Zidovudine (AZT, Retrovir) is an anti-HIV drug that reduces the amount of virus in the body. Anti-HIV drugs such as zidovudine slow down or prevent damage to the immune system, and reduce the risk of developing AIDS-related illnesses.
Zidovudine belongs to a class of drugs known as nucleoside reverse transcriptase inhibitors (NRTIs). When HIV infects a cell, the enzyme reverse transcriptase copies the viral single-stranded RNA genome into double-stranded viral DNA. This viral DNA is then integrated into the CD4 chromosomal DNA and can go on to reproduce in the body. Four natural nucleosides complete the DNA synthesis: adenosine, cytidine, quanosine, and thymidine. An NRTI drug substitutes a defective version of one of the nucleosides, causing premature termination of the proviral DNA chain.
The drug is usually referred to by its generic name, zidovudine, which is abbreviated to ZDV. The abbreviation AZT is sometimes 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. GlaxoSmithKline’s patent on zidovudine expired in September 2005. Consequently, generic versions of the drug can now be sold in the United States and the European Union.
A generic version called Zidovir is manufactured by the Indian manufacturer Cipla. Other generic versions of zidovudine include Viro-Z (Ranbaxy), Aviro-Z (Ranbaxy) and Zido-H (Genixpharma).
Zidovudine is available combined with lamivudine in one pill, known by the trade name Combivir from GlaxoSmithKline. Each Combivir pill contains 300mg zidovudine and 150mg lamivudine. Generic versions of this co-formulation include called Duovir (Cipla), Virocomb (Ranbaxy) and a version made by Aurobindo Pharma.
A pill that combines 300mg zidovudine, 150mg lamivudine and 300mg abacavir, known as Trizivir, is also available from GlaxoSmithKline. It was approved in the United States in November 2000 and in the European Union in March 2001.
Zidovudine (AZT, Retrovir) is a common component of combination anti-HIV regimens. Zidovudine was taken as a single drug treatment when there were no other treatments available for HIV. However, single drug therapy is no longer used because it is a weak treatment for HIV and leads to rapid development of drug resistance.
Zidovudine should be taken in combination with at least two other anti-HIV drugs to suppress HIV in the blood to very low levels. However, zidovudine monotherapy is sometimes taken during pregnancy, to avoid the possible side-effects of other anti-HIV drugs, as a way of reducing the risk of HIV being passed on from mother to child.
Zidovudine successfully crosses the blood-brain barrier and is effective against HIV in the brain and the central nervous system. Zidovudine is active against HIV-1 and HIV-2.
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)
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 does not increase a person’s chances of AIDS-free survival in the long-term, although it does reduce rates of disease progression in the short-term. 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. (HIV Trialists' Collaborative Group.)
Zidovudine (AZT, Retrovir) 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. It is important to take the drug as prescribed in order to maintain the right level of the drug in the blood. If blood levels of the drug fall too low, this will allow the development of resistance to zidovudine and may affect future treatment options.
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.
The commonest side-effects of zidovudine are nausea, vomiting, headache, dizziness, fatigue, 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. Nausea and vomiting may also be reduced by making the following adjustments to diet:
- Taking zidovudine before meals.
- Eating many small meals during the day rather than three large ones.
- Avoiding spicy food, fried foods and sweets.
- Consuming more cool foods and drinks.
- Drinking plenty of water, apple juice, flat ginger ale or cola.
- Eating dry foods such as crackers.
Other side-effects occasionally reported from zidovudine include rashes, severe muscle pain and inflammation, nausea, insomnia, nail discoloration, and kidney disorders. These toxicities are more severe and more common in people with damaged immune systems.
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.
A recent meta-analysis of 54 trials of zidovudine, funded by GlaxoSmithKline, concluded that severe anaemia is rare, occurring in less than 2% of patients. Overall, zidovudine doubled the risk of anaemia, but this was also increased by higher viral loads and lower haemoglobin levels before starting therapy. The analysis also found that taking zidovudine in Combivir or Trizivir almost doubled the risk of anaemia, but the reasons for this are unknown. (Edwards)
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.
There is a small risk of muscle damage (myopathy) after prolonged treatment with zidovudine, with some pain, wasting and weakness usually in the muscles around the hips, thighs and buttocks. (Arnaudo) Blood tests for muscle enzymes can detect this wasting early on if it is suspected.
Rare adverse reactions to zidovudine include developing an enlarged fatty liver and raised levels of lactic acid. (Freiman) These complications 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 AZT does not worsen these conditions. Halving the zidovudine dose may be recommended in these patients.
The nucleoside reverse transcriptase inhibitors (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 (d4T, Zerit) is the NRTI most closely associated with this syndrome, there is evidence that zidovudine may also trigger it. To date, the mechanism is unknown although it is probably linked to mitochondrial DNA damage caused by these drugs. (Caron) (Collins) Consequently, treatment guidelines are currently recommending that patients avoid zidovudine in favour of other NRTIs such as abacavir (Ziagen) or the nucleotide reverse transcriptase inhibitor (NtRTI) tenofovir (Viread) to reduce the risks of fat loss.
A study in rats has also suggested that zidovudine may contribute to endothelial dysfunction, a loss of elasticity in the blood vessels that is an early sign of cardiovascular disease. (Jiang)
There has also been speculation that long-term use of zidovudine may cause cancer. This view is based on laboratory studies and tests in rats and mice. However, there is no evidence to date that long-term use of zidovudine causes cancer in humans.
Anecdotal reports of changes in skin pigmentation in people of African origin are frequently heard by community organisations, but data have not been systematically collected to demonstrate how common this problem is.
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.
As with all other anti-HIV drugs, strains of HIV that are resistant to zidovudine (AZT, Retrovir) may emerge after a period of treatment. The emergence of drug-resistant strains coincides with a fall in the effectiveness of the drug.
If zidovudine is taken as a single drug treatment, resistance emerges within a few months. A combination of three or more antiretroviral drugs that can suppress HIV to very low levels in the blood reduces the likelihood of drug resistance developing. Furthermore, using zidovudine in combination with lamivudine (3TC, Epivir) may make it more difficult for HIV to develop resistance to zidovudine.
Zidovudine resistance is particularly unwelcome, since certain resistance mutations appear to be associated with more rapid disease progression. (d'Aquila) However, a person who has zidovudine-resistant virus may continue taking zidovudine because the drug may still be effective against HIV in the brain. Zidovudine-resistant HIV is also less infectious than wild-type virus. (Tremblay)
The pattern of mutations caused by the thymidine analogues, including zidovudine and stavudine (d4T, Zerit), 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.
There is considerable cross-resistance amongst the nucleoside reverse transcriptase inhibitors (NRTIs). This means that once resistance to one NRTI has developed, other NRTIs may have less effect on HIV viral load. (Mayers) Zidovudine-resistant strains persist in the body long after a person stops taking zidovudine.
Cross-resistance to the majority of the available NRTIs can severely restrict future treatment options. It can be caused by TAMs, or by one of two other sets of mutations:
- Mutations in reverse transcriptase at codons 62, 75, 77, 116 and 151.
- A T69S mutation, plus the insertion of six amino acids at the same position.
There is evidence that people who take zidovudine as part of their first antiretroviral regimen have a better chance of viral suppression when they switch to a regimen containing stavudine, compared with people who start with stavudine and then switch to zidovudine. Conversely, HIV that is resistant to lamivudine may still be susceptible to zidovudine, while virus that is resistant to zidovudine may subsequently become sensitive to the drug again once lamivudine resistance has emerged. Although the application of these observations remains to be established in clinical trials, these findings suggest that zidovudine may be used successfully after failure of a lamivudine-containing regimen, even if zidovudine resistance has occurred in a previous drug combination.
A similar relationship has been observed between didanosine (ddI, Videx / VidexEC) and zidovudine. The L74V mutation, which is selected by didanosine, can re-sensitise HIV with TAMs to zidovudine. Zidovudine may therefore be a suitable option after failure of a didanosine-containing regimen, even if zidovudine resistance has previously occurred. (Miranda)
Zidovudine (AZT, Retrovir) should not be taken with stavudine (d4T, Zerit), as these two drugs reduce each other’s anti-HIV effects. A similar interaction occurs between zidovudine and ribavirin (Copegus / Rebetol / Virazole), which is used to treat hepatitis C.
Zidovudine is removed from the body by the kidneys after chemical modification or ‘glucuronidation’ in the liver. Other medicines that are removed in the same way may interact with zidovudine and may require dose adjustments. For example, co-administration of zidovudine with the tuberculosis drug rifampicin (Rifadin / Rimactane) can lead to elevations in rifampicin levels, although it is not known whether this is clinically significant. Similarly, the drug probenecid (Benuryl / Probecid), which is used to prevent kidney toxicity due to cidofovir (Vistide) treatment for cytomegalovirus infection, reduces the metabolism of zidovudine. This leads to elevated levels of zidovudine and increased risk or severity of side-effects.
Patients taking the anti-convulsant drug phenytoin (Epanutin) with zidovudine should be closely monitored, as co-administration of the drugs can cause increases or decreases in phenytoin levels. Studies have shown that atovaquone (Wellvone) and valproic acid (Depakote) also increase exposure to zidovudine.
The risk of low white blood cell counts (neutropenia) is increased in patients taking ganciclovir (Cymevene), doxorubicin (Caelyx / Myocet), trimetrexate or cotrimoxazole (Septrin) at the same time as zidovudine. The risk of anaemia is increased in patients taking pyrimethamine plus sulphadiazine (Fansidar), used for treating toxoplasmosis.
Methadone (Methadose) increases levels of zidovudine by about twofold, so people taking both drugs need only take half the standard dose of zidovudine to get the same anti-HIV effect.
Other drugs that should be co-administered with zidovudine with caution include:
- Cimetidine (Dyspamet / Tagamet).
- Indometacin (Rimacid).
- Ketoprofen (Orudis / Orovail).
- Naproxen (Naprosyn / Synflex).
Similarly, the risk of zidovudine-related side-effects may be increased with the following drugs:
- Amphotericin (Fungilin / Fungizone).
- Interferon alfa (Intron-A / Roferon-A / Viraferon).
- Ribavirin (Copegus / Rebetol / Virazole).
- Systemic pentamidine (Pentacarinat).
- Vinblastine (Velbe).
- Vincristine (Oncovin).
Patients taking these drugs alongside zidovudine should be closely monitored for kidney and blood problems.
Zidovudine (AZT, Retrovir) is often prescribed to children and infants. It was licensed for use in a syrup formulation in HIV-infected children aged over three months in 1990. The recommended dose for children has been 360 to 480mg/m² per day, divided into three or four doses, with a maximum of 200mg per dose. (Brady) Large volumes of the syrup are not well tolerated by older children.
In 2008, the US FDA approved new dosing guidelines that allow for twice or thrice daily dosing in children 6 weeks to 18 years. Dosage can be calculated by weight or by body surface area. The new label has recommendations for twice daily or three times daily dosing by weight or by body surface area. Capsules and tablets have also been approved for use in children who are able to swallow them.
The new guidelines advise that children 4kg to <9kg receive 24mg/kg daily, administered as 12mg twice daily or 8mg three times a day. Children from 9 to <30kg should receive 18mg daily (divided doses of 9 bid or 6 three times daily), and children 30kg or more should receive 600mg daily, dosed at 300mg twice a day or 200mg three times a day.
Alternatively, dosing for zidovudine can be based on body surface area (BSA) for each child. The recommended oral dose is 480mg/m2/day in divided doses (240mg/m2 twice daily or 160mg/m2 three times daily). In some cases the dose calculated by mg/kg will not be the same as that calculated by BSA.
Side-effects of zidovudine in children are similar to adults, with anaemia being the most common. (McKinney) (Pizzo)
Combivir is only approved for use in children over 12 years of age, while Trizivir is not approved for use in those younger than 18 years.
Zidovudine (AZT, Retrovir) is the only anti-HIV drug that is fully approved for use during pregnancy.
Current guidelines from the British HIV Association recommend that pregnant women take the anti-HIV drugs they require regardless of their pregnancy, with the exception of efavirenz (Sustiva). (Hawkins) However, women who would otherwise not require HIV therapy due to high CD4 cell counts and low viral loads, can reduce the chance of mother-to-baby transmission by taking zidovudine during pregnancy and labour. (Mandelbrot) (CDC, 1998) (Larbalestier) Current guidelines recommend zidovudine monotherapy in women with HIV viral loads below 10,000 copies/ml and wild-type virus who do not require or want to take antiretroviral therapy during pregnancy and are willing to deliver by caesarean section prior to the onset of labour.
Zidovudine monotherapy should begin in the third trimester of pregnancy, at a dose of 100mg five times per day. During labour, zidovudine should be administered intravenously at 2mg/kg over one hour, followed by 1mg/kg per hour until the umbilical cord is clamped. The baby should then be given 2mg/kg zidovudine by mouth every six hours starting within twelve hours of birth, until six weeks of age. For babies that cannot be given the oral solution, zidovudine should be given intravenously at 1.5mg/kg, infused over 30 minutes, every six hours. (Connor, 1994) (CDC, 1994)
There are no serious short-term side-effects of zidovudine monotherapy for the mother or the child, and studies have found no long-term effects of zidovudine treatment before or during birth on birth defects, growth, development or risk of tumours in uninfected babies. (Connor, 1995) (Lipshultz) (Hanson) (Brouwers) (Culnane) Preliminary findings also suggest there is no difference in the risk of disease progression between women who take zidovudine and who take a placebo, after 18 months follow-up. (Bardeguez) However, there is some evidence that babies who do become infected after zidovudine exposure may have worse outcomes than HIV-positive babies who do not receive zidovudine before or during birth. (Italian Register for HIV Infection in Children) (de Souza) Further studies following mothers and babies are underway.
Although breastfeeding by HIV-positive women is not recommended, mothers given zidovudine during birth also tend to have lower viral loads in their breastmilk, thereby further reducing the chances of transmission to breastfed infants. However, when women stop taking zidovudine, there is a burst in viral load, which may increase infant exposure to the virus. (Manigart)
The addition of nevirapine (Viramune) to short-course zidovudine for the mother or baby may further reduce the chance of mother-to-child transmission of HIV.
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