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Chapter: Modern Pharmacology with Clinical Applications: Therapy of Human Immunodeficiency Virus

Drug Therapy of HIV Infection: Nucleoside Reverse Transcriptase Inhibitors

Nucleoside Reverse Transcriptase Inhibitors

Nucleoside Reverse Transcriptase Inhibitors


The NRTIs are nucleoside analogues that act as com-petitive inhibitors of reverse transcriptase. After conver-sion 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 in-hibitor. 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 sys-tem; 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 acido-sis and severe hepatomegaly with hepatic steatosis; this results from the toxic effects of these drugs on mito-chondria. Those at highest risk include women, obese individuals, alcoholics, and patients with prolonged ex-posure 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 re-sults 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 ef-fective 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 treat-ment of HIV infection in adults and children and for postexposure prophylaxis. It is used alone or in combi-nation 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 fac-tors. Cross-resistance to multiple nucleoside analogues has been documented.


Caution should be exercised when zidovudine is ad-ministered to patients with preexisting anemia or neu-tropenia and to those with advanced cases of AIDS. Dosage adjustment is required for patients with signifi-cant 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- , trimethoprim–sulfamethoxazole, dap-sone, foscarnet, flucytosine, ganciclovir, and valganci-clovir. Probenecid and interferon- inhibit the elimina-tion of zidovudine; therefore, a dosage reduction of zidovudine is necessary when the drugs are adminis-tered 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.



Stavudine (d4T, Zerit) is a thymidine nucleoside ana-logue that is active against HIV-1 and HIV-2. It is ap-proved for the therapy of HIV infection as part of a multidrug regimen and is also used for postexposure prophylaxis.


The adverse effects with which stavudine is most fre-quently associated are headache, diarrhea, skin rash, nausea, vomiting, insomnia, anorexia, myalgia, and weakness. Peripheral neuropathy consisting of numb-ness, tingling, or pain in the hands or feet is also com-mon with higher doses of the drug. Significant elevation of hepatic enzymes may be seen in approximately 10 to 15% of patients. Lactic acidosis occurs more frequently with stavudine than with other NRTIs. Viral resistance to stavudine may develop, and cross-resistance to zi-dovudine and didanosine may occur.


Stavudine should be used with caution in patients at risk for hepatic disease and those who have had pan-creatitis. Persons with peripheral neuropathy, the el-derly, and those with advanced HIV disease are at in-creased risk for neurotoxicity. Dosage adjustment is required for patients with renal insufficiency.


Stavudine possesses several clinically significant in-teractions with other drugs. Although hydroxyurea en-hances the antiviral activity of stavudine and didano-sine, combination therapy that includes stavudine and didanosine, with or without hydroxyurea, increases the risk of pancreatitis. Combinations of stavudine and di-danosine should not be given to pregnant women be-cause of the increased risk of metabolic acidosis. Zidovudine inhibits the phosphorylation of stavudine; thus, this combination should be avoided.



Didanosine (ddI, Videx) is an adenosine analogue with activity against HIV-1, HIV-2, and HTLV-I. It is ap-proved as part of a multidrug regimen for the therapy of HIV infection and is also used as postexposure HIV prophylaxis.


The most common adverse effect produced by di-danosine is diarrhea. Abdominal pain, nausea, vomiting, anorexia, and dose-related peripheral neuropathy may occur. Pancreatitis occurs rarely, as do hyperuricemia, bone marrow suppression, retinal depigmentation, and optical neuritis. Resistance to didanosine appears to re-sult from mutations different from those responsible for zidovudine resistance.


Didanosine should be used with great caution in in-dividuals who have a history of pancreatitis. Didanosine tablets contain phenylalanine and should not be taken by phenylketonurics. Didanosine should be used cau-tiously in patients with gout, peripheral neuropathy, and advanced AIDS.


Buffering agents that are compounded with didano-sine to counteract its degradation by gastric acid may interfere with the absorption of other drugs that require acidity (e.g., indinavir, delavirdine, ketoconazole, fluoro-quinolones, tetracyclines, dapsone). An enteric-coated formulation (Videx EC) that dissolves in the basic pH of the small intestine is not susceptible to these interac-tions. Ganciclovir and valganciclovir can increase blood levels of didanosine. The use of zalcitabine with didano-sine is not recommended because that combination car-ries an additive risk of peripheral neuropathy. The com-bination of didanosine with stavudine increases the risk of pancreatitis, hepatotoxicity, and peripheral neuropa- thy. Stavudine should not be given with didanosine to pregnant women because of the increased risk of meta-bolic acidosis.




Lamivudine (3TC, Epivir) is a cytosine nucleoside analogue with activity against HIV-1, HIV-2, and hep-atitis B virus. It is approved as part of a multidrug reg-imen for the therapy of HIV infection in adults and children and has been used for HIV postexposure pro-phylaxis. Combination products contain lamivudine with either zidovudine (Combivir) or zidovudine and abacavir (Trizivir).


Lamivudine is the best-tolerated NRTI. Its most common adverse effects include headache, malaise, fa-tigue, and insomnia. Pancreatitis is rare. Gastroin-testinal complaints are common with lamivudine– zidovudine therapy but are probably mainly due to the zidovudine component. Lamivudine resistance some-times occurs early in treatment. Cross-resistance to zal-citabine, didanosine, and abacavir can occur simultane-ously. Withdrawal of lamivudine in patients infected with both hepatitis B virus and HIV can cause a flare-up of hepatitis symptoms.


Lamivudine is associated with an increased risk of pancreatitis in children and should be used with great cau-tion in children who have had pancreatitis or are at high risk for it. Dosage adjustment is necessary in patients with renal impairment. Lamivudine should not be used in com-bination with zalcitabine, because they inhibit each other’s activation by phosphorylation. Trimethoprim in-hibits the renal elimination of lamivudine.




Abacavir (Ziagen) is a guanosine nucleoside analogue indicated for the therapy of HIV-1 infection in adults and children. It is used as part of a multidrug regimen and is available in a fixed-dose combination with zi-dovudine and lamivudine (Trizivir). It is also used for postexposure HIV infection prophylaxis.


Abacavir is associated with side effects such as anorexia, nausea, vomiting, malaise, headache, and in-somnia. A potentially fatal hypersensitivity reaction de-velops in approximately 5% of patients, usually early in the course of treatment. Fever and rash are the most common symptoms of this reaction; malaise, respiratory symptoms, and gastrointestinal complaints may also oc-cur. Resistance to abacavir may be associated with re-sistance to zidovudine, didanosine, and lamivudine.


Abacavir undergoes extensive hepatic metabolism; therefore, patients with liver disease should be moni-tored closely if this drug is given. Ethanol inhibits the metabolism of abacavir because it competes for metabolism by alcohol dehydrogenase. Abacavir is not known to inhibit or induce cytochrome P450 isozymes.




Zalcitabine (ddC, Hivid) is a cytidine analogue active against HIV-1, HIV-2, and hepatitis B virus. It is used for the treatment of HIV infection in adults and asymp-tomatic children as part of a multidrug regimen. It may be less effective than the other nucleoside inhibitors and is used less frequently.


Peripheral neuropathy occurs in up to 50% of pa-tients taking zalcitabine. Stomatitis, esophageal ulcera-tion, hepatotoxicity, rash, and pancreatitis may occur. Zalcitabine should be used with caution in individuals with a history of pancreatitis, liver disease, or alcohol abuse. Dosage adjustment is necessary for individuals with renal impairment. Zalcitabine should not be used in combination with didanosine, lamivudine, or stavudine.


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