Continuing Education Activity

Zidovudine is a medication used in the management and treatment of HIV-1. It is in the nucleoside reverse transcriptase inhibitor class of medications. This activity reviews the indications, mechanism of action, and contraindications for zidovudine as a valuable agent in the treatment of HIV-1. This activity will highlight the mechanism of action, adverse event profile, and other key factors (e.g., off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, relevant interactions) pertinent for interprofessional healthcare team members in the treatment of patients with HIV-1 and related conditions.

Objectives:

• Identify the mechanism of action of zidovudine.
• Describe the potential adverse effects of zidovudine.
• Outline the appropriate monitoring for toxicity with zidovudine.
• Explain the interprofessional team strategies for improving care coordination and communication to advance zidovudine and improve outcomes.

Indications

Zidovudine was the first medication to be FDA approved for the treatment of human immunodeficiency virus type 1 (HIV-1).[1] Currently, the indications of zidovudine include:

FDA Approved Indications

• Treatment of HIV-1 infection[1]
• Prevention of perinatal HIV-1 transmission (mother to fetus transmission)[2]

Non-FDA Approved Indications (off label uses)

• HIV-1 nonoccupational postexposure prophylaxis[3]
• Adult T cell leukemia-lymphoma (ATL) in combination with interferon-alpha (IFN)[4]

Human immunodeficiency virus or HIV primarily disrupts CD4+ T cells, thus compromising the host's immune system. The virus replicates via reverse transcriptase, and if not treated properly, it can progress to acquired immunodeficiency syndrome. It is imperative that providers screen and treat at-risk patient populations. If patients are left untreated, their CD4+ T cell count can drop to dangerous levels, leaving them susceptible to deadly opportunistic infections and neoplasms.[5]

Mechanism of Action

Zidovudine is a synthetic analog of the nucleoside thymidine classified as a nucleoside reverse transcriptase inhibitor (NRTI). Zidovudine functions as an anti-viral agent by being incorporated into newly made viral DNA in place of thymidine and acting as a viral DNA chain terminator. This inhibits the ability of HIV-1 reverse transcriptase to make viral DNA from the RNA template, which interferes with the HIV-1 life cycle.[6]

Zidovudine requires intracellular conversion by host cell kinases to be transformed to the active triphosphate form.[6] While the plasma half-life of zidovudine is approximately 1 hour, the intracellular conversion to the triphosphate form causes it to be trapped inside the cell. Due to the intracellular trapping in addition to the intracellular half-life of approximately 7 hours, zidovudine allows for a more rational dosing frequency.[7]

The antiretroviral effects of zidovudine seen with HIV-1 are also the assumed mechanism of action for adult T cell leukemia-lymphoma, caused by the retroviral human T cell leukemia/lymphotropic leukemia virus type 1 (HTLV-1).[8]

The bioavailability of zidovudine is around 64%, with food only slowing the absorption and not reducing the amount absorbed. About 14% of zidovudine is renally excreted unchanged, and 74% is renally excreted as zidovudine 5'-glucuronide after being glucuronidated. A small portion is also metabolized by other microsomal pathways.[9]

Administration

Zidovudine is administered orally and intravenously; however, the injectable formulation is not readily available. 

Treatment of HIV-1 Infection (not to be used as monotherapy)

• Adult oral dosing[10]:

  • 300 mg twice daily
• Pediatric oral dosing[11]:

  • 4 to < 9 kg: 12 mg/kg twice daily
  • ≥9 to <30 kg: 9 mg/kg twice daily
  • ≥30 kg: 300 mg twice daily

Prevention of Perinatal HIV-1 Transmission given Intrapartum

Monotherapy with zidovudine is now considered suboptimal.[12][13][14]

• IV: Loading dose of 2 mg/kg for 1 hour, followed by a continuous infusion of 1 mg/kg/hour 

HIV-1 Nonoccupational Postexposure Prophylaxis [15]

• Orally: 300 mg twice daily in combination with other antiretroviral agents for 28 days

ATL in Combination with IFN [16]

• Orally: 750 mg/m^2 twice daily tapered down to 300 mg twice daily as tolerated.

Adverse Effects

Zidovudine has a high frequency of several side effects that limits its use.[3]

Side effects include:[3][6][17][18]

• Nausea/vomiting (18.8 to 89%)
• Diarrhea (7 to 78%)
• Headaches (15 to 38%)
• Myalgias
• Insomnia
• Bone marrow suppression (has been reported as high as 45%)
• Peripheral myopathy
• Elevated liver enzymes
• Lactic acidosis
• Hepatotoxicity

Drs. Jain and Mayer conducted an editorial review in which they examined studies that involved zidovudine for HIV-1 nonoccupational postexposure prophylaxis. Their research found that 11.7 to 16.5% of patients stopped taking zidovudine due to side effects and that side effects were reported as high as 54.5% in those that did complete a 28-day regimen that included zidovudine.[3] Due to higher side effects and lower completion rates, tenofovir-containing regimens are recommended over zidovudine-containing regimens.[19]

Long-term treatment with zidovudine can cause a modest elevation of liver enzymes. The elevated liver enzymes do not require dose adjustments due to the elevations being asymptomatic and transient in most cases. Rare cases of acute cholestatic hepatitis, severe acute fatty liver with lactic acidosis, and noncirrhotic portal hypertension. Some of the hepatotoxicity has been attributed to zidovudine causing inhibition of the mitochondrial gamma polymerase leading to mitochondrial depletion and dysfunction.[17]

Bone marrow suppression seen with zidovudine includes neutropenia, leukopenia, and anemia. Anemia requiring blood transfusions was reported to be as high as 19.7% with the use of zidovudine.[18] Anemia and neutropenia are usually reversible when zidovudine is stopped.[9]

Contraindications

Zidovudine is contraindicated for patients with severe life-threatening hypersensitivity reactions to this medication, including anaphylaxis and Stevens-Johnson syndrome. Anaphylaxis may present with difficulty breathing, diffuse rash, and hypotension. Stevens-Johnson syndrome is a very painful blistering skin condition. Prompt discontinuation of zidovudine therapy is critical if any of these symptoms arise.[18][20]

Monitoring

Patients on zidovudine should be monitored closely for nausea, vomiting, diarrhea, headaches, myalgias, insomnia, bone marrow suppression, peripheral myopathy, lactic acidosis, elevated liver enzymes, and hepatotoxicity. Prescribers, pharmacists, nursing, and other healthcare professionals should be aware of drug interactions and take precautions to mitigate side effects. A complete metabolic panel (CMP) and complete blood count (CBC) should be monitored routinely.

Trimethoprim can inhibit renal elimination of zidovudine resulting in higher than expected concentrations of zidovudine.[7]

Probenecid has also been reported to increase side effects of zidovudine, likely from either decreased excretion and/or metabolism.[18]

Zidovudine should be monitored closely when using other medications that cause bone marrow suppression.

Zidovudine crosses the placenta and penetrates breast milk.[7] More trials are needed, but zidovudine appears to be relatively safe in pregnancy.[6] 

Toxicity

There is not a known antidote for zidovudine. Therefore, zidovudine should be stopped in cases of overdose or toxicity suspected from the use of zidovudine.

Three following case reports of zidovudine overdose:

• A patient who ingested 20 grams of zidovudine in addition to temazepam 6 hours prior to presentation complained of drowsiness but was otherwise well. His blood counts were trended, and his hemoglobin had a mild reduction to 12.5 g/dl three days after the overdose from his baseline of 14.2 g/dl.[21]
• A patient who ingested 10 to 20 grams of zidovudine in addition to phenobarbital and triazolam 8 hours prior to presentation complained of headache and nausea. His vitals were stable, but a physical exam was significant for ocular nystagmus and upper and lower extremity ataxia. Hemoglobin was stable at 14.8 g/dl. He was given intravenous fluids and his nystagmus and ataxia resolved within 48 hours. At six weeks follow-up, his hemoglobin was 17.0 g/dl.[22]
• A patient who ingested approximately 20 grams of zidovudine in addition to testing positive for benzodiazepines and tetrahydrocannabinol presented with baseline anemia with hemoglobin of 9.8 g/dl. At 24 hours, he was noted to be lethargic and fatigued. At 48 hours, his hemoglobin dropped to a nadir of 8.7 g/dl. The patient did well overall and was not observed to have any neurotoxicity or psychiatric disturbance.[23]

Enhancing Healthcare Team Outcomes

Zidovudine is classified as an NRTI that is FDA approved for the treatment of HIV-1 infection and prevention of perinatal HIV-1 transmission, although it is not currently recommended as a first-line agent or used as monotherapy.[24][25][26] [Level 1] It has also been studied for use in HIV-1 nonoccupational postexposure prophylaxis and ATL combined with IFN. The use of zidovudine monotherapy for HIV-1 nonoccupational postexposure prophylaxis is estimated to be approximately 81%, although it is no longer used as a first-line agent.[26] [Level 3] Initial use of zidovudine included intravenous administration, however more recently, it is only given orally. The use of zidovudine has been limited due to the high frequency of side effects associated with it.

Interprofessional communication and coordination of care by clinicians, infectious disease specialists, mid-level practitioners, nurses, pharmacists, and other health professionals are necessary to improve outcomes and patient safety. Providers should monitor the patient for side effects and check routine blood work, including a CMP and CBC. Pharmacists should monitor for drug-drug interactions, such as sulfamethoxazole/trimethoprim increasing plasma levels of zidovudine, verify appropriate dosing, and convey their recommendations to the provider. Nurses should monitor for common side effects such as nausea, vomiting, diarrhea, headaches, and myalgias and report their findings to the provider. This interprofessional approach to patient care will optimize antiviral therapy outcomes. [Level 5]

Understanding the treatment options for HIV-1 is important for nurses, doctors, and pharmacists, all acting as an interprofessional team. Communication is vital to making sure patients receive prompt retroviral therapy, especially when trying to reduce the likelihood of maternal-fetal transmission. HIV-1 requires prompt treatment with antiretroviral therapy to maintain an adequate CD4+ T cell count and prevent some dangerous sequelae resulting from a reduced CD4+ T cell count. Clinicians should give attention to at-risk populations and screen patients with associated risk factors. Prompt treatment with antiretroviral therapies such as zidovudine can provide life-saving immunological support. Zidovudine plays a crucial role in helping prevent the maternal-fetal transmission of HIV-1 in pregnant patients. Zidovudine has not only proven to reduce the likely hood of vertical transmission, but it has also demonstrated the capacity to provide prophylaxis for those children exposed in utero.

Clinicians must provide patient education about the importance of maintaining compliance with zidovudine. This way, patients can maintain an adequate immune response and be less likely to become susceptible to opportunistic infections or neoplasms. This therapy will, in turn, improve the quality of life and survival rates of patients with HIV-1. Patients who are infected and become pregnant should receive proper counseling on treatment that will help prevent vertical maternal-fetal transmission. HIV-1 needs to be on all clinicians' differentials when dealing with certain opportunistic infections, neoplasm, and patient populations. Those who are infected should receive prompt, highly active antiretroviral therapy. Treatment with zidovudine has proven to be effective in several clinical scenarios.[18][27][28]

Specialty trained HIV care nurses review the importance of compliance with patients, check for side effects, follow up on laboratories, and inform prescribing providers of patient issues. Board-certified infectious disease pharmacists can consult with the prescriber on appropriate dosing and regimen, evaluate interactions, and educate patients. These interprofessional interventions are examples of how coordinated healthcare team dynamics can improve patient outcomes when using zidovudine therapy.

Review Questions

• Access free multiple choice questions on this topic.
• Comment on this article.

References

1.

Chaudhuri S, Symons JA, Deval J. Innovation and trends in the development and approval of antiviral medicines: 1987-2017 and beyond. Antiviral Res. 2018 Jul;155:76-88. [PMC free article: PMC7126013] [PubMed: 29758235]

2.

Bhana N, Ormrod D, Perry CM, Figgitt DP. Zidovudine: a review of its use in the management of vertically-acquired pediatric HIV infection. Paediatr Drugs. 2002;4(8):515-53. [PubMed: 12126455]

3.

Jain S, Mayer KH. Practical guidance for nonoccupational postexposure prophylaxis to prevent HIV infection: an editorial review. AIDS. 2014 Jul 17;28(11):1545-54. [PMC free article: PMC4566923] [PubMed: 24785956]

4.

El Hajj H, Tsukasaki K, Cheminant M, Bazarbachi A, Watanabe T, Hermine O. Novel Treatments of Adult T Cell Leukemia Lymphoma. Front Microbiol. 2020;11:1062. [PMC free article: PMC7270167] [PubMed: 32547515]

5.

Rachlis AR. Zidovudine (Retrovir) update. CMAJ. 1990 Dec 01;143(11):1177-85. [PMC free article: PMC1452857] [PubMed: 2224694]

6.

Sperling R. Zidovudine. Infect Dis Obstet Gynecol. 1998;6(5):197-203. [PMC free article: PMC1784811] [PubMed: 9894173]

7.

Lee BL, Safrin S, Makrides V, Gambertoglio JG. Zidovudine, trimethoprim, and dapsone pharmacokinetic interactions in patients with human immunodeficiency virus infection. Antimicrob Agents Chemother. 1996 May;40(5):1231-6. [PMC free article: PMC163297] [PubMed: 8723472]

8.

Ishitsuka K. Diagnosis and management of adult T-cell leukemia/lymphoma. Semin Hematol. 2021 Apr;58(2):114-122. [PubMed: 33906721]

9.

Anderson PL, Rower JE. Zidovudine and Lamivudine for HIV Infection. Clin Med Rev Ther. 2010;2:a2004. [PMC free article: PMC2954111] [PubMed: 20953318]

10.

Pialoux G, Raffi F, Brun-Vezinet F, Meiffrédy V, Flandre P, Gastaut JA, Dellamonica P, Yeni P, Delfraissy JF, Aboulker JP. A randomized trial of three maintenance regimens given after three months of induction therapy with zidovudine, lamivudine, and indinavir in previously untreated HIV-1-infected patients. Trilège (Agence Nationale de Recherches sur le SIDA 072) Study Team. N Engl J Med. 1998 Oct 29;339(18):1269-76. [PubMed: 9791142]

11.

Fauchet F, Treluyer JM, Frange P, Urien S, Foissac F, Bouazza N, Benaboud S, Blanche S, Hirt D. Population pharmacokinetics study of recommended zidovudine doses in HIV-1-infected children. Antimicrob Agents Chemother. 2013 Oct;57(10):4801-8. [PMC free article: PMC3811467] [PubMed: 23877688]

12.

Mofenson LM, Lambert JS, Stiehm ER, Bethel J, Meyer WA, Whitehouse J, Moye J, Reichelderfer P, Harris DR, Fowler MG, Mathieson BJ, Nemo GJ. Risk factors for perinatal transmission of human immunodeficiency virus type 1 in women treated with zidovudine. Pediatric AIDS Clinical Trials Group Study 185 Team. N Engl J Med. 1999 Aug 05;341(6):385-93. [PubMed: 10432323]

13.

Connor EM, Sperling RS, Gelber R, Kiselev P, Scott G, O'Sullivan MJ, VanDyke R, Bey M, Shearer W, Jacobson RL. 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 03;331(18):1173-80. [PubMed: 7935654]

14.

Mofenson LM., Centers for Disease Control and Prevention, U.S. Public Health Service Task Force. U.S. Public Health Service Task Force recommendations for use of antiretroviral drugs in pregnant HIV-1-infected women for maternal health and interventions to reduce perinatal HIV-1 transmission in the United States. MMWR Recomm Rep. 2002 Nov 22;51(RR-18):1-38; quiz CE1-4. [PubMed: 12489844]

15.

Winston A, McAllister J, Amin J, Cooper DA, Carr A. The use of a triple nucleoside-nucleotide regimen for nonoccupational HIV post-exposure prophylaxis. HIV Med. 2005 May;6(3):191-7. [PubMed: 15876286]

16.

Malpica L, Pimentel A, Reis IM, Gotuzzo E, Lekakis L, Komanduri K, Harrington T, Barber GN, Ramos JC. Epidemiology, clinical features, and outcome of HTLV-1-related ATLL in an area of prevalence in the United States. Blood Adv. 2018 Mar 27;2(6):607-620. [PMC free article: PMC5873228] [PubMed: 29545256]

17.

LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. National Institute of Diabetes and Digestive and Kidney Diseases; Bethesda (MD): Jun 25, 2020. Zidovudine. [PMC free article: PMC547852] [PubMed: 31643535]

18.

Langtry HD, Campoli-Richards DM. Zidovudine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy. Drugs. 1989 Apr;37(4):408-50. [PubMed: 2661194]

19.

Territo H, Vaqar S, Justiz Vaillant AA. StatPearls [Internet]. StatPearls Publishing; Treasure Island (FL): May 8, 2023. HIV Prophylaxis. [PMC free article: PMC534852] [PubMed: 30521273]

20.

Kemnic TR, Gulick PG. StatPearls [Internet]. StatPearls Publishing; Treasure Island (FL): Sep 20, 2022. HIV Antiretroviral Therapy. [PubMed: 30020680]

21.

Hargreaves M, Fuller G, Costello C, Gazzard B. Zidovudine overdose. Lancet. 1988 Aug 27;2(8609):509. [PubMed: 2900428]

22.

Spear JB, Kessler HA, Lehrman SN, de Miranda P. Zidovudine overdosage. Ann Intern Med. 1988 Jul 01;109(1):76-7. [PubMed: 3163905]

23.

Pickus OB. Overdose of zidovudine. N Engl J Med. 1988 May 05;318(18):1206. [PubMed: 3163102]

24.

Walmsley SL, Antela A, Clumeck N, Duiculescu D, Eberhard A, Gutiérrez F, Hocqueloux L, Maggiolo F, Sandkovsky U, Granier C, Pappa K, Wynne B, Min S, Nichols G., SINGLE Investigators. Dolutegravir plus abacavir-lamivudine for the treatment of HIV-1 infection. N Engl J Med. 2013 Nov 07;369(19):1807-18. [PubMed: 24195548]

25.

João EC, Morrison RL, Shapiro DE, Chakhtoura N, Gouvèa MIS, de Lourdes B Teixeira M, Fuller TL, Mmbaga BT, Ngocho JS, Njau BN, Violari A, Mathiba R, Essack Z, Pilotto JHS, Moreira LF, Rolon MJ, Cahn P, Prommas S, Cressey TR, Chokephaibulkit K, Werarak P, Laimon L, Hennessy R, Frenkel LM, Anthony P, Best BM, Siberry GK, Mirochnick M. Raltegravir versus efavirenz in antiretroviral-naive pregnant women living with HIV (NICHD P1081): an open-label, randomised, controlled, phase 4 trial. Lancet HIV. 2020 May;7(5):e322-e331. [PMC free article: PMC7323582] [PubMed: 32386720]

26.

Günthard HF, Saag MS, Benson CA, del Rio C, Eron JJ, Gallant JE, Hoy JF, Mugavero MJ, Sax PE, Thompson MA, Gandhi RT, Landovitz RJ, Smith DM, Jacobsen DM, Volberding PA. Antiretroviral Drugs for Treatment and Prevention of HIV Infection in Adults: 2016 Recommendations of the International Antiviral Society-USA Panel. JAMA. 2016 Jul 12;316(2):191-210. [PMC free article: PMC5012643] [PubMed: 27404187]

27.

Kupiec KE, Johnson JW, Barroso LF, Wrenn RH, Williamson JC. Zidovudine as modern day salvage therapy for HIV infection. AIDS Patient Care STDS. 2014 Nov;28(11):570-4. [PMC free article: PMC4216478] [PubMed: 25365419]

28.

Canals F, Masiá M, Gutiérrez F. Developments in early diagnosis and therapy of HIV infection in newborns. Expert Opin Pharmacother. 2018 Jan;19(1):13-25. [PubMed: 28764578]

Disclosure: Zachary Edwards declares no relevant financial relationships with ineligible companies.

Disclosure: Curtis Ingold declares no relevant financial relationships with ineligible companies.

Disclosure: Chaudhary Ehtsham Azmat declares no relevant financial relationships with ineligible companies.