GlaxoSmithKline (Retrovir)

		Generics: Aurobindo Pharma (India); Cipla (India); Ranbaxy Laboratories (India); Roxane Laboratories (USA)

Zidovudine was the first drug to be approved for treatment of HIV infection. FDA approval was granted in 1987 for advanced HIV disease in adults and in 1990 for pediatric use. Initial approval was based on evidence of a short-term survival advantage over placebo when zidovudine was given to patients with advanced HIV disease.(1) Although the survival benefit of therapy with zidovudine alone lasted only for several months, combination therapies including zidovudine were later found to delay the complications of HIV infection by many months or years. Approval was expanded in 1990 to include less-advanced stages of HIV disease. FDA approval of zidovudine for prevention of HIV transmission from mothers to infants was granted in 1994.

On September 17, 2005, GlaxoSmithKline's patent for zidovudine expired. Several generic formulations are now approved by the FDA for use in the United States and other countries. Previously, these generic products had received "tentative approval" status for purchase and use as only part of the President's Emergency Plan for AIDS Relief (PEPFAR) in resource-limited countries. For a table of FDA-approved drugs for use under PEPFAR, see HIV InSite's PEPFAR overview.

Zidovudine is available in capsule, tablet, and syrup formulations, and in intravenous form. Zidovudine is also available in combination with lamivudine as a single tablet (Combivir), and in combination with lamivudine and abacavir as a single tablet (Trizivir). Generic versions of lamivudine/zidovudine have been granted "tentative approval" status by the FDA for purchase and use as part of PEPFAR.

Dosing of Zidovudine Adult 300 mg BID 200 mg TID Pediatric* Neonatal See Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection 4 weeks to <18 years Weight 4 kg to <9 kg Weight ≥9 kg to <30 kg Weight ≥30 kg 12 mg/kg BID or 8 mg/kg TID (total daily dosage: 24 mg/kg/day) 9 mg/kb BID or 6 mg/kg TID (total daily dosage: 18 mg/kg/day) Adult dosage Prevention of Mother-to-Child Transmission See Mother-to-Child Transmission Guidelines

Key to abbreviations: BID, twice daily; TID, 3 times daily.

		Zidovudine is not FDA approved for use in children <4 weeks of age. However, it has been studied in younger children; see Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection.

		Use zidovudine syrup for children who are unable to swallow pills (if the intravenous formulation is needed; see Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection for dosage information).

		Zidovudine dosage may be based on body surface area (BSA) instead of on body weight; the recommended dosage (syrup, capsules, or tablets) is 240 mg/m2 BID or 160 mg/m2 TID; maximum dosage 300 mg BID or 200 mg TID

		There are no food restrictions.

		Dosage adjustment is recommended in renal insufficiency.

		Please consult product labeling for detailed dosing information zidovudine tablets, capsules, or syrup or zidovudine intravenous.

		FDA Pregnancy Category C.

Many antiretroviral combinations containing zidovudine have been found to be effective at suppressing HIV viral load and increasing CD4 cell counts, and prolonging AIDS-free survival. In general, 3-drug combinations that include a protease inhibitor or nonnucleoside reverse transcriptase inhibitor have been found to have a more sustained effect than nucleoside-only combinations.

Zidovudine and stavudine should not be used in combination because they compete with each other for activation by intracellular phosphorylation, resulting in diminished antiviral activity.(2)

Among the nucleoside analogues, zidovudine is associated with the highest rate of bone-marrow toxicity, most commonly manifesting as neutropenia or anemia. Patients receiving zidovudine in combination with other myelosuppressive drugs must be closely monitored for these effects.

Treatment guidelines of the U.S. Department of Health and Human Services no longer designate zidovudine as a "preferred" component of initial therapy. Instead they include zidovudine + lamivudine or emtricitabine as an "alternative" dual-nucleoside backbone for use in initial treatment of HIV infection.

A direct comparison of zidovudine with stavudine, each in combination with lamivudine and the protease inhibitor indinavir as initial therapy,(3) found no difference in the two regimens in maintaining viral load suppression at 48 weeks. Although serious adverse events were not significantly different between treatment arms, there was increased nausea and vomiting in the zidovudine-containing arm, and increased diarrhea and rash in the stavudine-containing arm.

A comparison of zidovudine with abacavir, each in combination with lamivudine and efavirenz as initial therapy, showed equivalent rates of virologic suppression at 48 weeks, and greater increases in CD4 cell count in the abacavir group.(4) A 48-week comparison of zidovudine + lamivudine with tenofovir + emtricitabine, each in combination with efavirenz in previously untreated patients, found lower rates of virologic suppression in the zidovudine + lamivudine group (HIV RNA <50 copies/mL in 70% vs 80%; p = .02), and higher rates of treatment-limiting adverse effects (such as anemia).(5)

Symptomatic side effects of zidovudine include loss of appetite, nausea, vomiting, malaise, headache, weakness, and dizziness. These symptoms frequently resolve within the first few weeks of treatment, but can lead to early treatment discontinuation.

There is evidence that nucleoside analogues may be associated with mitochondrial toxicity leading to potentially serious long-term side effects such as lactic acidosis and disorders of body fat composition and lipid metabolism.(6) It is important to assess patient motivation and discuss possible side effects and strategies for their management before treatment with zidovudine is initiated.

Resistance to zidovudine is associated with the selection of 1 or more of several resistance mutations, in particular at reverse transcriptase codons 41, 67, 70, 210, 215, and 219.

Implications of zidovudine resistance for treatment with other antiretrovirals

The addition of lamivudine or didanosine may maintain selective pressure for zidovudine-sensitive variants. In clinical trials, individuals treated with zidovudine monotherapy for many months experienced suppression of viral load lasting months to years following the addition of lamivudine and indinavir,(7) suggesting that resistance to zidovudine may take time to emerge or may be reversible with the addition of lamivudine. High-level resistance to zidovudine is associated with some degree of resistance to stavudine and tenofovir as well.

Implications of resistance to other antiretrovirals for treatment with zidovudine

Although HIV resistant to didanosine or lamivudine may retain susceptibility to zidovudine, treatment with stavudine may select mutations associated with zidovudine resistance. Zidovudine should be considered in choosing therapy for individuals experiencing viral recurrence on prior regimens, but resistance testing may be helpful in assessing the utility of zidovudine in the individual situation.

In a retrospective analysis, zidovudine was found to be effective in reducing the risk of HIV infection following occupational exposure.(8) For this reason, zidovudine is generally included in postexposure prophylaxis regimens, although in cases of likely exposure to zidovudine-resistant HIV, the use of alternative agents is consistent with USPHS guidelines.

Zidovudine regimens including antenatal, peripartum, and neonatal treatment have shown a dramatic reduction in mother-to-child transmission of HIV in previously untreated mothers.(9) Currently, the USPHS recommends the inclusion of zidovudine in an effective antenatal regimen when possible, but not when stavudine is part of the preferred maternal treatment. (Peripartum and neonatal administration of zidovudine is recommended even when the maternal regimen includes stavudine.)