Mother to Infant Transmission of ART in Utero
Background: As efforts intensify to eliminate perinatal HIV transmission, understanding kinetics of maternal-to-child transfer of antiretrovirals during pregnancy and breastfeeding is critical. Antiretroviral levels in plasma, cord blood, and breastmilk reflect exposure over short intervals. Hair concentrations reflect cumulative exposure and can uniquely quantify in utero transfer of maternal medications to infants. We measured plasma and hair antiretroviral levels in HIV-infected Ugandan mothers and their infants at delivery and during breastfeeding to assess transfer.
Methods: HIV-infected pregnant women were randomized to lopinavir/ritonavir- or efavirenz-based therapy in a larger trial (the Prevention of Malaria and HIV disease in Tororo, PROMOTE). At 0, 8, and 12 weeks postpartum, plasma antiretroviral levels were measured in 117 mother–infant pairs; hair levels were assayed at 12 weeks. Ratios and correlations of infant:maternal concentrations were calculated.
Results: By 12 weeks, 90.4% of mothers reported exclusive breastfeeding. Hair and plasma levels over time suggest moderate (47%) to extensive (87%) in utero transfer of lopinavir and ritonavir, respectively, but negligible transfer of either via breastfeeding. Moderate transfer of efavirenz occurs during pregnancy and breastfeeding (40% cumulative; 15% during breastfeeding). Despite differences in exposure, no infant seroconversions or correlations between infant hair/plasma antiretroviral levels and adverse effects were observed.
Conclusions: Using a unique approach combining hair and plasma data, we found that different antiretrovirals have distinct kinetics of mother-to-infant transfer. Efavirenz transfers during both pregnancy and breastfeeding, whereas lopinavir and ritonavir transfer only in utero. Further study of the degree and timing of maternal-to-child transfer by antiretroviral will help optimize strategies that protect infants and minimize toxicities during periods of risk.
The prevention of HIV transmission during pregnancy and breastfeeding is an urgent priority with the Global Plan for the Elimination of New HIV Infections among Children by 2015 (UNAIDS) report outlining an ambition to halt perinatal HIV transmission worldwide. Significant strides have been made in the resource-rich setting in nearly eliminating perinatal transmission, but more than 330,000 children are newly infected around the globe annually. "Option B" and "Option B+" of the World Health Organization guidelines recommend antepartum and postpartum or lifelong use of triple antiretroviral combinations for HIV-infected women, respectively, to minimize risks of infant infection and maximize maternal benefit, but little is known about the timing and degree of transfer of maternal antiretrovirals to infants during periods of risk. Such information can be used to identify the optimal maternal antiretroviral regimen(s) to maximize infant protection and minimize toxicity during pregnancy and breastfeeding.
Limited studies have examined transplacental and breastmilk transfer of antiretrovirals using surrogate measures of drug exposure or assays that may not reflect long-term exposure in the infant. For instance, antiretroviral concentrations in cord blood reflect maternal exposure over a short time period and do not accurately represent exposure in a newborn already capable of metabolism. Single plasma or urine levels of antiretrovirals in infants at delivery provide only a "snapshot" of recent exposure and do not reflect long-term exposure in utero. Ex vivo human placental perfusion models can only simulate in vivo conditions and do not account for the effects of infant metabolism. Breastmilk concentrations of antiretrovirals similarly do not incorporate the effects of infant absorption and maturing infant metabolism. Finally, single infant plasma levels during breastfeeding represent only recent exposure and can demonstrate significant day-to-day variation. Given the limitations of these standard measures, no study to date has been able to accurately quantify cumulative exposure to antiretrovirals in the infant during pregnancy and breastfeeding.
As a monitoring matrix, neonatal hair is highly effective in quantifying prenatal exposure to medications and other substances ingested by the mother, with feasibility and accuracy advantages over matrices such as cord blood, meconium, or infant plasma. Hair levels reflect drug uptake from the systemic circulation over weeks to months, capturing cumulative exposure to medications. Infant hair growth starts at approximately 10 weeks of gestation and neonatal scalp hair predominantly reflects drug exposure during the third trimester. Infant hair replaces neonatal hair (defined as developing antenatally and in early infancy) at approximately 3 months of life, so that analysis of drug concentrations in baby hair up to 12 weeks of life reflects a combination of drug exposure in utero and cumulative drug exposure from breastfeeding, if present. Plasma levels of maternal drug in breastfeeding infants reflect exposure over the past 1–3 days, so that combining hair and plasma level monitoring in infants out to 12 weeks of age is a unique approach to determine the timing of maternal-to-infant drug transfer both during pregnancy and breastfeeding.
Our group has pioneered the use of small hair samples to monitor antiretroviral adherence and exposure in the HIV treatment and prevention setting. We have developed methods to extract and analyze protease inhibitors and nonnucleoside reverse transcriptase inhibitors from hair. In HIV-infected individuals, we have demonstrated that hair levels of antiretrovirals are the strongest independent predictor of virological success in large cohorts, surpassing single plasma levels and self-reported adherence as predictors of treatment outcome. To determine the degree and timing of transfer of lopinavir/ritonavir (LPV/r) versus efavirenz (EFV) from women to their infants during pregnancy and breastfeeding, we collected plasma and hair samples from mother–infant pairs within a randomized clinical trial of HIV-infected pregnant and breastfeeding women receiving combination antiretroviral therapy in Uganda.
Abstract and Introduction
Abstract
Background: As efforts intensify to eliminate perinatal HIV transmission, understanding kinetics of maternal-to-child transfer of antiretrovirals during pregnancy and breastfeeding is critical. Antiretroviral levels in plasma, cord blood, and breastmilk reflect exposure over short intervals. Hair concentrations reflect cumulative exposure and can uniquely quantify in utero transfer of maternal medications to infants. We measured plasma and hair antiretroviral levels in HIV-infected Ugandan mothers and their infants at delivery and during breastfeeding to assess transfer.
Methods: HIV-infected pregnant women were randomized to lopinavir/ritonavir- or efavirenz-based therapy in a larger trial (the Prevention of Malaria and HIV disease in Tororo, PROMOTE). At 0, 8, and 12 weeks postpartum, plasma antiretroviral levels were measured in 117 mother–infant pairs; hair levels were assayed at 12 weeks. Ratios and correlations of infant:maternal concentrations were calculated.
Results: By 12 weeks, 90.4% of mothers reported exclusive breastfeeding. Hair and plasma levels over time suggest moderate (47%) to extensive (87%) in utero transfer of lopinavir and ritonavir, respectively, but negligible transfer of either via breastfeeding. Moderate transfer of efavirenz occurs during pregnancy and breastfeeding (40% cumulative; 15% during breastfeeding). Despite differences in exposure, no infant seroconversions or correlations between infant hair/plasma antiretroviral levels and adverse effects were observed.
Conclusions: Using a unique approach combining hair and plasma data, we found that different antiretrovirals have distinct kinetics of mother-to-infant transfer. Efavirenz transfers during both pregnancy and breastfeeding, whereas lopinavir and ritonavir transfer only in utero. Further study of the degree and timing of maternal-to-child transfer by antiretroviral will help optimize strategies that protect infants and minimize toxicities during periods of risk.
Introduction
The prevention of HIV transmission during pregnancy and breastfeeding is an urgent priority with the Global Plan for the Elimination of New HIV Infections among Children by 2015 (UNAIDS) report outlining an ambition to halt perinatal HIV transmission worldwide. Significant strides have been made in the resource-rich setting in nearly eliminating perinatal transmission, but more than 330,000 children are newly infected around the globe annually. "Option B" and "Option B+" of the World Health Organization guidelines recommend antepartum and postpartum or lifelong use of triple antiretroviral combinations for HIV-infected women, respectively, to minimize risks of infant infection and maximize maternal benefit, but little is known about the timing and degree of transfer of maternal antiretrovirals to infants during periods of risk. Such information can be used to identify the optimal maternal antiretroviral regimen(s) to maximize infant protection and minimize toxicity during pregnancy and breastfeeding.
Limited studies have examined transplacental and breastmilk transfer of antiretrovirals using surrogate measures of drug exposure or assays that may not reflect long-term exposure in the infant. For instance, antiretroviral concentrations in cord blood reflect maternal exposure over a short time period and do not accurately represent exposure in a newborn already capable of metabolism. Single plasma or urine levels of antiretrovirals in infants at delivery provide only a "snapshot" of recent exposure and do not reflect long-term exposure in utero. Ex vivo human placental perfusion models can only simulate in vivo conditions and do not account for the effects of infant metabolism. Breastmilk concentrations of antiretrovirals similarly do not incorporate the effects of infant absorption and maturing infant metabolism. Finally, single infant plasma levels during breastfeeding represent only recent exposure and can demonstrate significant day-to-day variation. Given the limitations of these standard measures, no study to date has been able to accurately quantify cumulative exposure to antiretrovirals in the infant during pregnancy and breastfeeding.
As a monitoring matrix, neonatal hair is highly effective in quantifying prenatal exposure to medications and other substances ingested by the mother, with feasibility and accuracy advantages over matrices such as cord blood, meconium, or infant plasma. Hair levels reflect drug uptake from the systemic circulation over weeks to months, capturing cumulative exposure to medications. Infant hair growth starts at approximately 10 weeks of gestation and neonatal scalp hair predominantly reflects drug exposure during the third trimester. Infant hair replaces neonatal hair (defined as developing antenatally and in early infancy) at approximately 3 months of life, so that analysis of drug concentrations in baby hair up to 12 weeks of life reflects a combination of drug exposure in utero and cumulative drug exposure from breastfeeding, if present. Plasma levels of maternal drug in breastfeeding infants reflect exposure over the past 1–3 days, so that combining hair and plasma level monitoring in infants out to 12 weeks of age is a unique approach to determine the timing of maternal-to-infant drug transfer both during pregnancy and breastfeeding.
Our group has pioneered the use of small hair samples to monitor antiretroviral adherence and exposure in the HIV treatment and prevention setting. We have developed methods to extract and analyze protease inhibitors and nonnucleoside reverse transcriptase inhibitors from hair. In HIV-infected individuals, we have demonstrated that hair levels of antiretrovirals are the strongest independent predictor of virological success in large cohorts, surpassing single plasma levels and self-reported adherence as predictors of treatment outcome. To determine the degree and timing of transfer of lopinavir/ritonavir (LPV/r) versus efavirenz (EFV) from women to their infants during pregnancy and breastfeeding, we collected plasma and hair samples from mother–infant pairs within a randomized clinical trial of HIV-infected pregnant and breastfeeding women receiving combination antiretroviral therapy in Uganda.
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