Three distinct classes of antiretroviral medications have been labeled by the U.S. Food and Drug Administration (FDA) for use in the management of human immunodeficiency virus (HIV) disease (see accompanying table on page 2666). The three classes are the nucleoside analog reverse transcriptase inhibitors (NRTIs), the nonnucleoside reverse transcriptase inhibitors (NNRTIs) and the protease inhibitors (PIs). Combinations of these drugs delay progression of the disease and enhance quality of life.

Hovanessian reviewed the current literature on HIV treatment to summarize current antiretroviral therapy. Combinations of reverse transcriptase inhibitors became the standard in 1996. Popular combinations include zidovudine plus didanosine, zidovudine plus zalcitabine and zidovudine plus lamivudine. Adverse effects of zidovudine include headache, nausea, vomiting, fatigue, malaise, myalgia, neutropenia and anemia. The side effects of didanosine and zalcitabine include peripheral neuropathy. Pancreatitis can result from didanosine use. Lamivudine has a more benign side effect profile, with adverse reactions including headache, fatigue and gastrointestinal symptoms. Abacavir, the latest NRTI to be labeled by the FDA, has a similar side effect profile.

The NNRTIs also block reverse transcriptase. The three NNRTIs currently available are nevirapine, delavirdine and efavirenz. These medications can be used as part of the three or more antiretroviral drug combinations. Rash is the most common side effect of this class of medications, followed by gastrointestinal intolerance, headaches and elevated results on liver function tests.

PIs block the manufacture of active, functional proteins necessary to make the HIV particle infectious. Saquinavir was the first PI labeled by the FDA for use in the United States, and it is now available in the earlier, hard-gel formulation and a soft-gel formulation with enhanced bioavailability. Ritonavir, indinavir and nelfinivir are additional PIs that have been shown to decrease viral loads when used with NRTIs. Gastrointestinal side effects can occur with all the PI preparations. Indinavir is partly excreted in the urine and has been associated with nephrolithiasis. Adequate hydration decreases the frequency of stone formation. Nelfinavir, the latest PI to be FDA-labeled, is well tolerated, with diarrhea being the main side effect. Cases of PI-associated lipodystrophy, with the development of “buffalo humps” or fatty accumulations around the abdomen, have recently been described.

Errors occurring during viral replication lead to numerous mutant HIV strains, some of which confer resistance against the antiretroviral medications. This may make some of these agents less effective over time. Monotherapy appears to foster rapid resistance while dual therapy is more effective but only delays the emergence of resistance. Use of at least three medications, including two NRTIs and one NNRTI or PI has become the standard, along with early treatment. The plasma HIV viral level (viral load) is a reliable indicator of treatment success and disease progression.

Drug interactions are common with anti-retroviral agents and other medications. NRTIs are excreted primarily through the kidneys, making drug interactions less likely. The PIs undergo hepatic metabolism by the cytochrome P450 system and may, by competitive inhibition, increase serum levels of concomitantly taken medications metabolized by the same route. The NNRTIs may inhibit cytochrome P450 metabolism or increase clearance by inducing the cytochrome P450 system. Inducers of the P450 system, including rifampin and rifabutin, significantly lower the serum PI levels.

Hovanessian concludes with a review of recommendations from the Centers for Disease Control and Prevention for postexposure prophylaxis, including starting treatment as soon as possible after exposure, a four-week course of zidovudine and lamivudine for most significant HIV exposures, and the addition of a PI in relatively higher risk situations. Combivir, a combination formulation of zidovudine and lamivudine, make dosing easier.