March 1997
BETHESDA, Md. — A government panel concluded that the known benefits of zidovudine in preventing perinatal transmission of HIV outweigh the hypothetical cancer concerns raised by recent mouse studies.
However, the panel said, all pregnant women with HIV should be counseled about the potential risks and benefits of any treatment interventions. The panel emphasized the need for long-term follow-up of all children who are exposed in utero to antiretroviral therapy, even those who are not infected with HIV.
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"The theoretical risk of cancer has always been there," said Catherine Wilfert, MD, in a telephone interview. "This is not the first study to suggest a risk of cancer. There have been other studies that have shown this, and women have been told about this theoretical risk." Wilfert is professor of pediatrics and virology at Duke University Medical Center. She has also been an investigator within the Pediatric AIDS Clinical Trials Group (ACTG), a nationwide network of clinical trial sites.
The National Institutes of Health (NIH) convened the panel of experts to review the data from two mouse studies. The two studies were significantly different in design and produced different results, although the panel said both studies were well done.
One study by the National Cancer Institute (NCI) suggested that very high daily doses of zidovudine (ZDV, Retrovir, Glaxo-Wellcome) may induce lung and liver tumors in the offspring of pregnant mice given the drug during the last trimester of pregnancy. Doses used in the study were equivalent to 12 to 50 times the dose used by pregnant women.
This transplacental carcinogenic effect was not seen in a second study by Glaxo-Wellcome. Glaxo scientists treated pregnant mice with doses of ZDV that were higher than those given to humans, but were lower than the amount given to the mice in the NCI study. The Glaxo study did not find an increase in the incidence of tumors in the mothers or the offspring.
Both studies, however, did find an increase in the incidence of vaginal tumors in mice, which was consistent with toxicological findings reported in rodent studies in 1989. These tumors appeared to be a result of exposure to the drug present in the urine which comes in contact with vaginal cells.
This new data must be carefully evaluated because ZDV has had such a great track record in reducing perinatal transmission of HIV, and physicians are concerned that this new information could discourage ZDV use. ZDV can only prevent perinatal transmission if pregnant women take the medication, and a media scare might stop women from taking the drug. However, Wilfert and others insisted, to date, the concerns in mice have not been borne out in children.
"There have been no cases of human cancer [in children exposed to ZDV in utero]. The argument, however, is that the mice developed these cancers near the end of their lives. For humans, that will be decades from now," Wilfert explained. "In the meantime, HIV-infected babies die. I would much prefer my child to have a life with a theoretical risk of cancer than be dead with HIV."
Giving ZDV to pregnant mothers in accordance with the ACTG 076 protocol has greatly reduced the incidence of maternal-fetal transmission. About 6,000 infants are born to HIV-positive women each year, and before the ACTG 076 protocol, almost 25% of those babies became infected. Giving ZDV therapy during the last trimester of pregnancy and during delivery has reduced the odds of an infant having HIV to less than 8%. No other regimen has been studied as extensively in pregnant women or proven to be definitively effective.
Scientists have known for some time that some nucleoside analogues, including ZDV, can be carcinogenic in animals. No increase in the incidence of tumors in other organ sites has been seen in other studies conducted in adult rodents.
In infants, the short-term side effects of the ZDV regimen are mostly limited to mild anemia. This effect is self-limited and reversible, the NIH said in a summary report of the meeting. No tumors have been observed in approximately 1,000 babies exposed in utero to ZDV and followed for an average of three years. But experts agree that the long-term effects of this intervention on children remain unknown. The panel recommended that all children, whether infected or not, should be followed long term if they were born to HIV-infected mothers receiving ZDV during pregnancy. Although the panel did not specify what it meant by long term, this follow-up should include evaluation for late effects, including the development of tumors. Glaxo officials said they intend to follow the children treated in the landmark ACTG 076 trial until they turn 21.
Very little is known about the reliability of the mouse model in predicting human cancers from drugs. To be truly reliable, the long-term effects of a large number of different drugs given to mice and pregnant women would need to be compared. Long-term follow-up data in humans are only available for diethylstilbestrol (DES), which women once took to prevent miscarriages. DES was not effective in preventing miscarriages and had serious harmful effects: vaginal tumors developed in some daughters of women given DES. These tumors were similar to those seen in the offspring of pregnant mice given DES. However, the mechanisms of carcinogenicity of DES and ZDV are likely to be different, the panel said.
There are differences in the way humans and mice distribute, metabolize and excrete ZDV, Wilfert explained. Therefore, the clinical relevance of these two studies is uncertain. Still, the evidence cannot be ignored. Therefore, the panel recommended areas of research that might shed some additional light on this information.
The panel suggested that:
The panel also reminded the health care community that antiretroviral therapy has changed substantially since the ACTG 076 protocol was instituted. Women should not be denied other options for treating HIV just because they are pregnant. "Despite the fact that we have a deficiency of data in pregnant women, therapy has already changed for them. We do not want to hold women to just ZDV. But we are still working in the unknown with pregnant women because the studies are simply not there," Wilfert said.
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