AZT causes genetic damage to infants; long-term cancer risk unknown

Adam Legge
Published: 16 April 2007

Antiretroviral drugs used to prevent HIV transmission from mother to child can cause genetic damage in infants that may increase their risk of developing cancer in the future, according to new research.

The study authors are not recommending stopping the use of antiretrovirals during pregnancy but say children need close monitoring and new, safer drugs need to be developed.

Combinations, typically including the nucleoside analogue zidovudine (AZT, Retrovir), have reduced the mother-to-child transmission of HIV from around 25% to less than 2% in infants who are not breast-fed. Pregnant women with HIV in developed countries receive antiretroviral treatment as standard care during pregnancy and infants are given zidovudine for six weeks after birth.

Nucleoside analogues (NRTIs) work by inhibiting a viral enzyme called reverse transcriptase and incorporating themselves into the viral DNA, blocking the virus’ ability to duplicate.

But NRTIs can also incorporate into the DNA of human cells, raising concerns that this may have future health consequences.

Now researchers in the field have published two animal and two human studies in a special issue of the journal Environmental and Molecular Mutagenesis.

In the first animal study, researchers gave AZT in various doses to female mice and rats during the last week of pregnancy and looked at the tissue of their offspring two year later.

The found a clear increase in the development of a cancer that affects the cells lining blood vessels - called haemangiosarcoma - in male mice and leukaemia in female rats (Walker 2007). There was also some evidence of increased risk of liver cancer and glioma – cancer of the central nervous system.

The second animal study looked at the offspring of mice given AZT during pregnancy. The researchers found genetic mutations in two genes - K-ras and p53 – which are associated with lung cancer in humans. The rates of lung cancer were significantly higher in those mice whose mother had been given the highest doses of AZT (Hong 2007).

The authors of this study said that their data suggest that infants exposed to AZT in the womb may be at increased risk of cancer as they age.

The two human studies looked for evidence of DNA damage in the blood of infants born to mothers who had been taking antiretroviral therapy.

In the first the researchers studied immature blood cells in the blood of both the newborns and their mothers for the presence of micronuclei – small, damaged pieces of broken-off DNA.

The micronucleus test is commonly used to study the potential DNA-damaging effects of chemicals.

They found a ten-fold increase in the number of micronucleated blood cells – in both the infants and the mothers who had been taking antiretrovirals. But the frequency of these abnormal blood cells dropped in the first six months after birth to normal levels (Witt 2007).

In the second human study researchers looked at a gene involved in building red blood cell walls - glycophorin A (GPA) - in the blood of children born to women who had been taking both zidovudine and lamivudine (Epivir).

They found GPA damage was more likely in the children of mothers who had taken both drugs, and these mutations were still present a year after birth (Escobar 2007).

Author of this last study, Dr Patricia Escobar of the department of environmental and occupational health at the University of Pittsburgh, said the results were “troubling” but emphasised: “There is a need for careful monitoring of the future health of children who received AZT-based therapies [in the womb], the development of new safer NRTIs and the identification of drugs that will mitigate the side effects of antiretroviral therapy.”

References

Walker DM et al. Transplacental carcinogenicity of 3’-Azido-3’Deoxythymidine in B6C3F1 mice and F344 rats. Environmental and Molecular Mutagenesis 48:283-298, 2007.

Hong H-H L. Genetic alterations in K-ras and p53 cancer genes in lung neoplasms from Swiss (Cd-1) male mice exposed transplacentally to AZT. Environmental and Molecular Mutagenesis 48: 299-306, 2007.

Will KL et al. Elevated frequencies of micronucleated erythrocytes in infants exposed to zidovudine in utero and postpartum to prevent mother-to-child transmission of HIV. Environmental and Molecular Mutagenesis 48: 322-329, 2007.

Escobar PA et al. Genotoxicity assessed by the Comet and GPA assays following in vitro exposure of human lymphoblastoid cells (H9) or perinatal exposure of mother-child pairs to AZT or AZT-3TC. Environmental and Molecular Mutagenesis 48: 330-343, 2007.

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