Background We evaluated the efficacy of a maternal triple-drug antiretroviral regimen or infant nevirapine prophylaxis for 28 weeks during breast-feeding to reduce postnatal transmission of human immunodeficiency virus type 1 (HIV-1) in Malawi. Methods We randomly assigned 2369 HIV-1–positive, breast-feeding mothers with a CD4+ lymphocyte count of at least 250 cells per cubic millimeter and their infants to receive a maternal antiretroviral regimen, infant nevirapine, or no extended postnatal antiretroviral regimen (control group). All mothers and infants received perinatal prophylaxis with single-dose nevirapine and 1 week of zidovudine plus lamivudine. We used the Kaplan–Meier method to estimate the cumulative risk of HIV-1 transmission or death by 28 weeks among infants who were HIV-1–negative 2 weeks after birth. Rates were compared with the use of the log-rank test. Results Among mother–infant pairs, 5.0% of infants were HIV-1–positive at 2 weeks of life. The estimated risk of HIV-1 transmission between 2 and 28 weeks was higher in the control group (5.7%) than in either the maternal-regimen group (2.9%, P = 0.009) or the infant-regimen group (1.7%, P<0.001). The estimated risk of infant HIV-1 infection or death between 2 and 28 weeks was 7.0% in the control group, 4.1% in the maternal-regimen group (P = 0.02), and 2.6% in the infant-regimen group (P<0.001). The proportion of women with neutropenia was higher among those receiving the antiretroviral regimen (6.2%) than among those in either the nevirapine group (2.6%) or the control group (2.3%). Among infants receiving nevirapine, 1.9% had a hypersensitivity reaction. Conclusions The use of either a maternal antiretroviral regimen or infant nevirapine for 28 weeks was effective in reducing HIV-1 transmission during breast-feeding. (ClinicalTrials.gov number, NCT00164736.)

P regnancy-induced hypertension (PIH) or pregnancyaggravated hypertension (PAH) occurs in B7% of pregnant women, but whether medical treatment for mildto-moderate gestational hypertension is necessary is controversial. Knowledge of the long-term effects of prenatal exposure to antihypertensive medications is necessary so that risks to the infant can be weighed against benefits to the mother. This historical cohort study examined the functional development of children whose mothers were treated with labetalol or methyldopa or received no antihypertensive medication (bed rest only) for mildto-moderate gestational hypertension.The children studied were born at 12 Dutch hospitals (7 teaching hospitals, 5 general hospitals) whose mothers agreed to participate in the study. The mothers of these children had received prenatally either labetalol or methyldopa, or were treated only with bed rest for gestational hypertension. Functional development was measured at ages 4 to 10 year using standard tests that assessed IQ, concentration, memory, motor development, and behavior. Linear regression and the Pearson w 2 tests were used to compare the 3 groups.A total of 4000 hospital records were reviewed, from which data on 355 mother-child pairs were extracted; 99 were treated with labetalol, 101 with methyldopa, and 155 with bed rest. Of these 355 women, 275 agreed to allow their children to participate. Ultimately, 203 children met eligibility criteria, and 202 underwent testing. Pregnancy characteristics were determined from the patients' hospital records. Compared with the medication groups, the bedrest only patients had a later onset of hypertension, more often had PIH rather than PAH, and were less likely to receive any other drugs for their disorder. Nearly 20% of women in the labetalol and methyldopa groups received phenobarbital during the pregnancy. Infants in the bed-rest group were less likely than those in the medication groups to be born very preterm, but were more likely to be small for gestational age. The groups did not differ significantly for modes of delivery and the presence of other pregnancy complications. Treatment in the methyldopa group began earlier in the pregnancy compared to women in the labetalol group, and women receiving methyldopa more frequently received other medical treatments for PIH/PAH.There was a trend towards better gross motor development for children in the labetalol and bed-rest groups compared to youngsters in the methyldopa group, but this was not statistically significant. More children in the labetalol group had attention deficit hyperactivity disorder compared to children whose mothers received methyldopa or were only on bed rest during the pregnancy. Children in the methyldopa group were more likely to have sleeping problems as reported by their parents than children in the labetalol or bed-rest groups. Other aspects of functional development were not found to differ among the three groups.In this historical cohort study, prenatal exposure to labetalol was associated with an inc...

Summary Background In resource-limited settings where no safe alternative to breastfeeding exists, WHO recommends that antiretroviral prophylaxis be given to either HIV-infected mothers or infants throughout breastfeeding. We assessed the effect of 28 weeks of maternal or infant antiretroviral prophylaxis on postnatal HIV infection at 48 weeks. Methods The Breastfeeding, Antiretrovirals, and Nutrition (BAN) Study was undertaken in Lilongwe, Malawi, between April 21, 2004, and Jan 28, 2010. 2369 HIV-infected breastfeeding mothers with a CD4 count of 250 cells per μL or more and their newborn babies were randomly assigned with a variable-block design to one of three, 28-week regimens: maternal triple antiretroviral (n=849); daily infant nevirapine (n=852); or control (n=668). Patients and local clinical staff were not masked to treatment allocation, but other study investigators were. All mothers and infants received one dose of nevirapine (mother 200 mg; infant 2 mg/kg) and 7 days of zidovudine (mother 300 mg; infants 2 mg/kg) and lamivudine (mothers 150 mg; infants 4 mg/kg) twice a day. Mothers were advised to wean between 24 weeks and 28 weeks after birth. The primary endpoint was HIV infection by 48 weeks in infants who were not infected at 2 weeks and in all infants randomly assigned with censoring at loss to follow-up. This trial is registered with ClinicalTrials.gov, number NCT00164736. Findings 676 mother–infant pairs completed follow-up to 48 weeks or reached an endpoint in the maternal-antiretroviral group, 680 in the infant-nevirapine group, and 542 in the control group. By 32 weeks post partum, 96% of women in the intervention groups and 88% of those in the control group reported no breastfeeding since their 28-week visit. 30 infants in the maternal-antiretroviral group, 25 in the infant-nevirapine group, and 38 in the control group became HIV infected between 2 weeks and 48 weeks of life; 28 (30%) infections occurred after 28 weeks (nine in maternal-antiretroviral, 13 in infant-nevirapine, and six in control groups). The cumulative risk of HIV-1 transmission by 48 weeks was significantly higher in the control group (7%, 95% CI 5–9) than in the maternal-antiretroviral (4%, 3–6; p=0·0273) or the infant-nevirapine (4%, 2–5; p=0·0027) groups. The rate of serious adverse events in infants was significantly higher during 29–48 weeks than during the intervention phase (1·1 [95% CI 1·0–1·2] vs 0·7 [0·7–0·8] per 100 person-weeks; p<0·0001), with increased risk of diarrhoea, malaria, growth faltering, tuberculosis, and death. Nine women died between 2 weeks and 48 weeks post partum (one in maternal-antiretroviral group, two in infant-nevirapine group, six in control group). Interpretation In resource-limited settings where no suitable alternative to breastfeeding is available, antiretroviral prophylaxis given to mothers or infants might decrease HIV transmission. Weaning at 6 months might increase infant morbidity Funding US Centers for Disease Control and Prevention.

In order to evaluate strategies to reduce HIV transmission through breast milk and optimize both maternal and infant health among HIV-infected women and their infants, we designed and implemented a large, randomized clinical trial in Lilongwe, Malawi. The development of protocols for large, randomized clinical trials is a complicated and lengthy process often requiring alterations to the original research design. Many factors lead to delays and changes, including study site-specific priorities, new scientific information becoming available, the involvement of national and international human subject committees and monitoring boards, and alterations in medical practice and guidance at local, national, and international levels. When planning and implementing a clinical study in a resource-limited setting, additional factors must be taken into account, including local customs and program needs, language and socio-cultural barriers, high background rates of malnutrition and endemic diseases, extreme poverty, lack of personnel, and limited infrastructure. Investigators must be prepared to modify the protocol as necessary in order to ensure participant safety and successful implementation of study procedures. This paper describes the process of designing, implementing, and subsequently modifying the Breastfeeding, Antiretrovirals, and Nutrition, (BAN) study, a large, ongoing, randomized breastfeeding intervention trial of HIVinfected women and their infants conducted at a single site in Lilongwe, Malawi. We highlight some of the successes, challenges, and lessons learned at different stages during the conduct of the trial.

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