Over the past two years, researchers throughout the nation have documented dramatic declines in mother-to-infant (perinatal) transmission of HIV, indicating the success of recent perinatal prevention efforts. In 1994, clinical trials conducted by the National Institutes of Health (NIH) showed that HIV-infected women could reduce the risk of transmitting the virus to their babies by as much as two-thirds through administration of zidovudine (ZDV or AZT) during pregnancy, labor, and delivery, and by giving their babies AZT for the first 6 weeks after birth. In 1994, the Public Health Service (PHS) issued guidelines for using AZT during pregnancy, and in 1995, published guidelines for routinely counseling all pregnant women about HIV and offering them an HIV test.
As health care providers across the country have incorporated these guidelines into clinical practice, perinatal HIV transmission has dropped dramatically. On a national level, the number of children reported to CDC with perinatally acquired AIDS declined 27% between 1992 and 1995, with the most dramatic drop in cases occurring in 1994 and 1995. Additionally, research from numerous states has documented a declining rate of perinatal HIV transmission.
Among women in CDC's Perinatal AIDS Collaborative Transmission Study (PACTS), AZT use increased following the publication of CDC guidelines, and the rate of perinatal transmission dropped from 21% to 11%. The PACTS study includes women from 4 cities, New York City, Newark, Atlanta, and Baltimore.
Another multi-site study, the Women and Infants Transmission Study (WITS), tracks perinatal transmission in several groups of women from New York, Massachusetts, Illinois, Texas, and Puerto Rico. In the WITS study, the rate of perinatal transmission dropped to 8% in 1994, declining from a rate of 19% prior to the AZT guidelines.
In North Carolina, perinatal HIV transmission dropped from 21% in 1993 to 6.2% in the first half of 1996.
In New York City, perinatal transmission rates have dropped to as low as 5% among the infants of women who followed the AZT guidelines.
Ongoing Research to Improve Perinatal HIV Prevention
Despite these encouraging findings, challenges remain for perinatal prevention. Perhaps greatest among these is the need to ensure pregnant women have access to quality prenatal care early in pregnancy and can sustain care throughout pregnancy and beyond. In order for HIV-infected women to benefit from treatment advances for themselves and their children, they must be reached early in pregnancy with the opportunity to learn their HIV status and to consider treatment for their health and for preventing transmission to their children. When women are provided appropriate information and counseling, studies show that acceptance of HIV testing and AZT treatment is extremely high.
Yet, some children are infected despite AZT use by their mothers. AZT is not 100% effective in preventing transmission, and a great deal remains unknown about the mechanisms by which AZT reduces transmission, as well as the potential for long-term side-effects for the exposed women and children. Moreover, new combination therapies offer promise for improved treatment for HIV-infected women. Researchers must explore the possibility that AZT treatment during pregnancy may reduce the effectiveness of these therapies for women later in life. CDC, NIH, and other researchers continue to study these questions to determine if there are more effective, simpler, or safer preventive therapies or practices available. Research is ongoing in a number of areas:
PACTS and WITS are evaluating the impact of other factors on perinatal transmission, such as the mother's stage of HIV disease, and the time from rupture of membranes (water breaking) to delivery. These studies have found that when a mother's membranes have ruptured more than 4 hours before delivery, the risk of transmission is increased. These findings suggest that changes in obstetric practice may also help reduce HIV transmission. If physicians can reduce the duration of ruptured membranes, the chances of transmission can likely be reduced.
If a shorter course of AZT during pregnancy were shown to be as effective as the treatment regimen now recommended, both the costs and potential risks from AZT use could be reduced. In developing countries where over 90% of new HIV infections occur, the extensive AZT course now recommended in the U.S. is generally not feasible. CDC and other researchers are now working with researchers in developing countries to determine if administering AZT or other antiretrovirals for a shorter time period during pregnancy and/or during delivery will be as effective in reducing perinatal HIV transmission.
New combination therapies using protease inhibitors in combination with existing antiretroviral drugs such as AZT and 3TC have recently been shown to reduce the amount of HIV particles circulating in the blood of some infected individuals to non-detectable levels. While no one yet knows how long this effect will last or impact the disease progression, these results are promising for the quality of life of HIV-infected individuals. To determine if these or other therapies may be as, or even more, effective than AZT alone in preventing perinatal transmission, NIH is beginning to study both the safety and efficacy of other options for perinatal prevention.
Efforts to Further Explore Potential Long-Term Side Effects
Neither the mothers nor the children studied have reported serious side effects immediately following the AZT regimen currently recommend. Effects have been limited largely to mild, reversible anemia in the infants. Researchers do not know if the mothers or the infants exposed to AZT will experience any side effects over time. Current recommendations stress that a woman should make a personal decision about taking AZT only after she discusses the benefits and potential risks for herself and her child with her health care provider. Researchers have long been aware that AZT could potentially cause rare long-term side effects, even though none have been reported to date in any of the exposed children. Since the discovery of AZT's effectiveness in perinatal HIV prevention occurred recently, the oldest children exposed to this regimen are now 5 years old. The guidelines recommended that they be followed until age 21 to ensure that any side effects are detected.
To further explore any theoretical or potential risks of long-term side effects of AZT, two laboratory studies have recently examined the question of whether AZT may cause cancer in the offspring of pregnant mice exposed to various doses of the drug. The relevance of these studies for human beings is not known, and the studies arrived at different conclusions. The first study was designed to determine if AZT, when given in extremely high doses to pregnant mice, could result in cancer in their offspring. Researchers found that when AZT is given in these high doses to pregnant mice, it can cause tumors in the liver, lung, and genital tract of their infants. The second study was designed to examine the long-term outcomes in the offspring of mice given much lower doses of AZT (designed to replicate the level of AZT in the blood of pregnant women following current treatment guidelines). This study found no increase in tumors.
The relationship between the doses of AZT used in these studies and those used in clinical practice in humans is not well understood. Since very few drugs have been studied in mice, scientists do not know if these studies can be used to reliably predict long-term effects in humans. Moreover, mice metabolize AZT very differently than humans. For example, AZT collects in high concentrations in the urine of mice, but does not do so in humans. Tumors seen in the vaginal tract of mice could be related to the direct contact with urine. But researchers do not know the mechanisms by which AZT caused the tumors in mice. Researchers are therefore uncertain if the outcomes of either of these mouse studies have any relevance to human beings. At this point, the long-term risks to humans remain theoretical. NIH and CDC, along with a "blue ribbon" panel of scientific experts, have concluded that the dramatic benefits of AZT in preventing perinatal transmission far outweigh the hypothetical concerns raised by these mouse studies, and that the current treatment guidelines should not be changed. However, both agencies continue to support additional research and the practice of informing women of any potential risks of AZT use.
Providing Women and Their Physicians the Best Possible Information
As the science continues to evolve in all of these areas, it continues to be critical that women and their health care providers have the information they need to make the best decisions for their health and the health of their babies. Community leaders and organizations should play a key role in reaching women at risk with complete information in terms they can understand. The agencies of the PHS regularly review research findings, and when necessary, the PHS perinatal task force reviews all relevant guidelines. The perinatal task force will soon be convened to review recent data on other risk factors, alternate therapies for HIV-infected individuals, and potential toxicity of AIDS drugs. The task force will outline areas requiring further study and ensure that current guidance reflects knowledge to date.