Nucleoside Reverse Transcriptase Inhibitors

The NRTIs are nucleoside analogues that act as competitive inhibitors of reverse transcriptase. After conversion to the triphosphate form by host cell kinases, these drugs compete with nucleoside triphosphates for access to reverse transcriptase. All NRTIs lack a 3'-hydroxyl group; thus, their incorporation into a growing DNA chain results in its termination. These drugs block HIV replication and therefore the infection of new cells, but they have little effect on cells already infected with virus. Combination therapies often include two NRTIs that are analogues of different bases plus a protease inhibitor. The pharmacokinetic properties of the NRTIs are listed in Table 51.2.

The NRTIs inhibit cellular and mitochondrial DNA polymerases and various cellular kinases, resulting in toxicity. Toxicity varies with the state of the immune system; early in the infection there is less toxicity, while late in the infection there is substantially more. All NRTIs can produce a potentially fatal syndrome of lactic acidosis and severe hepatomegaly with hepatic steatosis; this results from the toxic effects of these drugs on mitochondria. Those at highest risk include women, obese individuals, alcoholics, and patients with prolonged exposure to NRTIs. All patients should be monitored for the development of hepatotoxicity; the drug should be discontinued if this occurs.

Resistance to these agents limits their usefulness, particularly as monotherapy. Resistance generally results from the appearance of mutations in reverse tran-scriptase; cross-resistance to multiple NRTIs also occurs.


Zidovudine (AZT, ZDV) was the first antiviral drug used against HIV. It is a thymidine analogue that is effective against HIV-1, HIV-2, and human T-cell lym-photrophic virus (HTLV) I and II. It is available as a single agent (Retrovir) or in fixed combinations with lamivudine (Combivir) or lamivudine and abacavir (Trizivir). Zidovudine, in combination with one or more other antiretroviral agents, is approved for the treatment of HIV infection in adults and children and for postexposure prophylaxis. It is used alone or in combination for the prevention of prenatal and perinatal transmission to the baby by HIV-infected pregnant women.

The most common adverse reactions to zidovudine are headache, nausea, vomiting, and anorexia. Fatigue, confusion, insomnia, malaise, hepatitis, myopathy, and myositis may also occur. Bone marrow toxicity occurs in up to 30% of patients taking zidovudine; anemia, neu-tropenia, and other hematological abnormalities can necessitate a dosage reduction, drug discontinuation, or therapy with erythropoietin or colony-stimulating factors. Cross-resistance to multiple nucleoside analogues has been documented.

Caution should be exercised when zidovudine is administered to patients with preexisting anemia or neu-tropenia and to those with advanced cases of AIDS. Dosage adjustment is required for patients with significant renal impairment and may also be necessary in those with hepatic impairment.

Zidovudine should be used cautiously with any other agent that causes bone marrow suppression, such as interferon-a, trimethoprim-sulfamethoxazole, dap-sone, foscarnet, flucytosine, ganciclovir, and valganci-clovir. Probenecid and interferon-p inhibit the elimination of zidovudine; therefore, a dosage reduction of zidovudine is necessary when the drugs are administered concurrently. Ribavirin inhibits the phosphoryla-tion reactions that activate zidovudine, and zidovudine similarly inhibits the activation of stavudine; thus, the coadministration of zidovudine with ribavirin or stavu-dine is contraindicated.

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