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Published in the Bulletin of Experimental Treatments for AIDS March 1997 issue, by the San Francisco AIDS Foundation. |
Women and AIDS: NIH Reaffirms Support for Perinatal AZT Despite Cancer Findingsby Liz Highleyman Reports of 2 recent studies have raised concerns about whether the use of AZT (Retrovir) to prevent perinatal HIV transmission might lead to the development of cancer in the children of HIV positive women. However, a National Institutes of Health (NIH) panel reviewed the studies and determined that in view of the known beneficial effect of AZT in reducing perinatal transmission, current U.S. Public Health Service (USPHS) guidelines recommending use of the drug should remain in effect. AZT was shown in AIDS Clinical Trials Group (ACTG) study 076 to be effective in reducing perinatal transmission rates; the drug was given to women during pregnancy and labor, and to infants following birth. In that study, perinatal transmission rates decreased from 22.6% for women and children not taking AZT to 7.6% for those who used the drug. The 076 regimen is considered the standard of care for preventing vertical transmission, as reflected in the USPHS guidelines released in August 1994. Since the initiation of widespread use of the regimen, according to epidemiological studies, rates of perinatal transmission have fallen from rates up to 25% to rates around 8%. The first study, conducted by the National Cancer Institute (NCI), gave AZT in very high doses to mice during the last trimester of pregnancy -- doses 12-50 times higher than those recommended for pregnant HIV positive women. Researchers observed an increased incidence of certain types of cancer in the mice's offspring. There was a several-fold increase in the incidence of lung and liver tumors, and an appearance of uncommon reproductive tract (vaginal) tumors in 17% of the female mice pups. It was also shown that AZT was incorporated into the DNA of various neonatal (newborn) mice tissues. The second study, conducted by AZT manufacturer Glaxo Wellcome, used AZT dosages that were roughly 3 times higher than those recommended for pregnant women. That study did not find an increased incidence of lung or liver cancers in mice pups. An increase in vaginal tumors was observed in pups who continued to receive AZT for their entire lifespan. This is in accordance with the results of an earlier AZT toxicology study that revealed in 1989 that the drug causes vaginal neoplasms (tumors) in adult mice. No increases in cancer in other parts of the body have been seen in adult mice or rats. The NCI and Glaxo studies were quite different, and it is not sur-prising that their results are dissimilar. The NCI study was designed to detect the highest number of tumors by using close to the maximum tolerated doses of AZT over a short period of time during pregnancy. The Glaxo study, in contrast, used doses more similar to those recommended for pregnant women over longer periods. On January 14, 1997, a Blue Ribbon advisory panel convened by the National Institutes of Allergy and Infectious Diseases (NIAID) -- made up of basic and clinical researchers, epidemiologists, women with HIV, and a expert in biomedical ethics -- unanimously concluded that the existing USPHS recommendations on perinatal AZT use should not be changed. The panel noted that while the NCI study did raise "hypothetical concerns," the known benefits of the perinatal AZT regimen "far outweigh" these concerns. The panel's report stated that there are "major differences between humans and mice in AZT distribution, metabolism and excretion, in duration of gestation and fetal development at birth, and in many facets of the maternal-fetal relationship. Therefore, the relationship between the regimens of AZT used in these 2 studies and those used in clinical practice in humans is complex, controversial and of uncertain relevance. The implications of these findings will require further study." The panel emphasized that pregnant women should be told about the new findings so that they could make informed decisions about treatment for themselves and their children. They further recommended that all children exposed to antiretroviral therapy in utero should receive long-term medical follow-up. So far, no babies born to women who have taken AZT during pregnancy are known to have developed cancer. However, given when these studies started, none of these children are more than 4 years old; medical monitoring will continue until the children who took part in ACTG 076 are 21 years old. Some advocates for women with HIV worry that AZT will be a repeat of the DES tragedy. The drug diethylstilbestrol (DES) was given to women in the 1940s and 1950s to treat menstrual disorders and prevent miscarriages. The drug was later proven to be a transplacental carcinogen (agent that causes cancer). Approximately 15% of the offspring of pregnant mice given DES in doses similar to those prescribed for humans developed vaginal tumors, and approximately .1% (1 in 1,000) of women whose mothers took DES during their pregnancies also have developed such tumors. Advocates claim that caution is warranted until more is known about the long-term effects of AZT use. They insist that no policies should be implemented that require HIV positive pregnant women to take AZT -- policies many fear will be the outcome of current mandatory testing efforts. To date, no other antiretroviral drugs have been study as extensively as AZT for the prevention of perinatal HIV transmission. However, it is reasonable to assume that new drugs and combination therapies may prove as or more effective; for example, preliminary studies of the use of the non-nucleoside reverse transcriptase inhibitor drug nevirapine appear promising. The NIH panel noted that "combination chemotherapy monitored by viral load measurements is now appropriate for many women who, until recently would have received the ACTG 076 [AZT monotherapy] regimen." They went on to recommend that the Public Health Service Task Force should conduct a "thorough reassessment of the USPHS guidelines" in light of new information regarding anti-HIV therapy, HIV pathogenesis and the dynamics of perinatal transmission. Liz Highleyman is on the editorial staff of BETA. NIAID. Summary of the meeting of a panel to review studies of transplacental toxicity of AZT. January 14, 1997. NIH panel reiterates support for Public Health Service recommendations regarding treatment of HIV-infected pregnant women with AZT. Glaxo Wellcome press release. January 14, 1997. Page last updated 1 April 1997 |
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