DNA Damage Caused by Drug Used To Prevent HIV Transmission from Mother to Child
3 May, 2007 12:04 pm
Last year, approximately 400,000 to 700,000 children world-wide were infected with human immunodeficiency virus (HIV-1), and the majority became infected during or shortly after birth. There is no cure once people are infected with HIV-1; therefore, prevention of infection is an important component of global efforts to control the virus. In 1994, treatment with zidovudine (AZT; a nucleoside reverse transcriptase inhibitor or NRTI) during the last two-thirds of pregnancy, during delivery, and for the first 6 weeks of an infant?s life was shown to reduce viral transmission from about 25% to 8%. This discovery was a monumental advancement in limiting the spread of this fatal infection.
In spite of this remarkable success, there is reason for concern about the long term health risks of AZT-based treatments.
AZT works by being preferentially inserted into the nascent DNA of the virus, killing most, but not all, of the virus. Later, it was learned that AZT is also inserted into the DNA of people, including babies and their HIV-1-infected mothers given the drug. Such DNA damage can alter the function of cells, but the long term health effects are unknown.
To understand these effects, mice and rats were used as models for investigating potential health risks of AZT in humans. AZT is also inserted into DNA of mice and rats, and rodents and humans have similar systems in their cells that attempt to repair this damage. In addition, two sets of tumor-related genes, one called tumor suppressor genes, and one called oncogenes (or tumor-enhancing genes) are shared by mice, rats, and people, performing the same functions in all three species. Thus, studies of the long term effects of NRTIs in mice and rats can give information about potential long term effects in children. Other studies were performed to look for evidence in children of overall signs of DNA damage. Results of several of these investigations are reported in a special issue concerning “Health Risks of Perinatal Nucleoside Reverse Transcriptase Inhibitors” in the April/May 2007 issue of Environmental and Molecular Mutagenesis, the official journal of the Environmental Mutagen Society that is published by John Wiley & Sons, Inc. (http://www.interscience.wiley.com/journal/emm).
In a study led by Dale M. Walker, mice and rats were exposed to different doses of AZT during the last seven days of the rodents’ pregnancy (about one-third of a human pregnancy) and the health of the animals was evaluated two years later (equivalent to mid-adulthood for humans). Clear evidence of an increase in cancer of cells lining blood vessels (hemangiosarcoma) was found in male mice and clear evidence of a type of leukemia (mononuclear cell leukemia) was found in female rats. There was also some evidence of increased cancer in the liver and in reproductive tissues. This study showed that cancer was a long term outcome of DNA damage caused by exposure to AZT prior to birth, and heightened the concern that tumors could occur later in life of similarly treated human babies.
In another study led by Hue-Hua Hong, pregnant mice were exposed to AZT throughout pregnancy, and lung cancers from their offspring were tested for permanent DNA changes or mutations in tumor-related genes. Mutations were found in K-ras, a gene that can enhance tumor formation, and in p53, a gene that protects against tumor formation. These findings were of concern because mutations in these genes have been shown to occur in cancers of humans.
Other studies looked for indicators of DNA damage in human babies who were treated with AZT during pregnancy to prevent HIV-1-infection. A study led by Patricia Escobar found DNA mutations (in the glycophorin A gene, that makes a protein on the red blood cell surface) in red blood cells of babies exposed to AZT plus lamivudine (a second NRTI), and these changes lasted at least through the babies’ first year of life. In another study led by Kristine Witt, the frequency of DNA damage at the chromosome level in immature red blood cells (or frequency of micronucleated reticulocytes, cells where breaks in DNA can be seen) was10-times higher in babies and mothers who received AZT plus lamivudine compared with those who received other drugs or no treatment during pregnancy.
All of the investigators performing this research recommended the continued use of AZT other NRTIs to prevent HIV-1-infection of babies. However, they all agreed that the results suggested that these babies may be at risk in later life for the development of cancer or other diseases caused by DNA mutations, and that these children should be followed closely to make sure that cancer and other health problems are detected early when they are most treatable.
Escobar P., 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, April 2007