July 15, 1999 A joint Uganda-U.S. study has found a highly effective and safe drug regimen for preventing transmission of HIV from an infected mother to her newborn that is more affordable and practical than any other examined to date. Interim results from the study, sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), demonstrate that a single oral dose of the antiretroviral drug nevirapine (NVP) given to an HIV-infected woman in labor and another to her baby within three days of birth reduces the transmission rate by half compared to a similar short course of AZT. If implemented widely in developing countries, this intervention potentially could prevent some 300,000 to 400,000 newborns per year from beginning life infected with HIV.
"This extraordinary finding is the most recent in our efforts to bring an end to AIDS, not only in the United States but in countries around the world," says Health and Human Services Secretary Donna E. Shalala. "American scientists along with our international partners are committed to developing treatments that not only work, but that are also feasible in other health care settings. These results achieve both those goals."
"This study represents the most promising advance to date toward the goal of finding strategies that can be used worldwide to prevent the spread of HIV from infected mothers to their infants," says NIAID Director Anthony S. Fauci, M.D. NIAID is a component of the National Institutes of Health.
In an announcement from Kampala this morning, Ugandan officials hailed the finding. "This research provides real hope that we may be able to protect many of Africa's next generation from the ravages of AIDS," says Crispus Kiyonga, M.B.Ch.B., Uganda's Minister of Health. "We commend the collaborative effort of our country's scientists, led by Professor Francis Mmiro from Makerere University Faculty of Medicine, and their U.S. colleagues, led by Dr. Brooks Jackson from The Johns Hopkins University School of Medicine."
Finding affordable interventions for developing countries is key to curtailing the global AIDS epidemic. In parts of the hardest-hit area, sub-Saharan Africa, up to 30 percent of pregnant women are infected with HIV, and 25 to 35 percent of their infants will be born infected. The UNAIDS estimates that approximately 1,800 HIV-infected babies are born every day in developing countries.
Unfortunately, the standard AZT regimen used to prevent perinatal HIV transmission in the United States is too expensive and impractical for widespread use in developing countries where many women may not receive prenatal care.
Based on average U.S. wholesale costs, the cost of the drug used in the nevirapine regimen in the current study is approximately 200 times cheaper than the long-course AZT used in the United States, and almost 70 times cheaper than a short course of AZT given to the mother during the last month of pregnancy - a regimen tested in Thailand by the Centers for Disease Control and Prevention and reported effective in 1998.
The Uganda study investigators, part of the NIAID-supported HIV Prevention Trials Network (HIVNET), opened the trial two years ago at Mulago Hospital, affiliated with Makerere University, in Kampala, Uganda. They completed enrollment last April. All women entered into the study were in their ninth month of pregnancy. None had taken antiretroviral drugs while pregnant.
The study, known as HIVNET 012, compared the safety and efficacy of two different short-course regimens of antiviral drugs administered late in pregnancy. The women were assigned at random to receive either a 200-mg dose of oral nevirapine at the onset of labor, followed by a 2-mg/kg oral dose given to their babies within three days of birth; or a 600-mg dose of AZT at the onset of labor, and 300-mg doses every three hours thereafter during labor. The infants born to mothers in the AZT group received 4 mg/kg given twice daily for the first week of life. Both drugs appeared to be safe and well-tolerated.
Study design, data collection and analysis was provided by a team of researchers led by Dr. Thomas Fleming, a biostatistican at the Fred Hutchinson Cancer Research Center and the University of Washington School of Public Health and Community medicine in Seattle.
For the interim analysis, the study team looked at data from 618 mothers (308 receiving AZT and 310 receiving nevirapine) and their infants.
Nevirapine was markedly more effective. At 14 to 16 weeks of age, 13.1 percent of infants who received nevirapine were infected with HIV, compared with 25.1 percent of those in the AZT group.
"In this study, the short-course nevirapine regimen resulted in a 47 percent reduction in mother-to-infant HIV transmission compared with a short course of AZT. The implications of this study for developing countries, where 95 percent of the AIDS epidemic is occurring, are profound," says Brooks Jackson, M.D., the lead U.S. investigator on the trial.
Long-term follow-up of both the mothers and their babies remains a high priority to assess any late drug toxicities as well as long-term survival. The mothers and their children will continue to be actively followed until the babies are 18 months old. This period is critical to establish the efficacy of the intervention because even if a baby is born HIV-free, he or she may acquire the virus during breastfeeding. The data analyzed so far cover only the first three months of the newborn's life. Ugandan and U.S. investigators will soon launch a follow-up study to evaluate the efficacy of nevirapine administered to the mother during labor and to the newborns for a longer period of time.
Breastfeeding is practiced widely in developing countries. Most studies indicate that the rate of HIV transmission via breastfeeding is highest in the first few months of life. No intervention has yet been shown to prevent HIV transmission through breast milk other than not breastfeeding.
The single-dose nevirapine regimen to mother and infant substantially lowers the cost barrier that has kept many countries from adopting drug strategies that prevent perinatal HIV transmission. Still, access to other health care services required to implement this regimen, such as counseling and voluntary HIV testing, are beyond available resources of many developing countries. But if further research upholds nevirapine's good safety record, the investigators say that potentially all pregnant women who live in areas of high HIV prevalence could receive the drug during labor, even in the absence of an established HIV diagnosis.
In the United States and other industrialized countries, many HIV-infected pregnant women already take combination drug regimens that include AZT. A study now being conducted in the United States and Europe is evaluating if adding nevirapine to standard treatment regimens will have any extra benefit in preventing perinatal HIV transmission in these countries. For pregnant women who do not know their HIV status until they begin labor, the nevirapine regimen provides a last-minute prevention option.
Nevirapine, developed by Boehringer Ingelheim Pharmaceuticals, is a non-nucleoside reverse transcriptase inhibitor, and is in a different class of antiviral drugs than AZT but works against the same HIV target enzyme that is critical for the virus to infect new cells. It can be easily stored at room temperature. Besides being inexpensive and potent, nevirapine is rapidly absorbed and transferred across the placenta to the infant, and it breaks down slowly. For these reasons, it was thought that even a single dose to the mother and infant might provide enough protection to the baby during the time of exposure to HIV at birth. In March 1996, nevirapine was licensed in the United States for treatment of HIV infection in adults. AZT, made by Glaxo Wellcome, was first approved in the United States to treat AIDS in 1987. In August 1994, AZT received an additional indication for use in preventing perinatal HIV transmission.
NIAID is a component of the National Institutes of Health (NIH). NIAID conducts and supports research to prevent, diagnose and treat illnesses such as HIV disease and other sexually transmitted diseases, tuberculosis, malaria, asthma and allergies. NIH is an agency of the U.S. Department of Health and Human Services.
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