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.
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.
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.
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
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.
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.
Lipsky, James J. "Antiretroviral Drugs for AIDS." The Lancet 348 (September 21, 1996): 800.
Williams, Ann B. "New Horizons: Antiretroviral Therapy in 1997." Journal of the Association of Nurses in AIDS Care 8 (July-August 1997): 26.
Project Inform. 205 13th Street, #2001, San Francisco, CA 94103. (415) 558-8669. <http://www.projinf.org>.
AIDS Clinical Trials Information Service website and telephone information line. Sponsored by Centers for Disease Control and Prevention, Food and Drug Administration, National Institute of Allergy and Infectious Diseases, and National Library of Medicine. 800-TRIALS-A (800-874-2572). <http://actis.org>.
HIV/AIDS Treatment Information Service website and telephone information line. Sponsored by Agency for Health Care Policy and Research, Centers for Disease Control and Prevention, Health Resources and Services Administration, Indian Health Service, National Institutes of Health, and Substance Abuse and Mental Health Services Administration. 800-HIV-0440 (800-448-0440). <http://www.hivatis.org>.
Project Inform National HIV/AIDS Treatment Hotline. 800-822-7422.
Samuel Uretsky, PharmD
Bioavailability—A measure of the amount of drug that is actually absorbed from a given dose.
Immune system—The body's natural defenses against disease and infection.
Inflammation—Pain, redness, swelling, and heat that usually develop in response to injury or illness.
Insomnia—A sleep disorder characterized by inability to either fall asleep or to stay asleep.
Mutates—Undergoes a spontaneous change in the make-up of genes or chromosomes.
Pancreas—A gland located beneath the stomach. The pancreas produces juices that help break down food and secretes insulin that helps the body use sugar for energy.
Pregnancy category—A system of classifying drugs according to their established risks for use during pregnancy. Category A: Controlled human studies have demonstrated no fetal risk. Category B: Animal studies indicate no fetal risk, but no human studies; or adverse effects in animals, but not in well-controlled human studies. Category C: No adequate human or animal studies; or adverse fetal effects in animal studies, but no available human data. Category D: Evidence of fetal risk, but benefits outweigh risks. Category X: Evidence of fetal risk. Risks outweigh any benefits.
Virus—A tiny, disease-causing particle that can reproduce only in living cells.