An estimated 430,000 children worldwide became infected with HIV in 2008, mostly through birth or breastfeeding from an HIV-infected mother. Many regions of the world are gaining increased access to complex antiretroviral drug regimens for preventing HIV transmission from a mother to her child. However, these strategies have not yet been directly compared with simpler antiretroviral drug regimens in terms of their safety, efficacy, feasibility and cost-effectiveness.
On January 15, a large, multinational clinical trial began to determine how best to reduce the risk of HIV transmission from infected pregnant women to their babies during pregnancy and breastfeeding while preserving the health of these children and their mothers.
The PROMISE ("Promoting Maternal-Infant Survival Everywhere") study aims to enroll 7,950 HIV-infected women who are pregnant or have recently given birth and 5,950 HIV-exposed infants of these women. The participants will come from as many as 18 countries whose levels of resources range from high to low. The International Maternal Pediatric Adolescent AIDS Clinical Trials network is conducting the study with funding from the National Institute of Allergy and Infectious Diseases and the Eunice Kennedy Shriver National Institute of Child Health and Human Development, both part of the National Institutes of Health. Led by protocol chair Mary Glenn Fowler, M.D., M.P.H., of the Makerere University–Johns Hopkins University Research Collaboration in Kampala, Uganda, the study team expects results in five to six years.
The HIV-infected women eligible to participate in PROMISE do not yet qualify for treatment—that is, their CD4+ T cell count, a measure of immune health, exceeds the level (350 cells per cubic millimeter of blood) at which highly active antiretroviral therapy (HAART) generally is recommended. HAART consists of a potent combination of three or more antiretroviral drugs.
The study addresses four distinct research questions. Most volunteers will participate in multiple components of the study to answer these questions. The first component will examine which of two proven strategies is safer and more effective at preventing mother-to-child HIV transmission before and during delivery: giving HIV-infected pregnant women a three-antiretroviral-drug regimen beginning as early as 14 weeks of gestation, or giving them the antiretroviral drug zidovudine beginning as early as 14 weeks of pregnancy and a single dose of the antiretroviral drug nevirapine during labor. The regimen of zidovudine and nevirapine is the standard of care in many countries for women who do not yet require treatment for their HIV infection. Some 4,400 women will be assigned at random to receive either one of these two interventions.
The second component of the PROMISE study will compare the safety and efficacy of two methods of preventing mother-to-child HIV transmission during breastfeeding. The study team will assign 4,650 mother-infant pairs at random either to receive a daily dose of infant nevirapine or to have the mothers take a three-antiretroviral-drug regimen throughout breastfeeding.
The third component of the PROMISE study will examine the effects of short-term use of a three-antiretroviral-drug regimen during pregnancy and breastfeeding to prevent mother-to-child HIV transmission on the health of HIV-infected mothers who do not yet need treatment. For such women, it remains unclear whether stopping the three-drug regimen after giving birth or ceasing to breastfeed would compromise their health. Although past studies have shown that interrupting treatment with antiretroviral drugs has a negative effect, the conditions in those studies are different enough from the conditions of the PROMISE study to make extrapolating the results difficult, according to the study investigators.
The 4,675 women participating in this third component of PROMISE will be assigned at random either to stop the three-antiretroviral-drug regimen after giving birth or weaning, or to continue the drug regimen indefinitely. The health of these two groups will be compared. In addition, the women who receive the time-limited three-drug regimen will be compared with the women who participated in the first component of PROMISE and did not receive the three-drug regimen, but rather took zidovudine during pregnancy and single-dose nevirapine during labor.
The last component of the PROMISE study involves protecting the health of HIV-exposed but uninfected infants. In resource-limited settings, it is standard to give the antibiotic cotrimoxazole once daily to infants exposed to HIV at birth until the infant has stopped breastfeeding and is known to be HIV-uninfected. While cotrimoxazole prophylaxis improves the survival rate of HIV-infected infants, it is not known whether continuing to administer the drug after weaning similarly would benefit HIV-exposed but uninfected children.
In this fourth component of the PROMISE study, nearly 2,290 HIV-exposed but uninfected, weaned infants under one year old will be assigned at random either to continue receiving cotrimoxazole or to receive a placebo through age 18 months. Neither the mothers of the infants nor the study team will know which infants are in which group. The study will determine whether continuing cotrimoxazole prophylaxis in HIV-exposed, uninfected infants from the time they stop breastfeeding through age 18 months decreases their risk of illness and death without causing side effects or generating bacterial resistance to cotrimoxizole.
Media inquiries can be directed to the NIAID Office of Communications at 301-402-1663, niaid.nih.gov.
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