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Reducing HIV Vertical Transmission Scrutinized

Reducing HIV Vertical Transmission Scrutinized Boston—Although anti-HIV drug regimens have had a profound impact on preventing mother-to-child transmission of HIV, researchers have been grappling with the potential health consequences of a treatment strategy commonly used in resource-poor countries for that purpose. Findings presented here at the 12th Annual Retrovirus Conference provide new evidence regarding some potential risks of this regimen—which consisted of a single dose of nevirapine during labor to the mother and a single dose to the newborn during the first 3 days after delivery—as well as some early evidence showing potential benefits from alternative regimens. Single-dose nevirapine for mothers and their newborn infants has been a cornerstone for reducing mother-to-child transmission in developing countries from about 30% to 13% or less. The regimen is “the little engine that could,” the strategy that provided the momentum to start programs for preventing vertical transmission in developing countries, where it has been offered to some 500 000 women, said James McIntyre, MD, director of the Perinatal HIV Research Unit at the University of the Witwatersrand in Johannesburg, South Africa. Although other treatments that combine antiretroviral drugs have been more effective in other settings, the simplicity and affordability of single-dose nevirapine have made it the most—and often, the only—feasible option for many resource-poor countries. But the practice has become increasingly controversial, particularly in light of recent findings from studies indicating that single-dose nevirapine during pregnancy might compromise a mother’s response to future treatment by promoting drug resistance. In the past 2 years, about 350 000 individuals in poor countries have started treatment with generic combinations of antiretroviral drugs, many of them including nevirapine, a nonnucleoside reverse transcriptase inhibitor. However, nevirapine resistance developing in an HIV-infected woman given the drug during pregnancy might compromise that woman’s response to future treatment with the drug. Drug resistance concerns Drug resistance concerns One of nevirapine’s attributes—a half-life of 21 days—makes it possible for a single dose to provide protection to the newborn at the time of delivery and for a brief time thereafter. But in the absence of other anti-HIV medications, the lingering amounts of nevirapine are insufficient to suppress viral replication, a situation that helps foster the emergence of nevirapine-resistant HIV strains. Drug resistance concerns Indeed, a new study using a more sensitive assay for drug-resistant mutations, revealed that drug-resistant HIV emerges in the majority of women provided intrapartum single-dose nevirapine reported Jeffrey A. Johnson, PhD, of the Centers for Disease Control and Prevention, in Atlanta, and colleagues from the United States and South Africa. The findings underscore “the importance of assessing the clinical implications of resistant variants,” they noted. Drug resistance concerns One possible clinical consequence is a reduction of effectiveness in preventing mother-to-child transmission of HIV when used in a subsequent pregnancy after a woman developed resistance to nevirapine during a first pregnancy. To examine this question, researchers from Johns Hopkins University, in Baltimore, the University of the Witwatersrand, and the National Institute for Communicable Diseases, in Johannesburg, South Africa, launched a study. They enrolled 106 women exposed to single-dose nevirapine in both their first and second pregnancies (2 of whom had evidence of nevirapine resistance before giving birth the second time) and compared them with 212 matched controls only exposed to the regimen in their second pregnancy. Breastfeeding frequency, ascertained up to 10 days postpartum, was about 7% for both groups of mothers; at 6 weeks postpartum, it was about 4% for both groups. Antiretroviral drugs can substantially reduce the risk of mother-to-child HIV transmission. (Photo credit: Alfredo L. Fort/Photoshare) Drug resistance concerns At 6 weeks after birth, 10.8% of infants born to women who had received nevirapine in their first pregnancy tested positive for HIV compared with 3.8% of infants born to women with no previous exposure to the drug, reported Neil Martinson, MBBCh, MPH, of Johns Hopkins University and the University of the Witwatersrand. Despite this difference, he noted, the transmission rate in women who were given nevirapine in both first and second pregnancies was similar to the transmission rates seen in other studies in women in the same population who received nevirapine for the first time. The 2 women who tested positive for nevirapine-resistant virus after their first intrapartum nevirapine treatment did not transmit the infection to their infants. Drug resistance concerns The researchers concluded that the effects of single-dose nevirapine do not appear to compromise its use in a second pregnancy. However, they noted, “numbers of women attending [prevention of mother-to-child transmission] programs for the second or third time are increasing and data are urgently needed to better inform decision making.” Considering combinations Considering combinations Triple-drug therapy with antiretroviral medications has reduced mother-to-child transmission to about 2% in wealthier countries such as the United States, but such regimens are far more costly and complicated than single-dose nevirapine. Concern about the development of nevirapine resistance in either mother or infant resulting from its use as monotherapy, however, is prompting researchers to seek affordable combination therapies for resource-poor countries. Considering combinations In a randomized trial involving nearly 1200 mother-infant pairs at 4 sites in Botswana, researchers compared two regimens. All the women received zidovudine from 34 weeks gestation until delivery and all the newborns received a single dose of nevirapine at birth and zidovudine for the first month of life. In addition, half of the women received single-dose nevirapine during labor. At 1 month, about 6% of the infants were infected, regardless of whether their mothers had received nevirapine. “There was no added benefit in adding a single dose of nevirapine to zidovudine,” said Roger L. Shapiro, MD, MPH, of Beth Israel Deaconess Medical Center, in Boston, suggesting that such a regimen might protect the infant while avoiding nevirapine exposure in the mother. Considering combinations And in a study of 329 pregnant HIV-infected women in Côte d’Ivoire, investigators evaluated another drug regimen that reduced mother-to-child transmission even further. Women were given Combivir, a combination of zidovudine and lamivudine, beginning from 32 weeks of gestation until 3 days after delivery, plus a single dose of nevirapine at the start of labor. Their newborns received zidovudine for 1 week and a single dose of nevirapine on their second day of life. At 6 weeks after delivery, only 4.7% of infants were infected, reported Francois Dabis, MD, of Université Victor Segalen, in Bordeaux, France. Considering combinations Giving the women a short course of triple therapy after delivery—the Combivir plus the lingering effects of the nevirapine—also helped minimize the development of nevirapine resistance mutations in the women. Overall frequency of resistance mutations in the mothers, determined 4 weeks postpartum, was 1.1% for nevirapine and 8.33% for lamivudine. Considering combinations “This is among the lowest [vertical] transmission rates in Africa, the lowest rate of nevirapine resistance when using single-dose nevirapine, and very low adverse effects,” noted Dabis. “This is very promising for low-income countries,” he said. Considering combinations “Some sites with appropriate infrastructure and training, and where national policies permit, are considering implementing this regimen to reduce resistance,” the Elizabeth Glaser Pediatric AIDS Foundation noted in a statement. “In the meantime, we need to provide women with a range of choices to prevent HIV infection in their infants.” Considering combinations The World Health Organization is considering revising its guidelines on nevirapine use in low-income countries, said Dabis. “The idea is to come up with a menu of options as simple and realistic as possible” to decrease mother-to-child transmission, he said, a menu that could include a single-dose nevirapine or a short course of combination therapy to triple-drug combination therapy in settings in which global efforts to expand access to antiretroviral therapy are taking hold. Considering combinations Experts stressed it is essential to keep single-dose nevirapine as an option when other regimens are unavailable. “We need to improve access to better regimens wherever possible,” said McIntyre. For the majority of pregnant women in the developing world who currently have access to nothing, “single-dose nevirapine is a starting point,” he added. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JAMA American Medical Association

Reducing HIV Vertical Transmission Scrutinized

JAMA , Volume 293 (17) – May 4, 2005

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Publisher
American Medical Association
Copyright
Copyright © 2005 American Medical Association. All Rights Reserved.
ISSN
0098-7484
eISSN
1538-3598
DOI
10.1001/jama.293.17.2079
Publisher site
See Article on Publisher Site

Abstract

Boston—Although anti-HIV drug regimens have had a profound impact on preventing mother-to-child transmission of HIV, researchers have been grappling with the potential health consequences of a treatment strategy commonly used in resource-poor countries for that purpose. Findings presented here at the 12th Annual Retrovirus Conference provide new evidence regarding some potential risks of this regimen—which consisted of a single dose of nevirapine during labor to the mother and a single dose to the newborn during the first 3 days after delivery—as well as some early evidence showing potential benefits from alternative regimens. Single-dose nevirapine for mothers and their newborn infants has been a cornerstone for reducing mother-to-child transmission in developing countries from about 30% to 13% or less. The regimen is “the little engine that could,” the strategy that provided the momentum to start programs for preventing vertical transmission in developing countries, where it has been offered to some 500 000 women, said James McIntyre, MD, director of the Perinatal HIV Research Unit at the University of the Witwatersrand in Johannesburg, South Africa. Although other treatments that combine antiretroviral drugs have been more effective in other settings, the simplicity and affordability of single-dose nevirapine have made it the most—and often, the only—feasible option for many resource-poor countries. But the practice has become increasingly controversial, particularly in light of recent findings from studies indicating that single-dose nevirapine during pregnancy might compromise a mother’s response to future treatment by promoting drug resistance. In the past 2 years, about 350 000 individuals in poor countries have started treatment with generic combinations of antiretroviral drugs, many of them including nevirapine, a nonnucleoside reverse transcriptase inhibitor. However, nevirapine resistance developing in an HIV-infected woman given the drug during pregnancy might compromise that woman’s response to future treatment with the drug. Drug resistance concerns Drug resistance concerns One of nevirapine’s attributes—a half-life of 21 days—makes it possible for a single dose to provide protection to the newborn at the time of delivery and for a brief time thereafter. But in the absence of other anti-HIV medications, the lingering amounts of nevirapine are insufficient to suppress viral replication, a situation that helps foster the emergence of nevirapine-resistant HIV strains. Drug resistance concerns Indeed, a new study using a more sensitive assay for drug-resistant mutations, revealed that drug-resistant HIV emerges in the majority of women provided intrapartum single-dose nevirapine reported Jeffrey A. Johnson, PhD, of the Centers for Disease Control and Prevention, in Atlanta, and colleagues from the United States and South Africa. The findings underscore “the importance of assessing the clinical implications of resistant variants,” they noted. Drug resistance concerns One possible clinical consequence is a reduction of effectiveness in preventing mother-to-child transmission of HIV when used in a subsequent pregnancy after a woman developed resistance to nevirapine during a first pregnancy. To examine this question, researchers from Johns Hopkins University, in Baltimore, the University of the Witwatersrand, and the National Institute for Communicable Diseases, in Johannesburg, South Africa, launched a study. They enrolled 106 women exposed to single-dose nevirapine in both their first and second pregnancies (2 of whom had evidence of nevirapine resistance before giving birth the second time) and compared them with 212 matched controls only exposed to the regimen in their second pregnancy. Breastfeeding frequency, ascertained up to 10 days postpartum, was about 7% for both groups of mothers; at 6 weeks postpartum, it was about 4% for both groups. Antiretroviral drugs can substantially reduce the risk of mother-to-child HIV transmission. (Photo credit: Alfredo L. Fort/Photoshare) Drug resistance concerns At 6 weeks after birth, 10.8% of infants born to women who had received nevirapine in their first pregnancy tested positive for HIV compared with 3.8% of infants born to women with no previous exposure to the drug, reported Neil Martinson, MBBCh, MPH, of Johns Hopkins University and the University of the Witwatersrand. Despite this difference, he noted, the transmission rate in women who were given nevirapine in both first and second pregnancies was similar to the transmission rates seen in other studies in women in the same population who received nevirapine for the first time. The 2 women who tested positive for nevirapine-resistant virus after their first intrapartum nevirapine treatment did not transmit the infection to their infants. Drug resistance concerns The researchers concluded that the effects of single-dose nevirapine do not appear to compromise its use in a second pregnancy. However, they noted, “numbers of women attending [prevention of mother-to-child transmission] programs for the second or third time are increasing and data are urgently needed to better inform decision making.” Considering combinations Considering combinations Triple-drug therapy with antiretroviral medications has reduced mother-to-child transmission to about 2% in wealthier countries such as the United States, but such regimens are far more costly and complicated than single-dose nevirapine. Concern about the development of nevirapine resistance in either mother or infant resulting from its use as monotherapy, however, is prompting researchers to seek affordable combination therapies for resource-poor countries. Considering combinations In a randomized trial involving nearly 1200 mother-infant pairs at 4 sites in Botswana, researchers compared two regimens. All the women received zidovudine from 34 weeks gestation until delivery and all the newborns received a single dose of nevirapine at birth and zidovudine for the first month of life. In addition, half of the women received single-dose nevirapine during labor. At 1 month, about 6% of the infants were infected, regardless of whether their mothers had received nevirapine. “There was no added benefit in adding a single dose of nevirapine to zidovudine,” said Roger L. Shapiro, MD, MPH, of Beth Israel Deaconess Medical Center, in Boston, suggesting that such a regimen might protect the infant while avoiding nevirapine exposure in the mother. Considering combinations And in a study of 329 pregnant HIV-infected women in Côte d’Ivoire, investigators evaluated another drug regimen that reduced mother-to-child transmission even further. Women were given Combivir, a combination of zidovudine and lamivudine, beginning from 32 weeks of gestation until 3 days after delivery, plus a single dose of nevirapine at the start of labor. Their newborns received zidovudine for 1 week and a single dose of nevirapine on their second day of life. At 6 weeks after delivery, only 4.7% of infants were infected, reported Francois Dabis, MD, of Université Victor Segalen, in Bordeaux, France. Considering combinations Giving the women a short course of triple therapy after delivery—the Combivir plus the lingering effects of the nevirapine—also helped minimize the development of nevirapine resistance mutations in the women. Overall frequency of resistance mutations in the mothers, determined 4 weeks postpartum, was 1.1% for nevirapine and 8.33% for lamivudine. Considering combinations “This is among the lowest [vertical] transmission rates in Africa, the lowest rate of nevirapine resistance when using single-dose nevirapine, and very low adverse effects,” noted Dabis. “This is very promising for low-income countries,” he said. Considering combinations “Some sites with appropriate infrastructure and training, and where national policies permit, are considering implementing this regimen to reduce resistance,” the Elizabeth Glaser Pediatric AIDS Foundation noted in a statement. “In the meantime, we need to provide women with a range of choices to prevent HIV infection in their infants.” Considering combinations The World Health Organization is considering revising its guidelines on nevirapine use in low-income countries, said Dabis. “The idea is to come up with a menu of options as simple and realistic as possible” to decrease mother-to-child transmission, he said, a menu that could include a single-dose nevirapine or a short course of combination therapy to triple-drug combination therapy in settings in which global efforts to expand access to antiretroviral therapy are taking hold. Considering combinations Experts stressed it is essential to keep single-dose nevirapine as an option when other regimens are unavailable. “We need to improve access to better regimens wherever possible,” said McIntyre. For the majority of pregnant women in the developing world who currently have access to nothing, “single-dose nevirapine is a starting point,” he added.

Journal

JAMAAmerican Medical Association

Published: May 4, 2005

Keywords: hiv,vertical disease transmission,nevirapine,single-dose regimen

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