March 03, 2004 Effect of ARVs on DNA of Infants
 I understand that the leading category of antiretrovirals, the nucleoside reverse transcription inhibitors (NRTIs), are analogs of the building blocks of DNA. If pregnant women take these drugs could it affect the DNA of their fetuses?
 Yes, at least for a specialized type of DNA (mitochondrial DNA) and conceivably for DNA in the nucleus as well. The extent and significance of the effects are not clear. Still it supports the importance of ready availability of contraception for women on ARVs.
The commonly-used NRTIs are well known to damage the DNA in the parts of the cell (mitochondria) that produce energy. Such damage produces many of the major NRTI side effects such as anemia, neuropathy, liver toxicity, myopathy and lactic acidosis. (HIV itself also causes damage to mitochondrial DNA).
With respect to effects of NRTIS on infants, evidence comes from use in developed countries (typically zidovudine alone) to prevent maternal-to-child transmission (MTCT) - given for a number of weeks to the mother late in pregnancy and to the infant for six weeks after birth. In general such infants appear to do well. However, some have shown clinical effects of mitochondrial damage (e.g. lactic acidosis and anemia). Moreover it appears some mitochondrial DNA damage from perinatal zidovudine can persist for at least as long as two years.
The long term implications of such findings are not clear. The major portion of DNA is of course in the nucleus. Animal data and some human data indicate damage to nuclear DNA as well. An important concern is potential increased subsequent susceptibility to cancer.
But triple-therapy ART given to women who are or may become pregnant presents an increased concern for the infant. First, because it includes two NRTIs (along with another potent drug). And, second because in can involve exposure in early pregnancy, including the vulnerable developmental period of the first trimester. Thus WHO's ART guidance states:
"For pregnant women, it may be desirable to initiate ART after the first trimester, although for pregnant women who are severely ill, the benefit of early therapy clearly outweighs any potential fetal risks and therapy should be initiated in these cases."
Clearly making quality, effective contraception readily available to avoid these risks is vital in any case. Thus the WHO guidance also states: "Women who are receiving ART and do not wish to become pregnant should have effective and appropriate contraceptive methods available to them in order to reduce the likelihood of unintended pregnancy."
References:
- Cossarizza A, Moyle G. Antiretroviral nucleoside and nucleotide analogues and mitochondria. AIDS 2004;18:137-51.
- Sperling RS et al. Safety of the maternal-infant zidovudine regimen utilized in the Pediatric AIDS clinical trial group 076 study. AIDS 1998;12:1805-13.
- Branch S et al. Persistent mitochondrial dysfunction and perinatal exposure to antiretroviral nucleoside analogues. Lancet 1999;353:1084-9.
- Poirier MC et al. Long-term mitochondrial toxicity in HIV-uninfected infants born to HIV-infected mothers. JAIDS 2003;33-175-83.
- Olivero OA et al. Transplacental genotocixity of combined antiretroviral nucleoside analogue therapy in Erythrocebus monkeys. JAIDS 2002;29:323-9.
- WHO. Scaling up antiretroviral therapy in resource-limited settings: Treatment guidelines for a public health approach. 2003 Revision, Geneva, December, 2003.
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The "Pearls" offer answers to commonly asked questions about family planning. These "Pearls" are prepared by Dr. James D. Shelton, Senior Medical Scientist, Office of Population, United States Agency for International Development (USAID)
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