Panel Affirms Importance of Prenatal AZT Use

In late 1994, results of the NIAID-funded study known as AIDS Clinical Trials Group (ACTG) 076, showed that the drug AZT dramatically reduces mother-to-infant transmission of HIV when given to HIV positive women during pregnancy and childbirth. Soon thereafter, a Public Health Service (PHS) Task Force and a number of professional organizations recommended that all pregnant women infected with HIV receive AZT. Several recent studies have documented an increase in AZT use during pregnancy and a concomitant decline in HIV transmission from mothers to infants.

Recently, a panel of experts unanimously concluded that these known benefits of AZT far outweigh hypothetical concerns about cancer risk raised by new data from an ongoing study. In that study, researchers from the National Cancer Institute (NCI) found that offspring of mice given massive doses of AZT during pregnancy had a several-fold increased risk for liver and lung tumors. The NIH convened the expert panel to review the NCI data as well as a second study conducted by scientists at Glaxo-Wellcome, Inc., the drug's manufacturer.

The Glaxo researchers also administered AZT to pregnant mice, but in doses that ranged from one-twelfth to one-fiftieth of those used in the NCI study. Still, AZT blood levels of mice in the Glaxo study were three times higher than those seen in pregnant women who receive the drug. In contrast to the NCI study, however, the Glaxo researchers found no increased risk for cancer among offspring of the mice that received AZT during pregnancy. "Both studies appear to be well done," says Jack Killen, M.D., director of NIAID's Division of AIDS (DAIDS). "It is not surprising that they come to different conclusions. The NCI study was designed to maximize the occurrence of transplacental carcinogenesis by giving large doses of the drug over a short period of time during pregnancy. The Glaxo-Wellcome study was designed to examine long-term effects of AZT administered in doses that approximate those used in clinical practice."

After careful consideration of these data, the panel affirmed the importance of pre- and perinatal antiretroviral therapy for HIV-infected women. At the same time, the panel strongly emphasized the need for careful long-term follow-up of all children exposed in utero to AZT, including those who are not infected with HIV. The short-term side effects of the AZT regimen used in ACTG 076 have been limited largely to mild, reversible anemia in the infant. No tumors have been observed to date among approximately 1,000 AZT-exposed children followed for an average of three years.

The panel also noted that the state of antiretroviral therapy has changed substantially in the years since the PHS recommendations on the use of AZT during pregnancy were developed and published. "Given the recent advances in combination chemotherapy regimens for HIV infection, a thorough reassessment of the PHS guidelines is needed," says Dr. Killen. The panel recommended that the PHS Task Force should be reconvened to carry out this important task.

A report of the panel's deliberations, titled "Summary of the Meeting of a Panel to Review Studies of Transplacental Toxicity of AZT," is available on the Internet via the NIAID home page at http://www.niaid.nih.gov. The report may also be obtained from the AIDS Clinical Trials Information Service (ACTIS) at 1-800-874-2572.

Panel Members Jack Killen, M.D., Chair Director, Division of AIDS NIAID Arthur J. Ammann, M.D. Pediatric AIDS Foundation Novato, Calif. Ronald Bayer, Ph.D. Columbia School of Public Health New York, N.Y. William A. Blattner, M.D. Institute of Human Virology University of Maryland Baltimore, Md. Edward Bresnick, Ph.D. Office of Research University of Massachusetts Medical Center Worcester, Mass. Jacqueline Clements Durham, N.C. Howard Minkoff, M.D. SUNY/Brooklyn Health Science Center at Brooklyn Brooklyn, N.Y. Eileen Monaghan Spencerport, N.Y. Nancy E. Mueller, S.D. Harvard School of Public Health Boston, Mass. June Osborn, M.D. Macy Foundation New York, N.Y. Henry Pitot, M.D., Ph.D. McArdle Laboratories University of Wisconsin Madison, Wis. Jean-Pierre Sommadossi, Ph.D. University of Alabama at Birmingham Department of Pharmacology Birmingham, Ala. Patricia N. Whitley-Williams, M.D. University of Medicine and Dentistry of New Jersey Robert Wood Johnson Medical School New Brunswick, N.J. Gerald Wogan, Ph.D. Massachusetts Institute of Technology Division of Toxicology Cambridge, Mass.