30 years of research toward an AIDS-free generation
Less than 2 years after the first known case of AIDS came reports of newborn infants with infections like those seen in adults. The NICHD immediately became involved in research to determine the cause and develop treatments to halt this infection in newborns.
What nobody yet knew was that unless a way was found to prevent mother-to-child transmission of HIV, 25% of women with the virus would pass it on to their newborn children.
The early years
The first reports of AIDS in the United States came in 1981. The physicians who treated those cases had no idea what was making their patients sick, much less that it was the beginning of a worldwide epidemic.
The first cases were observed among gay men, but the affected population soon expanded to include heterosexual intravenous drug users, people with hemophilia, and others who received blood transfusions. All seemed to have the same mysterious illness. All were treated for rare diseases that usually did not affect healthy people. They often died soon after entering the hospital.
Something was killing people. Nobody knew what or how—just that it possibly involved sex and it possibly involved blood.
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Finding the Cause and a Treatment
The strange condition was given the name "acquired immune deficiency syndrome"; today, it is known simply as AIDS. It was first reported in infants in December 1982.
The news that newborns could also get this disease only deepened the concern and the mystery. Babies with AIDS often spent their short lives very sick and died before the age of 2 years. New thinking was required. The investigators who reported finding the disease in infants thought it supported the idea that an "infectious agent" caused AIDS.
By early 1984, researchers at NIH and elsewhere had found the "agent." It was a virus, definitively linked to AIDS, and it came to be known as "human immunodeficiency virus," or HIV. A test for the virus was soon developed, and by 1985, NIH researchers had found a compound known as "zidovudine" that prevented HIV from copying itself. Almost immediately, the drug was tested in the clinic. The results were encouraging: People taking this drug got better.
As a result, people could be tested to find out if they were HIV positive, and they could receive an effective treatment.
What Is AIDS?
AIDS is the final stage of an HIV infection. Healthy adults often carry HIV for as many as 10 years before they develop AIDS. When they do, though, they become easy prey for diseases because their immune systems no longer work properly.
This is because HIV attacks the human immune system. This complex system includes a type of cell called a "helper" T cell or CD4+ cell. These cells "learn" to recognize an invader and then destroy it.
HIV specifically attacks CD4+ cells, the very cells mobilizing to get rid of the HIV. When the number of these cells gets too low, a person is vulnerable to infections. When people with HIV get to that point, we call it AIDS.
AIDS has no cure, but a variety of medicines are now available to keep the virus from reproducing. This effectively slows or stops progression of the disease. What was once a 100% fatal infection is now one people can live with for decades.
How Do Infants Get HIV?
The discovery of HIV explained almost nothing about how an infected woman could pass it on to her newborn—or how to prevent it. Yet something had to be done. HIV infection in infants progressed much faster than in adults because infants' immune systems have not matured.
Scientists wondered exactly how infants became infected—whether the baby was infected during birth or before, and whether the infection was transmitted through the mother's blood or other fluids. Researchers were unsure whether infants whose mothers were infected would always get the virus, and if not, why. In addition to being able to be transmitted during pregnancy or the birth process, HIV also appeared to be able to be passed from mother to child through breastfeeding.
In 1985 came the first report of a baby infected with HIV by breastfeeding. The child was delivered by cesarean section to a woman who was not infected with HIV. The mother contracted the virus through a blood transfusion made necessary by delivery complications and was breastfeeding her child. Soon afterward, both the mother and child were infected with the virus. Based on this information, very early in the HIV epidemic, women known to be infected with HIV in the United States were advised not to breastfeed their infants because of the potential added risk of infecting their infant through breast milk.
Beginning to Find Answers
The earliest work to answer the many important questions came when NICHD researchers began the Mothers and Infants Cohort Study in Brooklyn and the Bronx in 1986. The study continued until 1991, and the participants were followed for several years afterward.
This research showed that a child born to a woman infected with HIV who did not breastfeed her infant had about a 25% chance of being infected. Factors that influenced whether the virus was transmitted included:
- The amount of HIV RNA in the mother's blood (called "viral load"), which determines how much virus the child is exposed to.
- The mother's immune cell count. A low CD4+ cell count indicates more advanced HIV disease and usually is associated with a high viral load in the mother's blood and genital fluids.
- The amount of time between rupture of maternal membranes and delivery. This determines the length of time the child is exposed to HIV in the maternal fluids.
- The baby's birth weight, which influences the child's overall health and well-being.
Other factors that led to increased transmission included high frequency of vaginal sex and intravenous cocaine and heroin use after the first trimester.
The NICHD rapidly ramped up domestic and international research into HIV infection in women and children.
With the knowledge that zidovudine was safe and reduced HIV viral replication in adults, scientists began to investigate whether it could prevent transmission of the virus from mother to child.
Researchers funded by the NICHD, the National Institute of Allergy and Infectious Diseases (NIAID), and the French National Institute for AIDS Research, gave zidovudine to HIV-infected mothers-to-be before and during labor, beginning as early as 14 weeks into their pregnancy. Their infants also received the drug for the first six weeks of their lives. The group of mothers and infants who received the drug was compared to a similar group that did not.
Zidovudine reduced the risk of transmission by two-thirds (from 25.5% to 8.3%). The study was so successful that it was stopped early so that the results could be reported and put into practice. This treatment became the standard way to care for pregnant HIV-infected women in the United States. The study's results were published in 1994, and the U.S. Public Health Service (USPHS) immediately put out guidelines for zidovudine use to prevent maternal-child HIV transmission. The next year, USPHS recommended HIV testing and counseling for all pregnant women in the United States. This became the standard in the western world.
The successes seen with zidovudine did not end the search for new and better treatments. As even more anti-HIV drugs became available, combination treatments became possible in the United States and other western countries. Such treatments were very successful. Studies quickly showed that adult patients receiving combination drug regimens initially with two drugs (dual therapy) and then with three drugs (called highly active antiretroviral therapy, or HAART) had dramatic drops in HIV levels. At the same time, their immune cell counts increased, producing equally dramatic improvement in their bodies' ability to fight diseases. HAART soon became the standard treatment in the United States.
Combination drug regimens also began to be used by pregnant HIV-infected women who needed it for their own health. The Women and Infants Transmission Study, conducted by researchers funded by NICHD in collaboration with NIAID and the National Institute of Drug Abuse (NIDA), evaluated the effectiveness of different anti-HIV drug regimens in preventing mother-to-child transmission over time. Over a 10-year period from 1990 through 2000, scientists found that combination anti-HIV drugs, particularly HAART, reduced the likelihood of a woman transmitting the virus to her child significantly more than zidovudine alone, with a risk of transmission of only 1.2% when the mother received HAART during pregnancy. Today in the United States, the use of HAART is recommended for all pregnant HIV-infected women during pregnancy.
Although use of HAART during pregnancy by HIV-infected mothers effectively reduces HIV transmission to less than 2%, there is a continued risk of transmission among women who are not diagnosed with HIV until they arrive in labor or in women whose first contact with a doctor is when they arrive in labor. Many of the remaining HIV infections in children in the United States occur in infants born to these women. With no prenatal care and no previous HIV treatment, how can transmission be stopped? The standard treatment in such cases was to give zidovudine to the infant for six weeks after birth, but could this be improved on?
To answer this question, NICHD researchers started a trial in 2007 that evaluated three anti-HIV therapy regimens given to infants after birth to prevent HIV transmission from mothers who had received no medication prior to delivery. If the mother was identified as HIV-infected during labor, she was given zidovudine then, but most women were not identified as HIV-infected until after delivery.
The newborns were divided into three groups. All three received zidovudine for six weeks. One group also received three doses of nevirapine (two-drug group) and another group had an added two weeks of two drugs (three-drug group). The study showed that giving combination regimens—either two or three drugs—to the infant when the mother had not received drugs during pregnancy reduced the risk of transmission during labor by 50 percent compared to use of zidovudine alone. The two- and three-drug regimens resulted in similar reductions in transmission.
This study provided conclusive evidence that transmission can be prevented even when the mother received no care before labor and delivery. It also showed that even in those cases, combined drug therapies work better to prevent HIV transmission.
An International Strategy
The battle seemed won with the news that HAART effectively reduced HIV transmission to 1.2%. HIV-infected mothers did not need to pass HIV on to their infants if they followed proven strategies—at least in the West, with its excellent medical care and access to resources. However, most new HIV infections were occurring in countries without those advantages.
A 2001 report titled "AIDS—The First 20 Years" recounted the bleak numbers. Roughly 31 million people were infected worldwide and an additional 22 million had already died, leaving 13 million "AIDS orphans" as one result of the epidemic. In 2000 alone, there were 5.3 million new infections, and 600,000 of these were among children 15 years old and younger. Approximately 70% of these infections were in sub-Saharan Africa, where adult infection rates in some areas exceeded 25%. High infection rates were also found in other resource-poor nations in the Caribbean, Southeast Asia, and Eastern Europe.
The high levels of adult infection in these countries were creating an epidemic of mother-infant transmissions. An important part of NICHD's response was forming partnerships with other Institutes and Centers within NIH and with international agencies to pool resources.
It is important to note that women in the studies conducted in the United States and Europe were not breastfeeding. In many developing countries, however, infant formula is neither affordable nor easily available, and clean water is also not available to make the formula safely. Moreover, breastfeeding is especially important in many parts of the world to prevent other common serious infections. If mothers with HIV could not breastfeed, their infants could be left vulnerable to malnutrition and infection. Yet in many places with poor sanitation, feeding with formula rather than breastfeeding can be just as threatening to a baby's well-being as HIV infection—in either case, the result can be early death. Scientists needed to find a way to prevent transmission while allowing breastfeeding.
In the late 1990s, NIH-funded researchers compared a drug called nevirapine with zidovudine in a group of HIV-infected women who breastfed their newborns. NIH-funded researchers gave a dose of nevirapine to one group of women at the beginning of labor and a dose to their newborns within 72 hours of birth. In another group, several doses of zidovudine were given to the mothers during labor, and the newborns received two doses of zidovudine daily for seven days. At the age of 14 to 16 weeks, infants in the nevirapine group had almost halved the risk of transmission compared to the infants in the zidovudine group. This study revealed two dramatic findings. First, a single dose of nevirapine to the mother in labor and to the newborn reduced the risk of transmission by almost 50%. However, the second was that with continued breastfeeding, this effectiveness was reduced by continued HIV transmission through breast milk.
Two Approaches to Preventing Breast Milk Transmission
Researchers evaluated two different ways to prevent HIV transmission through breastfeeding: either giving the anti-HIV drug nevirapine to the infant while breastfeeding or giving three anti-HIV drugs (HAART) to the mother while breastfeeding.
In a study funded by the NICHD and the Centers for Disease Control and Prevention (CDC), researchers compared giving 14 weeks of either extended nevirapine or extended nevirapine plus zidovudine to giving single-dose nevirapine only to the breastfeeding infants of mothers first identified as HIV-infected immediately after the birth. Extended nevirapine and nevirapine plus zidovudine were equally effective, and reduced the risk of breast milk transmission by 67% compared to single-dose nevirapine alone. The extended combination of nevirapine and zidovudine was no more effective than extended nevirapine alone and the combination was associated with more toxicity for the infant.
Further research demonstrated that longer administration of infant nevirapine was safe and superior to giving nevirapine during only the first one to two months of life. In a study of infants born to HIV-infected mothers in Uganda, Tanzania, Zimbabwe, and South Africa, administration of infant nevirapine for six months reduced the risk of breast milk transmission by half compared to administration of infant nevirapine for only six weeks.
In another study funded by the NICHD, CDC, and the World Health Organization (WHO), researchers evaluated an alternative approach. HIV-infected pregnant women who did not require treatment for their own health received either zidovudine during pregnancy plus single-dose nevirapine given during labor and to the newborn (with no further drugs to the infant during breastfeeding). They compared this to giving a HAART regimen to the mother during pregnancy and through six months of breastfeeding. Use of the triple-drug HAART regimen was safe and reduced the risk of transmission by 42% at six months—from 8.4% with zidovudine/single-dose nevirapine to 4.9% with the HAART regimen.
These studies showed that even among breastfeeding mothers in resource-poor countries, maternal-infant HIV transmission can be reduced to less than 5%.
Keeping Mothers Alive and Infants HIV-Free
Based on the results of these NIH-funded studies and other research, it is now clear that it is possible to stop new HIV infections among children and keep their mothers alive. It requires timely access to life-saving anti-HIV drugs for pregnant women living with HIV and their children. These drugs must be available for women's own health, as indicated, or as a prophylaxis to stop HIV transmission during pregnancy, delivery, and breastfeeding.
When anti-HIV drugs are available as prophylaxis, HIV transmission can be reduced to less than 5%. Additionally, preventing new HIV infection among women at increased risk of HIV and meeting the unmet family-planning needs of women living with HIV are important to reduce the need for antiretroviral prophylaxis and treatment.
The WHO has set a goal of virtual elimination of new pediatric HIV infections by 2015 in developing countries. Keys to achieving this goal are early identification of HIV-infected pregnant women, providing therapy to those who require it for their own health, and providing anti-HIV drugs to the infant or the mother for the duration of breastfeeding. An exciting new approach started in Malawi has been to initiate life-long HAART in all pregnant HIV-infected women. This will reduce the risk of a child being born with HIV to less than 5%—and will keep their mothers alive to raise them.
NICHD continues to conduct cutting-edge research to evaluate the safety of these approaches for both the mother and the child and to study how to optimally implement interventions identified by research as effective in preventing mother-to-child transmission.
For More Information
Cooper ER, Charurat M, Mofenson L, et al; Women and Infants' Transmission Study Group. (2002). Combination antiretroviral strategies for the treatment of pregnant HIV-1-infected women and prevention of perinatal HIV-1 transmission. Journal of Acquired Immune Deficiency Syndromes, 29(5), 484-494.
Coovadia HM, Brown ER, Fowler MG, et al., for the HPTN 046 protocol team. (2012). Efficacy and safety of an extended nevirapine regimen in infant children of breastfeeding mothers with HIV-1 infection for prevention of postnatal HIV-1 transmission (HPTN 046): a randomised, double-blind, placebo-controlled trial. Lancet, 379(9812), 221–228.
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Jackson JB, Musoke P, Fleming T, et al. (2003). 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. Lancet, 362(9387), 859-868.
Kumwenda NI, Hoover DR, Mofenson LM, et al. (2008). Extended antiretroviral prophylaxis to reduce breast-milk HIV-1 transmission. New England Journal of Medicine, 359(2), 119-129.
Kesho Bora Study Group, de Vincenzi I. (2011). Triple antiretroviral compared with zidovudine and single-dose nevirapine prophylaxis during pregnancy and breastfeeding for prevention of mother-to-child transmission of HIV-1 (Kesho Bora study): a randomised controlled trial. Lancet Infectious Diseases, 11(3), 171-180.
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NICHD. (2011). 30 Years of Milestones.
Nielsen-Saines K, Watts DH, Veloso VG, et al.; NICHD HPTN 040/PACTG 1043 Protocol Team. (2012). Three postpartum antiretroviral regimens to prevent intrapartum HIV infection. New England Journal of Medicine, 366(25), 2368-2379.
Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission. (2011, September). Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States.
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UNAIDS. (2011). World Aids Day Report 2011. How to get to zero: Faster. Smarter. Better. (PDF - 604 KB)
UNAIDS/World Health Organization. (2011). Countdown to Zero. Global Plan Towards Elimination of New HIV Infections Among Children by 2015 and Keeping Their Mothers Alive: 2011-2015. (PDF - 785 KB) Geneva, Switzerland: Joint United Nations Programme on HIV/AIDS.
World Health Organization. (2012, April). Programmatic update: use of antiretroviral drugs for treating pregnant women and preventing HIV infection in infants. (PDF - 116 KB) Executive Summary. Geneva, Switzerland: Author.