Deoxythymidine nucleoside analogue
| Clinical Use|
| Use in Initial vs Subsequent Therapy|
Adult and adolescent treatment guidelines of the U.S. Department of Health and Human Services (HHS) state that zidovudine + lamivudine is "not recommended" for initial treatment of HIV infection, because of greater risk of toxicity than recommended nucleoside medications. The HHS treatment guidelines for pregnant women consider zidovudine + lamivudine to be an "alternative" 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 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)
| 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.
|| || 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.|
|| || 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.|
|| || 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.|
|| || 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.|
|| || Moyle G. Clinical manifestations and management of antiretroviral nucleoside analog-related mitochondrial toxicity. Clin Ther. 2000 Aug;22(8):911-36; discussion 898.|
|| || 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.|
|| || 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.|
|| || 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.|
|| || 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.|