Skip to main content
SpringerLink
Log in

Zidovudine Toxicity

Clinical Features and Management

  • Review Article
  • Drug Experience
  • Published:
Drug Safety Aims and scope Submit manuscript

Summary

Zidovudine is a dideoxynucleoside analogue of thymidine. It acts by interfering with viral reverse transcriptase, thereby inhibiting human immunodeficiency virus (HIV) replication. Zidovudine has been shown in clinical trials to prolong survival of patients with acquired immune deficiency syndrome (AIDS) and advanced AIDS-related complex (ARC), and to delay progression to ARC or AIDS in patients with earlier disease. At the present time it is suggested that zidovudine be initiated when the CD4 lymphocyte count is less than 500 cells/mm3. Recent studies have suggested a delay in the development of AIDS in patients with CD4 counts over 500 cells/mm3, but ongoing studies will require confirmation.

The adverse reactions associated with zidovudine have been well described. It appears that haematological toxicity is associated with both the dose and stage of disease. Anaemia may present more often within the first 3 months of therapy, whereas neutropenia can occur early or late. Mild headache and gastrointestinal intolerance may occur early and in some cases limit tolerance to the drug. A number of neurological adverse reactions have been reported rarely including seizures and dose-reduction encephalopathy. The most significant late adverse reaction is that of myopathy, which occurs in patients receiving zidovudine for more than 6 months. With careful monitoring, the adverse reactions of zidovudine are manageable and patient tolerance of the medication is acceptable.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Anon. Recommendations for prophylaxis against Pneumocystis carinii pneumonia for adults and adolescents infected with human immunodeficiency virus. Morbidity and Mortality Weekly Report 41 (suppl.): 1–11, 1992

  • Broder S, Mitsuya H, Barry DW. Phosphorylation of 3′-azido-3′deoxythymidine and selective interaction of the 5′triphosphate with human immunodeficiency virus reverse transcriptase. Proceedings of the National Academy of Sciences of the United States of America 83: 8333–8337, 1986

    Article  PubMed  Google Scholar 

  • Chalmers AC, Greco CM, Meller RG. Prognosis in AZT myopathy. Neurology 41: 1181–1184, 1991

    Article  PubMed  CAS  Google Scholar 

  • Child S, Montaner J, Tsoukas C, Fanning M, Le T, et al. Canadian multicenter azidothymidine trial: AZT pharmacokinetics. Journal of Acquired Immune Deficiency Syndromes 4: 865–870, 1991

    PubMed  CAS  Google Scholar 

  • Collier AC, Bozzette S, Coombs RW, Causey DM, Schoenfeld DA, et al. A pilot study of low-dose zidovudine in human immunodeficiency virus infection. New England Journal of Medicine 323: 1013–1021, 1990

    Article  Google Scholar 

  • Cooper DA. The efficacy and safety of zidovudine therapy in early asymptomatic HIV infection. 8th International Conference on AIDS, Amsterdam, July 19–24, 1992, Abstract no. POB 3718, p. B210, 1992

    Google Scholar 

  • Cretton EM, Xie MY, Bevan RJ, Goudagon NM, Schinayi RF, et al. Catabolism of 3′-azido-3′-deoxythymidine in hepatocytes and liver microsomes with evidence of formation of 3′-amino-3′-deoxythymidine, a highly toxic catobolite for human bone marrow cells. Molecular Pharmacology 39: 258–266, 1991

    PubMed  CAS  Google Scholar 

  • Dalakas MC, Illa I, Pezeshkpour GH, Laukaitis JP, Cohen B, et al. Mitochondrial myopathy caused by long-term zidovudine therapy. New England Journal of Medicine 322: 1098–1105, 1990

    Article  PubMed  CAS  Google Scholar 

  • Don PC, Fusco F, Fried P, Batterman A, Duncanson FP, et al. Nail dyschromia associated with zidovudine. Annals of Internal Medicine 112: 145–146, 1990

    PubMed  CAS  Google Scholar 

  • Dubin G, Broffman MN. Zidovudine-induced hepatotoxicity. Annals of Internal Medicine 110: 85–86, 1989

    PubMed  CAS  Google Scholar 

  • Fischl MA, Galpin JE, Levine JD, Groopman JE, Henry DH, et al. Recombinant human erythropoietin for patients with AIDS treated with zidovudine. New England Journal of Medicine 322: 1488–1493, 1990c

    Article  PubMed  CAS  Google Scholar 

  • Fischl MA, Parker CB, Pettinelli C, Wulfsohn H, Hirsch MS, et al. A randomized, controlled trial of a reduced daily dose of zidovudine in patients with the acquired immunodeficiency syndrome. New England Journal of Medicine 323: 1009–1014, 1990b

    Article  PubMed  CAS  Google Scholar 

  • Fischl MA, Richman DD, Causey DM, Grieco MD, Bryson Y, et al. Prolonged zidovudine therapy in patients with AIDS and advanced AIDS-related complex. Journal of the American Medical Association 262: 2405–2410, 1989

    Article  PubMed  CAS  Google Scholar 

  • Fischl MA, Richman DD, Grieco MH, Gottlieb MS, Volberding PA, et al. The efficacy of azidothymidine in the treatment of patients with AIDS and AIDS-related complex: a double-blind, placebo-controlled trial. New England Journal of Medicine 317: 185–191 1987

    Article  PubMed  CAS  Google Scholar 

  • Fischl MA, Richman DD, Hansen N, Collier AC, Carey JT, et al. The safety and efficacy of zidovudine (AZT) in the treatment of subjects with mildly symptomatic human immunodeficiency virus type 1 (HIV) infection; a double-blind, placebo-controlled trial. Annals of Internal Medicine 112: 727–737, 1990a

    PubMed  CAS  Google Scholar 

  • Furman PA, Fyfe JA, St. Clair HH, Weinhold K, Rideout JL, et al. Phosphorylation of 3′-azido-5′-deoxythymidine and selective interaction of the 5′-triphosphate with human immunodeficiency virus transcriptase. Proceedings of the National Academy of Sciences of the United States of America 83: 8333–8337, 1986

    Article  PubMed  CAS  Google Scholar 

  • Gelmon K, Montaner JSG, Fanning M, Smith JRM, Falutz J, et al. Nature, time course and dose dependence of zidovudine-related side effects: results from the Multicentre Canadian Azidothymidine trial. AIDS 3: 555–561, 1989

    Article  PubMed  CAS  Google Scholar 

  • Gertner E, Thurn JR, Williams DN, Simpson M, Balfour HH, et al. Zidovudine-associated myopathy. American Journal of Medicine 86: 814–818, 1989

    Article  PubMed  CAS  Google Scholar 

  • Gill PS, Rarick M, Brynes RK, Causey D, Loureiro C, et al. Azidothymidine associated with bone marrow failure in the acquired immunodeficiency syndrome (AIDS). Annals of Internal Medicine 107: 502–505, 1987

    PubMed  CAS  Google Scholar 

  • Goldsmith JC, Irvine W. Reversible agranulocytosis related to azidothymidine therapy. American Journal of Hematology 30: 263–264, 1989

    Article  PubMed  CAS  Google Scholar 

  • Gorard DA, Henry K, Guiloff RJ. Necrotizing myopathy and zidovudine. Lancet 1: 1050, 1988

    Article  Google Scholar 

  • Graham NMH, Zeger SL, Park LP, Vermund SH, Detels R, et al. The effects on survival of early treatment of human immunodeficiency virus infection. New England Journal of Medicine 326: 1037–1042, 1992

    Article  PubMed  CAS  Google Scholar 

  • Groopman JE. Antiretroviral therapy and immunomodulators in patients with AIDS. American Journal of Medicine 90: 185–215, 1991

    Google Scholar 

  • Hamilton JD, Hartigan PM, Simberkoff MS, Day PL, Diamond GR, et al. A controlled trial of early versus late treatment with Zidovudine in symptomatic human immunodeficiency virus infection. New England Journal of Medicine, 326: 437–443, 1992

    Article  PubMed  CAS  Google Scholar 

  • Health Protection Branch. The potential for AZT to cause Cancer, Department of National Health and Welfare, Ottawa, 1989

    Google Scholar 

  • Helbert M, Robinson D, Peddle B, Forster S, Kocsis A, et al. Acute meningo-encephalitis on dose reduction of zidovudine. Lancet 1: 1249–1252, 1988

    Article  PubMed  CAS  Google Scholar 

  • Jacobson MA, de Miranda P, Gordon SM, Blum R, Volberding P, et al. Prolonged pancytopenia due to combined ganciclovir and zidovudine therapy. Journal of Infectious Diseases 158: 489–490, 1988

    Article  PubMed  CAS  Google Scholar 

  • Jacobson MA, McGrath MS, Joseph P, Molaghan JB, Tadepalli S, et al. Zidovudine-induced fever. Journal of Acquired Immunodeficiency Syndromes 2: 382–388, 1989

    CAS  Google Scholar 

  • Klecker JRRW, Collins JM, Yarchoan R, Thomas R, Jenkins JF, et al. Plasma and cerebrospinal fluid pharmacokinetics of 3′-azido-5′deoxythymidine: a novel pyrimidine analog with potential application for the treatment of AIDS and related diseases. Clinical Pharmacology and Therapeutics 41: 407–412, 1987

    Article  PubMed  Google Scholar 

  • Kuster H, Vogt M, Joos B, Nadai V, Luthy R. A method for the quantification of the intracellular zidovudine nucleotides. Journal of Infectious Diseases 164: 773–776, 1991

    Article  PubMed  CAS  Google Scholar 

  • Larder BA, Darby G, Richman DD. HIV with reduced sensitivity to zidovudine (AZT) isolated during prolonged therapy. Science 243: 1931–1934, 1989

    Article  Google Scholar 

  • Laskin DL, de Mirande P, Blum MR. Azidothymidine steady-state plasmacokinetics in patients with AIDS and AIDS related complex. Journal of Infectious Diseases 159: 745–747, 1989

    Article  PubMed  CAS  Google Scholar 

  • Lemp GF, Payne SF, Neal D, Temeso T, Rutherford GW. Survival trends for patients with AIDS. Journal of the American Medical Association 263: 402–406, 1990

    Article  PubMed  CAS  Google Scholar 

  • MacFadden DK. A method for rapid oral desensitization of patients allergic to AZT. 5th International Conference on AIDS, Montreal, June 4–9, 1989. Abstract no. TBP 321, p. 340, 1989

    Google Scholar 

  • Meng T, Fischl MA, Boota AM, Spector SA, Bennett D, et al. Combination therapy with zidovudine and dideoxycytidine in patients with advanced human immunodeficiency virus infection. A phase I/II study. Annals of Internal Medicine 116: 13–20, 1992

    PubMed  CAS  Google Scholar 

  • Moore RD, Creagh-Kirk T, Keruly J, Link G, Wang MC et al. Longterm safety and efficacy of zidovudine in patients with advanced human immunodeficiency virus disease. Archives of Internal Medicine 151: 981–986, 1991

    Article  PubMed  CAS  Google Scholar 

  • National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health and US Public Health Service. State-of-the-art conference on azidothymidine therapy for early HIV infection. American Journal of Medicine 89: 335–344, 1990

    Article  Google Scholar 

  • Northfelt DW, Mayer A, Kaplan LD, Abrams DI, Hadley WK, et al. The usefulness of diagnostic bone marrow examination in patients with human immunodeficiency virus (HIV) infection. Journal of Acquired Immune Deficiency Syndromes 4: 659–666, 1991

    PubMed  CAS  Google Scholar 

  • Pottage JC, Benson CA, Spear JB, Landley AL, Kessler HA, et al. Treatment of human immunodeficiency virus-related thrombocytopenia with zidovudine. Journal of the American Medical Association 260: 3045–3048, 1988

    Article  PubMed  Google Scholar 

  • Richman DD, Fischl MA, Grieco MH, Gottlieb MS, Volberding PA, et al. The toxicity of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex (ARC): a double-blind placebo-controlled trial. New England Journal of Medicine 317: 192–197, 1987

    Article  PubMed  CAS  Google Scholar 

  • Rooke R, Tremblay M, Soudeyns H, DeStafano L, Yao J, et al. Isolation of drug-resistant variants of HIV-1 from patients on long-term Zidovudine (AZT) therapy. AIDS 3: 411–415, 1989

    Article  PubMed  CAS  Google Scholar 

  • Sattler FR, Ko R, Antoniskis D, Shields M, Cohen J, et al. Acetaminophen does not impair clearance of zidovudine. Annals of Internal Medicine 114: 937–940, 1991

    PubMed  CAS  Google Scholar 

  • Schmitt FA, Bigley JW, McKinnis R, Logue PE, Evans RW, et al. Neuropsychological outcome of zidovudine (AZT) treatment of patients with AIDS and AIDS-related complex. New England Journal of Medicine 319: 1573–1578, 1988

    Article  PubMed  CAS  Google Scholar 

  • Simpson DM. Myopathy associated with human immunodeficiency virus (HIV) but not zidovudine. Correspondence. Annals of Internal Medicine 109: 842, 1988

    PubMed  CAS  Google Scholar 

  • Simpson DM, Bender AN. Human immunodeficiency virus-associated myopathy, analysis of 11 patients. Annals of Neurology 24: 79–84, 1988

    Article  PubMed  CAS  Google Scholar 

  • Spear JB, Benson CA, Pottage Jr JC, Paul DA, Landay AL, et al. Rapid rebound of serum human immunodeficiency virus antigen after discontinuing zidovudine therapy. Journal of Infectious Diseases 158: 1132–1133, 1988

    Article  PubMed  CAS  Google Scholar 

  • Sperling RS, Stratton P, O’Sullivan MJ, Boyer P, Watts DH, et al. A survey of zidovudine use in pregnant women with human immunodeficiency virus infection. New England Journal of Medicine 326: 857–861, 1992

    Article  PubMed  CAS  Google Scholar 

  • Volberding PA, Lagokos SW, Koch MA, Pettinelli C, Myers MW, et al. Zidovudine in asymptomatic human immunodeficiency virus infection: a controlled trial in persons with fewer than 500 CD4-positive cells per cubic millimeter. New England Journal of Medicine 322: 941–949, 1990

    Article  PubMed  CAS  Google Scholar 

  • Wainberg MA, Falutz J, Fanning MM, Gill J, Gelmon K. Cessation of zidovudine Therapy may lead to increased replication of HIV-1. Journal of the American Medical Association 261: 865–866, 1989

    Article  PubMed  CAS  Google Scholar 

  • Watts DH, Brown ZA, Tartaglione T, Burchett SK, Opheim K, et al. Pharmacokinetic disposition of zidovudine during pregnancy. Journal of Infectious Diseases 163: 226–232, 1991

    Article  PubMed  CAS  Google Scholar 

  • Weidner DA, Bridges EG, Cretton EM, Sommadossi JP. Comparative effects of 3′-azido-3′deoxythymidine and its metabolite 3′-amino-3′deoxythymidine on hemoglobin synthesis in K-562 human leukemia cells. Molecular Pharmacology 41: 252–258, 1992

    PubMed  CAS  Google Scholar 

  • Yarchoan R, Klecker RW, Weinhold KS, Markham PD, Wyerly HK, et al. Administration of 3′-azido-5′deoxythymidine, an inhibitor of HTLV III/LAV replication, to patients with AIDS or AIDS-related complex. Lancet 1: 575–586, 1986

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Sunnybrook Health Science Centre and Wellesley Hospital, Division of Infectious Diseases, Department of Medicine, University of Toronto, JB 126A, 160 Wellesley Street East, Toronto, Ontario, M4Y 1J3, Canada

    Anita Rachlis &  Mary M. Fanning

Authors
  1. Anita Rachlis
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mary M. Fanning
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rachlis, A., Fanning, M.M. Zidovudine Toxicity. Drug-Safety 8, 312–320 (1993). https://doi.org/10.2165/00002018-199308040-00005

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00002018-199308040-00005

Keywords

Search

Navigation