Treatment Issues, Vol 11, No 1; January 1997
Saundra Johnson

The two studies were very different in concept and result, and these differences made drawing inferences from the data very difficult.

One study, conducted by the National Cancer Institute (NCI), was designed to potentiate any tendency of AZT to cause tumors. Mice received doses of AZT near the maximum tolerated dose. There was a significant dose-related increase in tumors found in the lungs of both male and female mouse offspring and in the livers of the males. Also, seven of the study's 46 AZT-exposed female mice experienced reproductive tract tumors versus none of the 30 female control mice. (But note that incidence of hematopoietic cancers -- lymphomas, leukemia and the like -- was dramatically lower in the male and female mice exposed to AZT in utero.)

The other mouse study, which was carried out by AZT's manufacturer, Glaxo Wellcome, was designed to replicate the dosing rate and schedule used in ACTG 076 and look at carcinogenic effects in offspring over time. This study found no increase of tumors following the pregnant mice's exposure to AZT.

After presentations to the NIH panel by the two studies' investigators, a discussion ensued over whether cancers seen in mice are predictive of those in humans under the same conditions. There are only a few drugs that have been tested in this way, and of these, DES is the only one on which we have long term follow up. The offspring of mice given DES developed tumors similar to the tumors seen in the children of women given DES to prevent miscarriage. It is believed that DES and AZT cause cancer in different ways, however.

The panel was unanimous in concluding that the benefits of AZT in preventing perinatal transmission appear to far outweigh the concerns raised by the NCI mouse study. It considered that the data in and of itself does not suggest the need for changes in treatment recommendations or public health policy. The panel then drafted several research, clinical, public information and policy priorities that tempered its position in support of AZT:

* Reassessment of the PHS guidelines in the broader context of the rapid change in state-of-the-art treatment of women with HIV since the guidelines were first developed and published (single agent versus combination therapy).

* Improvement in public awareness of the industry-sponsored, and now under-used, pregnancy registry of those exposed to antiretroviral drugs before birth and aggressive monitoring of all such exposed children.

* Greater emphasis on studying perinatal interventions that maximize the safety and minimize the likelihood of long-term side effects.

* Completion of the full two-year follow-up of the mice in the NCI study.

* Additional research on transplacental carcinogenesis of nucleoside analogs like AZT, including investigation into the tumor-inducing mechanism and its relationship to the amount of AZT administered (with results confirmed in at least one other species).

* Determination of the relationship between AZT pharmacokinetics and AZT incorporation into blood cells and solid tissues.

* Full disclosure to women of the theoretical risk of cancer in their offspring during counseling about interventions to reduce perinatal HIV transmission.

As Treatment Issues went to press, Eric Goosby, Director of the Office of HIV/AIDS Policy, announced that a date would be set in the coming week for reconvening the original panel to review the current PHS guidelines. A formal statement will be sent to all women involved in perinatal transmission trials and to the PHS for dissemination to physicians.

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