In a long-term study that began in November 1997, Ugandan and U.S. researchers have found that the initial advantage gained by infants who, along with their mothers, received one dose of NVP was largely sustained by the group of children until they reached 18 months of age, with few serious side effects attributable to NVP. This finding offers compelling new evidence that short-course NVP effectively and safely reduces the number of children who eventually become infected with HIV. Efficacy data for all time points up to 18 months are published in the Sept. 13 issue of the British journal The Lancet. A final follow-up study will be conducted in 2004 when the children are five years old.
"This landmark study could have far-reaching implications in resource-poor countries where breastfeeding and mother-to-child HIV transmission are both common," says Anthony S. Fauci, M.D., director of NIAID. "Indeed, the potential for lessening the burden of HIV/AIDS with this NVP regimen makes this work a very important public health breakthrough."
This study, named HIVNET 012, has tracked the efficacy over time of a single dose of NVP to a mother and her infant in comparison with a more complicated AZT treatment in preventing HIV transmission. HIV can be transferred to an infant before birth, during birth or through the mother's breast milk. More than 600 HIV-infected pregnant women were enrolled in the study. One group of women received a single dose of NVP during labor, while their infants received one dose within three days of birth. A second group of women received AZT one or more times during labor, while their infants received doses twice daily throughout the first week. This regimen was followed because of AZT's shorter half-life. A third, much smaller group of women and their infants received a placebo. (The placebo was discontinued early in the study when there was evidence that AZT was superior to the placebo.) Approximately 99 percent of the study participants breastfed their children. After 18 months, most of the women had completed breastfeeding, with the average duration lasting 9 months.
"Our study was driven by the need to find an inexpensive, safe and effective method of preventing HIV transmission in countries where it may not be practical to administer AZT," says J. Brooks Jackson, M.D., of the Johns Hopkins University School of Medicine, who co-directed the study with Professor Francis Mmiro, MBChB, of Makerere University in Kampala, Uganda.
After 18 months, infants enrolled in the NVP regimen sustained a 41 percent reduction in risk for HIV infection when compared with infants taking in the AZT regimen. (At 18 months, 25.8 percent of children in the AZT group were infected with HIV, while 15.7 percent of those in the NVP group were HIV-infected, yielding a difference of 41 percent when a time variable is considered.) These data are consistent with the 42 percent risk reduction for the NVP group when the babies were 6 to 8 weeks of age. The cost savings of using nevirapine in the study were substantial, approximately 70 times less than the AZT treatment.
The researchers speculate that the long-lasting benefits of NVP are not due to any persistently protective role provided by the drug itself since it is metabolized within 10 days; rather, infants receiving NVP, as with some other effective antiretroviral regimens, gain a protective advantage during the first few weeks of life, the time of greatest risk of HIV transmission. Although babies in both groups continued to acquire HIV throughout the study, they did so at approximately the same rate, enabling the NVP group to maintain its overall reduced risk even as the children grew older.
In 2002, approximately 800,000 children worldwide became infected with HIV through mother-to-child transmission, with more than 90 percent residing in resource-poor countries. The manufacturer of NVP, Boehringer-Ingelheim, has offered to provide the drug at no cost to developing countries that implement a plan of providing the drug to pregnant, HIV-seropositive women and their infants. Despite the regimen's availability, Dr. Jackson says, obstacles remain to implementing this regimen in resource-poor nations. For example, prenatal HIV testing and counseling are often not available, and child-maternal health care facilities and infrastructure may be weak in many of these countries. "We would love to see these obstacles overcome," says Dr. Jackson, "because it would mean that some several hundred thousand infants would be spared from HIV infection each year." Several nonprofit outreach organizations are now offering anti-HIV drug assistance programs, including NVP treatment for mothers and their infants, in countries such as Kenya, Uganda, Cameroon and Rwanda. In the United States, HIV-infected mothers and their infants are routinely treated with multi-drug antiretroviral regimens.
"This study has clearly demonstrated that meaningful, long-term, complicated and sophisticated studies can be conducted in resource-poor developing countries," said Edmund C. Tramont, M.D., director of NIAID's Division of AIDS.
This study also received support from other NIH components, including the National Institute of Child Health and Human Development; the National Institute on Drug Abuse; and the National Institute of Mental Health.
NIAID is a component of the National Institutes of Health (NIH), which is an agency of the Department of Health and Human Services. NIAID supports basic and applied research to prevent, diagnose and treat infectious and immune-mediated illnesses, including HIV/AIDS and other sexually transmitted diseases, illness from potential agents of bioterrorism, tuberculosis, malaria, autoimmune disorders, asthma and allergies. HIVNET, which stands for the HIV Network for Prevention Trials, is a multi-center, collaborative research network whose mission is to carry out HIV prevention efficacy trials. HIVNET was established in 1993 by NIAID's Division of AIDS and has now been incorporated into the HIV Prevention Trials Network.
Reference: J. Brooks Jackson et al. Intrapartum and neonatal single-dose nevirapine compared with zidovudine for prevention of mother-to-child transmission of HIV-1 in Kampala, Uganda: 18-month follow-up of the HIVNET 012 randomised trial. The Lancet 362(9387):859-67 (2003).
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