Zidovudine

Detailed information

Zidovudine is an anti-HIV drug that reduces the amount of virus in the body. Anti-HIV drugs such as zidovudine slow down damage to the immune system and prevent the occurrence of AIDS-related illnesses.

Zidovudine belongs to a class of drugs known as nucleoside reverse transcriptase inhibitors (NRTIs).

The drug is usually referred to by its generic name, zidovudine, which is abbreviated to ZDV. The abbreviation AZT is also used, which stands for azidothymidine. Its chemical name is 3’-azido-3’-deoxythymidine.

Zidovudine is manufactured under the trade name Retrovir by GlaxoSmithKline. Retrovir was the first drug licensed to treat HIV infection, having been approved by the United States Food and Drug Administration (FDA) in 1987. Numerous generic versions of zidovudine are available.

Zidovudine is also available in a combination pill with lamivudine, either under the trade name Combivir, manufactured by ViiV Healthcare or in generic versions.

A pill that combines 300mg zidovudine, 150mg lamivudine and 300mg abacavir, known as Trizivir, is also available from ViiV Healthcare. It was approved in the United States in November 2000 and in the European Union in March 2001.

Effectiveness

Zidovudine is rarely used in antiretroviral therapy nowadays and has been replaced by better tolerated drugs. In lower- and middle-income settings zidovudine may be used in combination with lamivudine in second-line treatment, but its use is becoming less frequent. Zidovudine may also be used in regimens for pregnant women with HIV beginning treatment around the time of delivery and as part of a post-exposure prophylaxis regimen for infants exposed to HIV.

Zidovudine was taken as a single drug treatment when there were no other treatments available for HIV and then in combination with lamivudine. It was used widely during the 1990s as part of three-drug combinations but was replaced by tenofovir or abacavir in the early 2000s. 

Zidovudine was licensed in March 1987 after trials showed that a dose of 1200mg per day reduced opportunistic infections and increased CD4 counts and survival among people with AIDS, when compared to placebo over 24 weeks.(Fischl, 1987) However, longer-term follow-up of this study failed to show a benefit of zidovudine over placebo. (Fischl, 1989) Later studies confirmed that the lower dose of 600mg per day resulted in similar anti-HIV effects but with less toxicity. (Fischl, 1990)

Further studies tested zidovudine monotherapy among HIV-positive people without symptoms of AIDS. A 1989 placebo-controlled trial called ACTG 019, which enrolled 1338 asymptomatic patients with CD4 cell counts below 500 cells/mm3, found that in the short-term 500 or 1500mg zidovudine every day delayed progression to severe symptomatic disease or AIDS. (Volberding, 1990) A separate arm of the study compared the effects of zidovudine or a placebo for people with CD4 cell counts above 500 cells/mm3, finding no clinical benefit of starting zidovudine early, although zidovudine recipients did sustain a higher CD4 count than those given placebo. (Volberding, 1995) However, a subsequent study concluded that the reduction in quality of life brought about by zidovudine’s side effects in this study approximately equalled the increase in quality of life associated with the delay in disease progression. (Lederking)

Glossary

nucleoside reverse transcriptase inhibitor (NRTI)

In a process called reverse transcription, HIV copies its genetic material from RNA to DNA before inserting the proviral DNA in the host cell genome. Nucleoside reverse transcriptase inhibitors insert a nucleoside into the proviral DNA of HIV, terminating the chain of proviral DNA and preventing the incorporation of proviral DNA into the genome of a host cell. NRTIs (also known as ‘nukes’) include abacavir, emtricitabine, lamivudine and zidovudine.

placebo

A pill or liquid which looks and tastes exactly like a real drug, but contains no active substance.

monotherapy

Taking a drug on its own, rather than in combination with other drugs.

mutation

A single change in gene sequence. Some HIV mutations cause the virus to become resistant to certain antiretroviral (ARV) drugs.

progression

In medicine, this usually refers to advancement or worsening of a disease. 

The largest single study of zidovudine monotherapy in asymptomatic HIV infection, known as Concorde, suggested that there was no advantage in starting zidovudine before symptoms develop in the longer term. Almost 1750 participants were randomly assigned either to start taking 1000mg zidovudine a day in four doses, or to receive a placebo until they developed symptoms or until they chose to switch from trial capsules to open zidovudine because of falling CD4 cell counts. The results showed that after three years there was no detectable difference between immediate versus deferred use of zidovudine in terms of disease progression, development of AIDS or survival, but that the patients treated immediately had more severe side effects. (Concorde Co-ordinating Committee)

Numerous other studies examined the effect of zidovudine monotherapy at various doses and in patients at various stages of HIV infection throughout the late 1980s and early 1990s. (Cooper) (Mulder) (Hamilton) (Simberkoff) (Merigan) (Gardner) A meta-analysis of 15 of these trials by the HIV Trialists’ Collaborative Group published in 1999 confirmed these controversial findings of the Concorde Study – that zidovudine monotherapy did not increase a person’s chances of AIDS-free survival in the long-term, although it did reduce rates of disease progression in the short-term. (HIV Trialists' Collaborative Group.)

However, these studies revealed that adding another NRTI delayed both disease progression and death, paving the way for combination therapy in the treatment of HIV infection. Later studies demonstrated the efficacy of a combination of three antiretrovirals that included zidovudine.

Taking it

Zidovudine may be taken twice or three times a day. Most people generally find twice-daily regimens easier to manage.

The daily dose is 500 or 600mg. Zidovudine is usually taken as one 250mg capsule twice a day, but 100mg capsules are also available for dose variations. A reduced dose of 200mg twice a day may also be safe and effective in patients with low body weight of less than 60kg. (Cressey) A 300mg capsule has been discontinued in the United Kingdom due to low demand.

Zidovudine is also available as a syrup and as a solution for infusion into a vein. Both of these are at the concentration of 10mg/ml.

Zidovudine may be taken with or without food. However, to achieve maximum zidovudine levels in the body the drug should be taken on an empty stomach, although this is not essential.

Side effects

The commonest side effects of zidovudine are nausea, vomiting, diarrhoea, stomach pains, headache, dizziness,weakness and muscle pain. These often occur in the early weeks of treatment. Medicines to control nausea and headache can be prescribed before starting zidovudine.

When first prescribed, zidovudine was given in high doses, which commonly caused severe side effects. Recommended doses are now much lower, and as a result, side effects have lessened.

Zidovudine may damage the bone marrow, the substance in the body that produces blood cells. People with more advanced HIV infection are more likely to suffer blood deficiencies such as anaemia (low levels of red blood cells) or neutropenia (low levels of neutrophils, a type of white blood cell). (Wills) In combination with other risk factors for anaemia, such as other medications and opportunistic infections, taking zidovudine may result in more severe side effects.

People with low white blood cell counts or haemoglobin levels should not take zidovudine. Patients with severe kidney problems should take a reduced dose of zidovudine.

Patients starting zidovudine treatment should have their blood tested every two weeks for the first few months, for changes in levels of red or white blood cells.

Rare adverse reactions to zidovudine include developing an enlarged fatty liver and raised levels of lactic acid. (Freiman) These complications affect less than one in a thousand people and appear to be more common in obese women and people with risk factors for liver disease. People with pre-existing liver or kidney problems may need additional monitoring to ensure that zidovudine does not worsen these conditions. Halving the zidovudine dose may be recommended in these patients.

NRTIs as a class have been linked to body fat loss and metabolic changes seen among people on antiretroviral therapy. Although research suggests that stavudine is the NRTI most closely associated with this syndrome, zidovudine has also been linked to fat loss. Both drugs cause damage to mitochondrial DNA in fat cells, leading to loss of subcutaneous fat. For this reason, zidovudine is no longer used in first-line treatment.

Patients taking zidovudine should inform their doctor if they experience severe abdominal pain, shortness of breath, unusual tiredness or weakness, unusual bleeding or bruising, sore throat, fever or an injury that does not heal.

Resistance

The pattern of mutations caused by the thymidine analogues, including zidovudine and stavudine, is well characterised, involving the accumulation of up to six mutations at codons 41, 67, 70, 210, 215 and 219 of reverse transcriptase. These are called thymidine analogue mutations (TAMs) and affect sensitivity to all licensed NRTIs. In general, the more mutations that are present, the greater the level of resistance to zidovudine, with the T215Y/F mutation being the most significant.

Drug interactions

You should not take zidovudine with any of these drugs:

  • ganciclovir injections
  • ribavirin
  • rifampicin
  • stavudine.

The following drugs interact with zidovudine. They may make it more likely that you will have side effects, or you may need some extra monitoring, so make sure you tell your doctor if you are taking any of them:

  • aciclovir
  • amphotericin
  • atovaquone
  • clarithromycin
  • cotrimoxazole
  • dapsone
  • doxorubicin
  • fluconazole
  • flucytosine
  • ganciclovir
  • interferon
  • methadone
  • pentamidine
  • phenytoin
  • probenecid
  • pyrimethamine
  • sodium valproate (valproic acid)
  • vinblastine
  • vincristine.

Children

Zidovudine  is recommended as a component of a three-drug post-exposure prophylaxis regimen for infants exposed to HIV. Zidovudine should be given for four weeks after delivery. (BHIVA)

Zidovudine is recommended as an alternative agent for use in first-line treatment of children aged 2 weeks to 3 years of age. It may be used as part of the NRTI backbone in second-line treatment if resistance to lamivudine or emtricitabine is detected. (PENTA)

Zidovudine is dosed by weight in children:

  • body-weight 8-13 kg: 100 mg twice daily.
  • body-weight 14-20 kg: 100 mg, to be taken in the morning and 200 mg, to be taken in the evening.
  • body-weight 21-27 kg: 200 mg twice daily.
  • body-weight 28-29 kg: 200–250 mg twice daily.
  • body-weight 30 kg and above: 250-300 mg twice daily.

Pregnancy

The use of zidovudine during pregnancy is no longer recommended except in women not on treatment who have detectable viral load at the time of delivery. In these circumstances, women should begin oral treatment with zidovudine and lamivudine immediately and receive intravenous zidovudine during labour and delivery. Alternatively, zidovudine monotherapy during pregnancy may be offered to women with viral loads below 10,000 copies/ml who decline combination antiretroviral treatment during pregnancy. (BHIVA)

References

Fischl MA et al. The efficacy of 3'-azido-3'-deoxythymidine, an inhibitor of HTLV-III / LAV replication, to patients with AIDS or AIDS-related complex: a double-blind placebo-controlled trial. New England Journal of Medicine, 317: 185-191, 1987.

Fischl MA et al. Prolonged zidovudine therapy in patients with AIDS and advanced AIDS-related complex. JAMA, 262: 2405-2410, 1989.

Fischl MA 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, 1990.

Volberding PA et al. Zidovudine in asymptomatic HIV infection: a controlled trial in persons with fewer than 500 CD4-positive cells per cubic millimetre. New England Journal of Medicine, 322: 941-949, 1990.

Volberding PA et al. A comparison of immediate with deferred zidovudine therapy for asymptomatic HIV-infected adults with CD4 cell counts of 500 or more per cubic millimeter. New England Journal of Medicine, 333: 401-407, 1995.

Lederking WR et al. Evaluation of the quality of life associated with zidovudine treatment in asymptomatic human immunodeficiency virus infection. New England Journal of Medicine, 330: 738-743, 1994.

Concorde Co-ordinating Committee MRC / ANRS randomised double-blind controlled trial of immediate and deferred zidovudine in symptom-free HIV infection. The Lancet, 343: 871-881, 1994.

Cooper DA et al. Zidovudine in persons with asymptomatic HIV infection and CD4+ cell counts greater than 400 per cubic millimeter. New England Journal of Medicine, 329: 297-303, 1993.

Mulder JW et al. Zidovudine twice daily in asymptomatic subjects with HIV infection and a high risk of progression to AIDS: a randomized, double-blind placebo-controlled study. AIDS, 8: 313-321, 1994.

Hamilton JD 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.

Simberkoff MS et al. Long-term follow-up of symptomatic HIV-infected patients originally randomized to early versus later zidovudine treatment; report of a Veterans Affairs Cooperative Study. VA Cooperative Study Group on AIDS Treatment. Journal of Acquired Immune Deficiency Syndromes, 11: 142-150, 1996.

Merigan T et al. Placebo-controlled trial to evaluate zidovudine in treatment of human immunodeficiency virus infection in asymptomatic patients with haemophilia. Blood, 78: 900-906, 1991.

Gardner LI et al. Size and duration of zidovudine benefit in 1003 HIV-infected patients: US Army, Navy, and Air Force natural history data. Military Consortium for Applied Retroviral Research. Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology, 17: 345-353, 1998.

HIV Trialists' Collaborative Group. Zidovudine, didanosine, and zalcitabine in the treatment of HIV infection: meta-analyses of the randomised evidence. HIV Trialists' Collaborative Group. The Lancet, 353: 2014-2025, 1999.

Cressey TR et al. Intensive pharmacokinetics of zidovudine 200 mg twice daily in HIV-1 infected patients weighing less than 60kg on highly active antiretroviral therapy. Journal of Acquired Immune Deficiency Syndromes, 42: 387-388, 2006.

Wills TS Anemia prevalence among HIV patients: antiviral therapy and other risk factors. Antiviral Therapy, 8: S511, 2003.

Arnaudo E et al. Depletion of muscle mitochondrial DNA in AIDS patients with zidovudine-induced myopathy. The Lancet, 337: 508-510, 1991.

Freiman JP et al. Hepatomegaly with severe steatosis in HIV-seropositive patients. AIDS, 7: 379-385, 1993.

PENTA HIV Guidelines Writing Group. PENTA HIV first and second-line antiretroviral treatment guidelines 2019.

BHIVA Guidelines Writing Group. British HIV Association guidelines for the management of HIV in pregnancy and postpartum 2018 (2020 third interim update).

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