugs, particularly in multi-drug regimens, significantly slows disease progression.

Description

There are three main types of antiretroviral drugs, although only two steps in the viral replications process are blocked. Nucleoside analogs, or nucleoside reverse transcriptase inhibitors (NRTIs), such as didanosine (ddI, Videx), lamivudine (3TC, Epivir), stavudine (d4T, Zerit), zalcitabine (ddC, Hivid), and zidovudine (AZT, Retrovir), act by inhibiting the enzyme reverse transcriptase. Because a retrovirus is composed of RNA, the virus must make a DNA strand in order to replicate itself. Reverse transcriptase is an enzyme that is essential to making the DNA copy. The nucleoside reverse transcriptase inhibitors are incorporated into the DNA strand. This is a faulty DNA molecule which is incapable of reproducing.

The non-nucleoside reverse transcriptase inhibitors (NNRTIs), such as delavirdine (Rescriptor), loviride, and nevirapine (Viramune) act by binding directly to the reverse transcriptase molecule, inhibiting its activity.

Protease inhibitors, such as indinavir (Crixivan), nelfinavir (Viracept), ritonavir (Norvir), and saquinavir (Invirase) act on the enzyme protease, which is essential for the virus to break down the proteins in infected cells. Without this essential step, the virus produces immature copies of itself, which are non-infectious.

Because HIV mutates readily, the virus can develop resistance to single drug therapy. However, treatment with drug combinations appears to produce a durable response. Proper treatment appears to slow the progression of HIV infections and reduce the frequency of opportunistic infections.

Recommended dosage

Doses must be individualized based on the patient, and use of interacting drugs. The optimum combinations of antiretroviral drugs have not been determined, nor is there agreement on the stage of infection at which to start treatment.

Precautions

Although the antiretroviral drugs fall into three groups, each drug has a unique pattern of adverse effects and drug interactions. Since the drugs are used in various combinations, the frequency and severity of adverse effects will vary with the combination. Although most drug combinations show a higher rate of adverse events that single drug therapy, some patterns are not predictable. For example, indinavir has been reported to cause insomnia in 3% of patients, however, when used in combination with zidovudine, only 1.5% of patients complained of sleep difficulties.

The most severe adverse effects associated with the protease inhibitors are renal and hepatic toxicity. Patients have also reported a syndrome of abdominal distention and increased body odor, which may be socially limiting. Hemophilic patients have reported increased bleeding tendencies while taking protease inhibitors. The drugs are pregnancy category B. There have been no controlled studies of safety in pregnancy. HIV-infected mothers are advised not to breast feed in order to prevent transmission of the virus to the newborn.

The nucleoside reverse transcriptase inhibitors have significant levels of toxicity. Lactic acidosis in the absence of hypoxemia and severe hepatomegaly with steatosis have been reported with zidovudine and zalcitabine, and are potentially fatal. Rare cases of hepatic failure, considered possibly related to underlying hepatitis B and zalcitabine monotherapy, have been reported.

Abacavir has been associated with fatal hypersensitivity reactions. Didanosine has been associated with severe pancreatitis. Nucleoside reverse transcriptase inhibitors are pregnancy category C. There is limited information regarding safety during pregnancy. Zidovudine has been used during pregnancy to reduce the risk of HIV infection to the infant. HIV-infected mothers are advised not to breastfeed in order to prevent transmission of the virus to the newborn.

Efavirenz has been associated with a high frequency of skin rash, 27% in adults and 40% in children. Nevirapine has been associated with severe liver damage and skin reactions. All of the non-nucleoside reverse transcriptase inhibitors are pregnancy category C, based on animal studies.

Because of the high risk of viral resistance development, antiretroviral agents should be used in combination. If one drug in the group must be discontinued, it is recommended that all antiretroviral therapy be discontinued until a multi-drug regimen can be resumed. The nonnucleoside reverse transcriptase inhibitors particularly should not be used alone.

Interactions

Because of the high frequency of drug interactions associated with AIDS therapy, specialized references should be consulted.

Saquinavir is marketed in both hard and soft gelatin capsules. Because saquinavir in the hard gelatin capsule formulation (Invirase) has poor bioavailability, it is recommended that this formulation only be used in combination with other drugs which interact to raise saquinavir blood levels. Saquinavir soft gelatin capsules (Fortovase) are the preferred dosage form of this drug.