Researchers Report Ongoing Study Results Showing Lack of Long Term Effects of In Utero Exposure to AZT Among Uninfected Children Born to HIV-Infected Women
In the January 13, 1999 issue of The Journal of The American Medical Association (JAMA, Vol 281, No 2), researchers reported that there have been no significant differences in long term adverse events between children receiving AZT and those receiving placebo in study 076. In study 076, pregnant women and their newborns received a prescribed course of AZT treatment to prevent transmission of HIV from mother to child. Following is a summary review of the author's report.
Since the success of Study 076 in dramatically reducing transmission of HIV from mother to child by a prescribed course of AZT treatment, the use of AZT to prevent transmission has become widespread. Since the long term effects of in utero AZT exposure for mothers and their infants are unknown, and based upon theoretical concerns about the unknown long term effects, infant participants in 076 are being propesctively monitored for late effects in Study 219. In pre-clinical lifetime animal carcinogenicity studies, high dosages of AZT administered to adult redents have been associated with the development of vaginal epithelial neoplasms in female rodents receiving the highest doses, a finding that may be explained by the presence of high concentrations of unmetabolized AZT in the rodent urine and reflux from the bladder into the vagina. Short term adverse effects observed from AZT use in clinical trials for the treatment of HIV have included anemia, neutropenia, and elevated liver enzyme levels. The authors characterized these effects as reversible.
Study 076 was a randomized, double blind, placebo controlled trial of AZT for prevention of HIV-1 transmission conducted in the USA and France. Asymptomatic pregnant women who were pregnant and infected with HIV were randomized to receive either AZT or placebo. Women were treated with oral AZT prepartum and intravenous AZT during the intrapartum period. Newborns received the same randomized treatment as their mothers for the first 6 weeks of life. The study began enrolment in April 1991 and was closed to new enrollment and unblinded in February 1994 after an interim analysis showed a significant effect of AZT in reducing transmission of HIV.
All caregivers of the infants and children participating in 076 were offered enrollment in Study 219 to have long term follow-up to observe for any development of long term adverse events. Data from comprehensive history taking and physical exams, including physical growth measurements, immunological parameters, cognitive/development function, occurrence of neoplasms, quality of life, and mortality data are collected every 6 months for children younger than 2 years and at least annually after that. Cardiac and opthalmologic tests are also performed. Children are scheduled to be followed up until age 21 years. Since 1993, more than 2200 children initially enrolled in Pediatrics AIDS Clinical Trials Group studies have been followed in Study 219. This study analysis included children who participated in 076 and subsequently enrolloed in 219.
332 076 uninfected children (177 receiving AZT and 155 receiving placebo) were born at US centers on or before January 4, 1994 and were alive at the time 219 opened to enrollment in May 1993. 234 (122 receiving AZT and 112 receiving placebo) enrolled in 219. As of February 28, 1997 at the time of the last follow-up the median age of the children was 4.2 years (3.2-5.6 range) and 86% of the unifected children enrolled in 219 were still participating in the study. 26 children were lost to follow-up or their caregivers refused further contact.
The authors reported that average follow-up of 4.2 years results so far reveal no adverse outcomes with respect to growth, cognitive/developmental function, immune function, cancers, or mortality for the chiildren receiving AZT when compared to the children who received placebo. The authors said these results are reassuring and that birth registry data from the Antiretroviral Pregnancy Registry found no increased risk in the proportion of congenital birth defects among 301 infants exposed to AZT monotherapy during the antenatal period.. The authors also reported that one other study evaluated short term risk for tumors in 734 infants and children with known AZT exposure (including 115 children in the current study and 619 infants and children from the Women's and Infants Transmission Study). In this combined group with 1110 person-years follow-up, no neoplasms (tumors) have occurred. The authors listed several caveats. Only two-thirds of the children in the original 076 study are currently being followed up in this late-effects study. Maintaining uninfected children in a long term study is difficult. Many children are placed in foster care or adoption settings. Loss to follow-up is estimated to be about 10% per year.
Since early aggressive antiretroviral combination therapy is often utilized for treating pregnant women, there is a need for a framework in which to follow the infants born to the HIV-infected mothers. Other than 219 there does not yet appear to be such a mechanism in place. Combination therapy includes drugs other than AZT including protease inhibitors and NNRTIs. The potential for long term adverse outcomes from using these other drugs and from using combinations of drugs should be followed.