University of California, San Francisco Logo

University of California, San Francisco | About UCSF | Search UCSF | UCSF Medical Center

Home > Treatment > Drugs > Zidovudine
Zidovudine (Retrovir)
Back to Drug Profiles
Class
Background
Manufacturers for U.S. Market
Approval
Generic Approvals
Formulation and Dosing
Clinical Use
Use in Initial vs Subsequent Therapy
Potential Adverse Effects
Use in Initial vs Subsequent Therapy
Resistance
Implications of zidovudine resistance for treatment with other antiretrovirals
Implications of resistance to other antiretrovirals for treatment with zidovudine
Special Uses
References
Related Resources
DHHS Guidelines
Characteristics of NRTIs
Drug Interactions with NRTIs
Adverse Events of ARVs
Dosage Adjustments for ARV-ARV Drug Interactions (Adult Dosing)
Interactions Database
Stanford Resistance Figures/Notes
Drug Labeling (Package Inserts)
Zidovudine (Retrovir)
Zidovudine intravenous
ZDV/3TC (Combivir)
ZDV/3TC/ABC (Trizivir)
Class

Deoxythymidine nucleoside analogue

Background
Manufacturers for U.S. Market

ViiV Healthcare; generic formulations available from other manufacturers

Approval

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.

Generic Approvals

A number of generic formulations have been 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.

Formulation and Dosing

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 of the lamivudine/zidovudine have been granted "tentative approval" status by the FDA for purchase and use as part of PEPFAR. combination tablet are also available in the United States, and various generic coformulations that include zidovudine are available in other countries.

Dosing of Zidovudine
Adult300 mg BID
200 mg TID
Pediatric*NeonatalSee 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 TransmissionSee 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.
There are no data on dosage adjustment in hepatic impairment.
Please consult product labeling for detailed dosing information zidovudine tablets, capsules, or syrup or zidovudine intravenous.
FDA Pregnancy Category C.

Clinical Use
Use in Initial vs Subsequent Therapy

Adult and adolescent treatment guidelines of the U.S. Department of Health and Human Services designate zidovudine + lamivudine as an "acceptable" dual-nucleoside backbone for use in initial treatment of HIV infection. In pregnant women, the guidelines consider zidovudine + lamivudine the "preferred" dual-nucleoside option for combination therapy to prevent perinatal HIV transmission.

A direct comparison of zidovudine with stavudine, each in combination with lamivudine and the protease inhibitor indinavir as initial therapy,(2) 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.(3) 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).(4)

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

Potential Adverse Effects

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 persist and may lead to early treatment discontinuation.

Nucleoside analogues, including zidovudine, may be associated with mitochondrial toxicity leading to potentially serious long-term side effects such as lactic acidosis and disorders of body fat composition.(5)

Potential laboratory abnormalities include anemia and neutropenia, which may be severe. Concurrent administration of other myelosuppressive drugs increases the risk of bone marrow toxicity. Patients should be closely monitored for these effects.

It is important to assess patient motivation and discuss possible side effects and strategies for their management before treatment with zidovudine is initiated.

Use in Initial vs Subsequent Therapy

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.(6) Similarly, ribavirin and doxorubicin are antagonistic to zidovudine and should not be coadministered.

Resistance

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

Resistance to zidovudine appears to emerge over time in a stepwise manner, with successive mutations increasing the degree of viral resistance. Resistance generally proceeds along one of two mutation pathways. Depending on the specific mutations and the number of mutations, resistance to zidovudine is associated with some degree of resistance to other nucleoside analogues. The presence of resistance to lamivudine and emtricitabine (ie, the M184V mutation) may partially or fully reverse the effects of zidovudine resistance mutations.(7)

Implications of resistance to other antiretrovirals for treatment with zidovudine

Depending on the number of mutations and the specific mutations, resistance to other nucleoside analogues may result in resistance to zidovudine.

Treatment with stavudine may select mutations associated with zidovudine resistance.
Individual mutations associated with resistance to other nucleoside analogues are not usually found to confer resistance to zidovudine. However, the coexistence of more than 2 nucleoside resistance mutations often confers resistance to zidovudine.
The codon 184 mutation, associated with resistance to lamivudine and emtricitabine, does not confer resistance to zidovudine and, in fact, may increase susceptibility to zidovudine. When present with thymidine-associated mutations, it may partially restore sensitivity to zidovudine.
The K65R mutation, which may be selected by several nucleoside analogues, is associated with increased susceptibility to zidovudine.
Special Uses

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 recommended by USPHS guidelines as an option for inclusion in postexposure prophylaxis regimens, if exposure to zidovudine-susceptible HIV is likely.

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 combination of zidovudine plus lamivudine as the preferred nubleoside analogue backbone in an effective antenatal regimen. It also recommends peripartum (in women with HIV RNA >400 copies/mL) and neonatal administration of zidovudine.

References
1.   Fischl MA, Richman DD, Grieco MH, et al. The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. A double-blind, placebo-controlled trial. N Engl J Med. 1987 Jul 23;317(4):185-91.
2.   Squires KE, Gulick R, Tebas P, et al. A comparison of stavudine plus lamivudine versus zidovudine plus lamivudine in combination with indinavir in antiretroviral naive individuals with HIV infection: selection of thymidine analog regimen therapy (START I). AIDS. 2000 Jul 28;14(11):1591-600.
3.   DeJesus E, Herrera G, Teofilo E, et al; CNA30024 Study Team. Abacavir versus zidovudine combined with lamivudine and efavirenz, for the treatment of antiretroviral-naive HIV-infected adults. Clin Infect Dis. 2004 Oct 1;39(7):1038-46.
4.   Gallant JE, DeJesus E, Arribas JR, et al; Study 934 Group. Tenofovir DF, emtricitabine, and efavirenz vs. zidovudine, lamivudine, and efavirenz for HIV. N Engl J Med. 2006 Jan 19;354(3):251-60.
5.   Moyle G. Clinical manifestations and management of antiretroviral nucleoside analog-related mitochondrial toxicity. Clin Ther. 2000 Aug;22(8):911-36; discussion 898.
6.   Havlir DV, Tierney C, Friedland GH, et al. In vivo antagonism with zidovudine plus stavudine combination therapy. J Infect Dis. 2000 Jul;182(1):321-5.
7.   Larder BA, Kemp SD, Harrigan PR. Potential mechanism for sustained antiretroviral efficacy of AZT-3TC combination therapy. Science. 1995 Aug 4;269(5224):696-9.
8.   Cardo DM, Culver DH, Ciesielski CA, et al. A case-control study of HIV seroconversion in health care workers after percutaneous exposure. Centers for Disease Control and Prevention Needlestick Surveillance Group. N Engl J Med. 1997 Nov 20;337(21):1485-90.
9.   Connor EM, Sperling RS, Gelber R, et al. Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. N Engl J Med. 1994 Nov 3;331(18):1173-80.