Predictors of Perinatal HIV Transmission Among Women Without Prior Antiretroviral Therapy in a Resource-Limited Setting: The Breastfeeding, Antiretrovirals and Nutrition Study.

BACKGROUND: To investigate potential risk factors for perinatal (intrauterine and intrapartum) mother-to-child transmission (MTCT) of HIV in women unexposed to antiretroviral therapy (ART) during pregnancy. METHODS: We compared factors according to perinatal MTCT outcome among 2275 ART-naive (until the onset of labor) HIV-infected women in the Breastfeeding, Antiretrovirals and Nutrition study (2004-2010) in Lilongwe, Malawi. Factors included HIV viral load during pregnancy, food security, demographic characteristics, hematologic and blood chemistry measures, medical history and physical factors. Associations with perinatal MTCT and interactions with maternal viral load were assessed using simple and multivariable logistic regression. RESULTS: There were 119 (115 intrauterine and 4 intrapartum) cases of perinatal MTCT, only one to a mother with <1000 HIV copies/mL. Maternal viral loads >10,000 copies/mL were common (63.1%). Lower maternal viral load (<1000 copies/mL and 1000.1-10,000 copies/mL) was associated with reduced odds of perinatal MTCT [adjusted odds ratio (aOR), 0.1; 95% confidence interval (CI): 0.01-0.4 and aOR, 0.2; 95% CI: 0.1-0.4, respectively), compared with maternal viral load >10,000 copies/mL. Low CD4+ T cell count (≤350 cells/µL) was only associated with perinatal MTCT in unadjusted models. Food shortage (aOR, 1.8; 95% CI: 1.2-2.6), sexually transmitted infection (STI) (past year; aOR, 1.9; 95% CI: 1.0-3.7), histories of herpes zoster (aOR, 3.0; 95% CI: 1.6-5.6) and tuberculosis (aOR, 2.5; 95% CI: 1.1-5.7) were associated with increased odds of perinatal MTCT. CONCLUSIONS: These findings confirm that lowering maternal HIV viral load is most important in preventing perinatal MTCT and support efforts to address food shortage, STI and tuberculosis prevention, while informing programs to improve ART coverage in pregnancy.

The effects of a lipid-based nutrient supplement and antiretroviral therapy in a randomized controlled trial on iron, copper, and zinc in milk from HIV-infected Malawian mothers and associations with maternal and infant biomarkers.

We evaluated effects of antiretroviral (ARV) therapy and lipid-based nutrient supplements (LNSs) on iron, copper, and zinc in milk of exclusively breastfeeding HIV-infected Malawian mothers and their correlations with maternal and infant biomarkers. Human milk and blood at 2, 6, and 24 weeks post-partum and blood during pregnancy (≤30 weeks gestation) were collected from 535 mothers/infant-pairs in the Breastfeeding, Antiretrovirals, and Nutrition study. The participants received ARV, LNS, ARV and LNS, or no intervention from 0 to 28 weeks post-partum. ARVs negatively affected copper and zinc milk concentrations, but only at 2 weeks, whereas LNS had no effect. Among all treatment groups, approximately 80-90% of copper and zinc and <50% of iron concentrations met the current adequate intake for infants at 2 weeks and only 1-19% at 24 weeks. Pregnancy haemoglobin was negatively correlated with milk iron at 2 and 6 weeks (r = -.18, p < .02 for both). The associations of the milk minerals with each other were the strongest correlations observed (r = .11-.47, p < .05 for all); none were found with infant biomarkers. At 2 weeks, moderately anaemic women produced milk higher in iron when ferritin was higher or TfR lower. At 6 weeks, higher maternal α-1-acid glycoprotein and C-reactive protein were associated with higher milk minerals in mildly anaemic women. Infant TfR was lower when milk mineral concentrations were higher at 6 weeks and when mothers were moderately anaemic during pregnancy. ARV affects copper and zinc milk concentrations in early lactation, and maternal haemoglobin during pregnancy and lactation could influence the association between milk minerals and maternal and infant iron status and biomarkers of inflammation.

Effect of Postnatal HIV Treatment on Clinical Mastitis and Breast Inflammation in HIV-Infected Breast-feeding Women.

BACKGROUND: The relationship between mastitis and antiretroviral therapy among HIV-positive, breast-feeding women is unclear. METHODS: In the Breastfeeding, Antiretrovirals, and Nutrition (BAN) study, conducted in Lilongwe, Malawi, 2369 mother-infant pairs were randomized to a nutritional supplement group and to one of three treatment groups: maternal antiretroviral therapy (ART), infant nevirapine (NVP) or standard of care for 24 weeks of exclusive breast-feeding and 4 weeks of weaning. Among 1472 HIV-infected women who delivered live infants between 2004 and 2007, we estimated cumulative incidence functions and sub-distribution hazard ratios (HR) of mastitis or breast inflammation comparing women in maternal ART (n = 487) or infant nevirapine (n = 492) groups to the standard of care (n = 493). Nutritional supplement groups (743 took, 729 did not) were also compared. RESULTS: Through 28-weeks post-partum, 102 of 1472 women experienced at least one occurrence of mastitis or breast inflammation. The 28-week risk was higher for maternal ART (risk difference (RD) 4.5, 95% confidence interval (CI) 0.9, 8.1) and infant NVP (RD 3.6, 95% CI 0.3, 6.9) compared to standard of care. The hazard of late-appearing mastitis or breast inflammation (from week 5-28) was also higher for maternal ART (HR 6.7, 95% CI 2.0, 22.6) and infant NVP (HR 5.1, 95% CI 1.5, 17. 5) compared to the standard of care. CONCLUSIONS: Mastitis or breast inflammation while breast-feeding is a possible side effect for women taking prophylactic ART and women whose infants take NVP, warranting additional research in the context of postnatal HIV transmission.

Toxicity of Amphotericin B Deoxycholate-Based Induction Therapy in Patients with HIV-Associated Cryptococcal Meningitis.

Amphotericin B deoxycholate (AmBd) is the recommended induction treatment for HIV-associated cryptococcal meningitis (CM). Its use is hampered by toxicities that include electrolyte abnormalities, nephrotoxicity, and anemia. Protocols to minimize toxicity are applied inconsistently. In a clinical trial cohort of AmBd-based CM induction treatment, a standardized protocol of preemptive hydration and electrolyte supplementation was applied. Changes in blood counts, electrolyte levels, and creatinine levels over 14 days were analyzed in relation to the AmBd dose, treatment duration (short course of 5 to 7 days or standard course of 14 days), addition of flucytosine (5FC), and outcome. In the 368 patients studied, the hemoglobin levels dropped by a mean of 1.5 g/dl (95% confidence interval [CI], 1.0 to 1.9 g/dl) following 7 days of AmBd and by a mean of 2.3 g/dl (95% CI, 1.1 to 3.6 g/dl) after 14 days. Serum creatinine levels increased by 37 µmol/liter (95% CI, 30 to 45 µmol/liter) by day 7 and by 49 µmol/liter (95% CI, 35 to 64µmol/liter) by day 14 of AmBd treatment. Overall, 33% of patients developed grade III/IV anemia, 5.6% developed grade III hypokalemia, 9.5% had creatinine levels that exceeded 220 µmol, and 6% discontinued AmBd prematurely. The addition of 5FC was associated with a slight increase in anemia but not neutropenia. Laboratory abnormalities stabilized or reversed during the second week in patients on short-course induction. Grade III/IV anemia (adjusted odds ratio [aOR], 2.2; 95% CI, 1.1 to 4.3; P = 0.028) and nephrotoxicity (aOR, 4.5; 95% CI, 1.8 to 11; P = 0.001) were risk factors for 10-week mortality. In summary, routine intravenous saline hydration and preemptive electrolyte replacement during AmBd-based induction regimens for HIV-associated CM minimized the incidence of hypokalemia and nephrotoxicity. Anemia remained a concerning adverse effect. The addition of flucytosine was not associated with increased neutropenia. Shorter AmBd courses were less toxic, with rapid reversibility.

Plasma Micronutrient Concentrations Are Altered by Antiretroviral Therapy and Lipid-Based Nutrient Supplements in Lactating HIV-Infected Malawian Women.

BACKGROUND: Little is known about the influence of antiretroviral therapy with or without micronutrient supplementation on the micronutrient concentrations of HIV-infected lactating women in resource-constrained settings. OBJECTIVE: We examined associations of highly active antiretroviral therapy (HAART) and lipid-based nutrient supplements (LNS) with concentrations of selected micronutrients in HIV-infected Malawian women at 24 wk postpartum. METHODS: Plasma micronutrient concentrations were measured in a subsample (n = 690) of Breastfeeding, Antiretrovirals, and Nutrition (BAN) study participants who were randomly assigned at delivery to receive HAART, LNS, HAART+LNS, or no HAART/no LNS (control). HAART consisted of protease inhibitor-based triple therapy. LNS (140 g/d) met energy and micronutrient requirements of lactation. Multivariable linear regression tested the association of HAART and LNS, plus their interaction, with micronutrient concentrations, controlling for season, baseline viral load, and baseline CD4 count. RESULTS: We found significant HAART by LNS interactions for folate (P = 0.051), vitamin B-12 (P < 0.001), and transferrin receptors (TfRs) (P = 0.085). HAART was associated with lower folate (with LNS: -27%, P < 0.001; without LNS: -12%, P = 0.040) and higher TfR concentrations (with LNS: +14%, P = 0.004; without LNS: +28%, P < 0.001), indicating iron deficiency. LNS increased folate (with HAART: +17%, P = 0.037; without HAART: +39%, P < 0.001) and decreased TfR concentrations (with HAART only: -12%, P = 0.023). HAART was associated with lower vitamin B-12 concentrations only when LNS was present (-18%, P = 0.001), whereas LNS increased vitamin B-12 only when no HAART was present (+27%, P < 0.001). HAART, but not LNS, was associated with higher retinol-binding protein (RBP; +10%, P = 0.007). We detected no association of HAART or LNS with selenium, ferritin, or hemoglobin. CONCLUSION: The association of HAART with lower folate, iron deficiency, and higher RBP plus the attenuation of LNS effects on folate and vitamin B-12 when combined with HAART has implications for the health of lactating HIV-infected women taking HAART in prevention of mother-to-child transmission programs. This trial was registered at clinicaltrials.gov as NCT00164736.

Antiretroviral Treatment Is Associated With Iron Deficiency in HIV-Infected Malawian Women That Is Mitigated With Supplementation, but Is Not Associated With Infant Iron Deficiency During 24 Weeks of Exclusive Breastfeeding.

OBJECTIVE: In resource-limited settings without safe alternatives to breastfeeding, the WHO recommends exclusive breastfeeding and antiretroviral (ARV) prophylaxis. Given the high prevalence of anemia among HIV-infected women, mothers and their infants (through fetal iron accretion) may be at risk of iron deficiency. We assessed the effects of maternal micronutrient-fortified lipid-based nutrient supplements (LNS) and maternal ARV treatment or infant ARV prophylaxis on maternal and infant iron status during exclusive breastfeeding from birth to 24 weeks. METHODS: The Breastfeeding, Antiretrovirals, and Nutrition study was a randomized controlled trial conducted in Lilongwe, Malawi, from 2004 to 2010. HIV-infected mothers (CD4 >200 cells/µL) and their infants were randomly assigned to 28-week interventions: maternal LNS/maternal ARV (n = 424), maternal LNS/infant ARV (n = 426), maternal LNS (n = 334), maternal ARV (n = 425), infant ARV (n = 426), or control (n = 334). Longitudinal models tested intervention effects on hemoglobin (Hb). In a subsample (n = 537) with multiple iron indicators, intervention effects on Hb, transferrin receptors (TfR), and ferritin were tested with linear and Poisson regression. RESULTS: In longitudinal models, LNS effects on maternal and infant Hb were minimal. In subsample mothers, maternal ARVs were associated with tissue iron depletion (TfR >8.3 mg/L) (risk ratio: 3.1, P < 0.01), but not in ARV-treated mothers receiving LNS (P = 0.17). LNS without ARVs was not associated with iron deficiency or anemia (P > 0.1). In subsample infants, interventions were not associated with impaired iron status (all P > 0.1). CONCLUSIONS: Maternal ARV treatment with protease inhibitors is associated with maternal tissue iron depletion; but LNS mitigates adverse effects. ARVs do not seem to influence infant iron status; however, extended use needs to be evaluated.

Reducing lost to follow-up in a large clinical trial of prevention of mother-to-child transmission of HIV: the Breastfeeding, Antiretrovirals and Nutrition study experience.

BACKGROUND/AIMS: Retaining patients in prevention of mother-to-child transmission of HIV studies can be challenging in resource-limited settings, where high lost to follow-up rates have been reported. In this article, we describe the effectiveness of methods used to encourage retention in the Breastfeeding, Antiretrovirals, and Nutrition study and analyze factors associated with lost to follow-up in the study. METHODS: The Breastfeeding, Antiretrovirals, and Nutrition clinical trial was designed to evaluate the efficacy of three different mother-to-child HIV transmission prevention strategies. Lower than expected participant retention prompted enhanced efforts to reduce lost to follow-up during the conduct of the trial. Following study completion, we employed regression modeling to determine predictors of perfect attendance and variables associated with being lost to follow-up. RESULTS: During the study, intensive tracing efforts were initiated after the first 1686 mother-infant pairs had been enrolled, and 327 pairs were missing. Of these pairs, 60 were located and had complete data obtained. Among the 683 participants enrolling after initiation of intensive tracing efforts, the lost to follow-up rate was 3.4%. At study's end, 290 (12.2%) of the 2369 mother-infant pairs were lost to follow-up. Among successfully traced missing pairs, relocation was common and three were deceased. Log-binomial regression modeling revealed higher maternal hemoglobin and older maternal age to be significant predictors of perfect attendance. These factors and the presence of food insecurity were also significantly associated with lower rates of lost to follow-up. CONCLUSION: In this large HIV prevention trial, intensive tracing efforts centered on reaching study participants at their homes succeeded in finding a substantial proportion of lost to follow-up participants and were very effective in preventing further lost to follow-up during the remainder of the trial. The association between food insecurity and lower rates of lost to follow-up is likely related to the study's provision of nutritional support, including a family maize supplement, which may have contributed to patient retention.

Evaluating the benefits of incorporating traditional birth attendants in HIV prevention of mother to child transmission service delivery in Lilongwe, Malawi.

The objective of our intervention was to examine the benefits of incorporating traditional birth attendants (TBA) in HIV Prevention of Mother to Child Transmission (PMTCT) service delivery. We developed a training curriculum for TBAs related to PMTCT and current TBA roles in Malawi. Fourteen TBAs and seven TBA assistants serving 4 urban health centre catchment areas were assessed, trained and supervised. Focus group discussions with the TBAs were conducted after implementation of the program. From March 2008 to August 2009, a total of 4017 pregnant women visited TBAs, out of which 2133 (53.1%) were directly referred to health facilities and 1,884 (46.9%) women delivered at TBAs and subsequently referred. 168 HIV positive women were identified by TBAs. Of these, 86/168 (51.2%) women received nevirapine and 46/168 (27.4%) HIV exposed infants received nevirapine. The challenges in providing PMTCT services included lack of transportation for referrals and absence of a reporting system to confirm the woman's arrival at the health center. Non-disclosure of HIV status by patients to the TBAs resulted in inability to assist nevirapine uptake. TBAs, when trained and well-supervised, can supplement efforts to provide PMTCT services in communities.

Plasma and breast-milk selenium in HIV-infected Malawian mothers are positively associated with infant selenium status but are not associated with maternal supplementation: results of the Breastfeeding, Antiretrovirals, and Nutrition study.

BACKGROUND: Selenium is found in soils and is essential for human antioxidant defense and immune function. In Malawi, low soil selenium and dietary intakes coupled with low plasma selenium concentrations in HIV infection could have negative consequences for the health of HIV-infected mothers and their exclusively breastfed infants. OBJECTIVE: We tested the effects of lipid-based nutrient supplements (LNS) that contained 1.3 times the Recommended Dietary Allowance of sodium selenite and antiretroviral drugs (ARV) on maternal plasma and breast-milk selenium concentrations. DESIGN: HIV-infected Malawian mothers in the Breastfeeding, Antiretrovirals, and Nutrition study were randomly assigned at delivery to receive: LNS, ARV, LNS and ARV, or a control. In a subsample of 526 mothers and their uninfected infants, we measured plasma and breast-milk selenium concentrations at 2 or 6 (depending on the availability of infant samples) and 24 wk postpartum. RESULTS: Overall, mean (± SD) maternal (range: 81.2 ± 20.4 to 86.2 ± 19.9 µg/L) and infant (55.6 ± 16.3 to 61.0 ± 15.4 µg/L) plasma selenium concentrations increased, whereas breast-milk selenium concentrations declined (14.3 ± 11.5 to 9.8 ± 7.3 µg/L) from 2 or 6 to 24 wk postpartum (all P < 0.001). Compared with the highest baseline selenium tertile, low and middle tertiles were positively associated with a change in maternal plasma or breast-milk selenium from 2 or 6 to 24 wk postpartum (both P < 0.001). With the use of linear regression, we showed that LNS that contained selenium and ARV were not associated with changes in maternal plasma and breast-milk selenium, but maternal selenium concentrations were positively associated with infant plasma selenium at 2 or 6 and 24 wk postpartum (P < 0.001) regardless of the study arm. CONCLUSIONS: Selenite supplementation of HIV-infected Malawian women was not associated with a change in their plasma or breast-milk selenium concentrations. Future research should examine effects of more readily incorporated forms of selenium (ie, selenomethionine) in HIV-infected breastfeeding women.

Changes in soluble transferrin receptor and hemoglobin concentrations in Malawian mothers are associated with those values in their exclusively breastfed, HIV-exposed infants.

Infant iron status at birth is influenced by maternal iron status during pregnancy; however, there are limited data on the extent to which maternal iron status is associated with infant iron status during exclusive breastfeeding. We evaluated how maternal and infant hemoglobin and iron status [soluble transferrin receptors (TfR) and ferritin] were related during exclusive breastfeeding in HIV-infected women and their infants. The Breastfeeding, Antiretrovirals, and Nutrition Study was a randomized controlled trial in Lilongwe, Malawi, in which HIV-infected women were assigned with a 2 × 3 factorial design to a lipid-based nutrient supplement (LNS), or no LNS, and maternal, infant, or no antiretroviral drug, and followed for 24 wk. Longitudinal models were used to relate postpartum maternal hemoglobin (n = 1926) to concurrently measured infant hemoglobin, adjusting for initial infant hemoglobin values. In a subsample, change in infant iron status (hemoglobin, log ferritin, log TfR) between 2 (n = 352) or 6 wk (n = 167) and 24 wk (n = 519) was regressed on corresponding change in the maternal indicator, adjusting for 2 or 6 wk values. A 1 g/L higher maternal hemoglobin at 12, 18, and 24 wk was associated with a 0.06 g/L (P = 0.01), 0.10 g/L (P < 0.001), and 0.06 g/L (P = 0.01), respectively, higher infant hemoglobin. In the subsample, a reduction in maternal log TfR and an increase in hemoglobin from initial measurement to 24 wk were associated with the same pattern in infant values (log TfR ß = -0.18 mg/L, P < 0.001; hemoglobin ß = 0.13 g/L, P = 0.01). Given the observed influence of maternal and initial infant values, optimizing maternal iron status in pregnancy and postpartum is important to protect infant iron status. This trial was registered at clinicaltrials.gov as NCT00164736.

Maternal weight loss during exclusive breastfeeding is associated with reduced weight and length gain in daughters of HIV-infected Malawian women.

Maternal weight loss during exclusive breastfeeding may influence the growth of exclusively breast-fed infants through impaired quality or quantity of breast milk. This study evaluated how maternal weight loss from 2 to 24 wk postpartum was related to infant weight and length gain in 1309 lactating HIV-infected mothers and their exclusively breast-fed infants. Malawian mother-infant pairs in the Breastfeeding, Antiretrovirals, and Nutrition Study were randomized with a 2 × 3 factorial design to a 2-arm nutritional intervention with a lipid-based nutrient supplement (LNS), meeting nutritional needs of lactation, or no LNS and a 3-arm antiretroviral (ARV) intervention (maternal, infant, or no ARV regimen). Linear regression models were used to relate maternal weight loss (weight loss vs. no weight loss) to infant weight and length gain from birth to 24 mo, stratifying by gender and controlling for maternal BMI at 2 wk (mean ± SD: 23.2 ± 3.0 kg/m(2)) and interacting maternal BMI with weight loss. In adjusted models, compared with daughters of women who did not lose weight, length and weight gain were lower in daughters whose mothers had a lower BMI at 2 wk postpartum coupled with the weight loss. For example, among mothers with an initial BMI of 18 kg/m(2), daughters of those who lost weight gained less weight [ß = -0.29 kg (95% CI: -0.53, -0.06)] and length [ß = -0.88 cm (95% CI: -1.52, -0.23)] from birth to 24 wk than daughters of those who gained weight. Though effects were only observed in girls, suggesting possible gender differences in suckling and feeding behavior, these findings indicate that maternal weight loss with low energy reserves represents a risk factor for poor infant growth outcomes.

Lipid-based nutrient supplements are feasible as a breastmilk replacement for HIV-exposed infants from 24 to 48 weeks of age.

The Breastfeeding, Antiretrovirals, and Nutrition (BAN) Study randomized HIV-infected mothers and their infants to receive either maternal lipid-based nutrient supplements (LNS) during lactation or no LNS and then to 1 of 3 antiretroviral drug (ARV) arms (maternal, infant, or no drugs). Assigned interventions were provided from 0 to 28 wk and all infants (n = 1619) were given LNS during (24-28 wk) and following (28-48 wk) weaning. This paper assesses the feasibility of infant LNS as a breastmilk replacement and uses longitudinal random effects models to examine associations of interventions, morbidity, and season with weight-for-age (WAZ), length-for-age (LAZ), and BMI-for-age (BMIZ) Z-scores from 24 to 48 wk. Infant LNS adherence was high (94.1% ate it daily). From 24 to 48 wk, mean WAZ (-0.42 to -0.76 SD; P < 0.001) and LAZ (-0.93 to -1.56 SD; P < 0.001) steadily declined, whereas BMIZ remained >0 throughout. A higher LAZ was associated with assignment to the maternal LNS arm (ß=0.19; P < 0.05). Lower WAZ and BMIZ were associated with seasonal food insecurity (ß=-0.08 and -0.09, respectively; both P < 0.001), fever (ß=-0.07 and -0.13; both P < 0.001), diarrhea (ß=-0.19 and -0.23; both P < 0.001), and assignment to the infant ARV arm (ß=-0.17 and -0.17; both P < 0.05). The magnitude of the season and morbidity effects was small and BAN infants had higher weights and lengths than their counterparts in the general population. High LNS adherence and the modest impact of morbidity on growth indicate that LNS is a feasible breastmilk replacement for HIV-exposed infants weaned early, but controlled trials are needed to quantify the effects of LNS on growth in this population.

Use of lipid-based nutrient supplements by HIV-infected Malawian women during lactation has no effect on infant growth from 0 to 24 weeks.

The Breastfeeding, Antiretrovirals, and Nutrition Study evaluated the effect of daily consumption of lipid-based nutrient supplements (LNS) by 2121 lactating, HIV-infected mothers on the growth of their exclusively breast-fed, HIV-uninfected infants from 0 to 24 wk. The study had a 2 × 3 factorial design. Malawian mothers with CD4(+) ≥250 cells/mm(3), hemoglobin ≥70 g/L, and BMI ≥17 kg/m(2) were randomized within 36 h of delivery to receive either no LNS or 140 g/d of LNS to meet lactation energy and protein needs, and mother-infant pairs were assigned to maternal antiretroviral drugs (ARV), infant ARV, or no ARV. Sex-stratified, longitudinal, random effects models were used to estimate the effect of the 6 study arms on infant weight, length, and BMI. Logistic regression models were used to calculate the odds of growth faltering [decline in weight-for-age Z-score (WAZ) or length-for-age Z-score (LAZ) >0.67] using the control arm as the reference. Although some differences between study arms emerged with increasing infant age in boys, there were no consistent effects of the maternal supplement across the 3 growth outcomes in longitudinal models. At the ages where differences were observed, the effects on weight and BMI were quite small (≤200 g and ≤0.4 kg/m(2)) and unlikely to be of clinical importance. Overall, 21 and 34% of infants faltered in WAZ and LAZ, respectively. Maternal supplementation did not reduce the odds of infant weight or length faltering from 0 to 24 wk in any arm. These results indicate that blanket supplementation of HIV-infected lactating women may have little impact on infant growth.

A lipid-based nutrient supplement mitigates weight loss among HIV-infected women in a factorial randomized trial to prevent mother-to-child transmission during exclusive breastfeeding.

BACKGROUND: Breastfeeding increases metabolic demands on the mother, and excessive postnatal weight loss increases maternal mortality. OBJECTIVE: We evaluated the efficacy of a lipid-based nutrient supplement (LNS) for prevention of excess weight loss in breastfeeding, HIV-infected women. DESIGN: The BAN (Breastfeeding, Antiretrovirals, and Nutrition) Study was a randomized controlled trial in Lilongwe, Malawi. At delivery, HIV-infected mothers and their infants were randomly assigned according to a 2-arm (with and without LNS) by 3-arm (maternal triple-antiretroviral prophylaxis, infant-nevirapine prophylaxis, or neither) factorial design. The 28-wk LNS intervention provided daily energy (700 kcal), protein (20 g), and micronutrients (except for vitamin A) to meet lactation needs. Women were counseled to breastfeed exclusively for 24 wk and to wean by 28 wk. Weight change (0-28 wk) was tested in an intent-to-treat analysis by using 2-factor ANOVA and with longitudinal mixed-effects models. RESULTS: At delivery, the LNS (n = 1184) and control (n = 1185) groups had similar mean weights and BMIs. Women receiving the LNS had less 0-28-wk weight loss (-1.97 compared with -2.56 kg, P = 0.003). This difference remained significant after adjustment for maternal antiretroviral drug therapy and baseline BMI. Women receiving antiretroviral drugs had more weight loss than did those not receiving antiretroviral drugs (-2.93 compared with -1.90 kg, P < 0.001). The benefit of the LNS for reducing weight loss was observed both in those receiving antiretroviral drugs (-2.56 compared with -3.32 kg, P = 0.019) and in those not receiving antiretroviral drugs (-1.63 compared with -2.16 kg, P = 0.034). CONCLUSIONS: The LNS reduced weight loss among HIV-infected, breastfeeding women, both in those taking maternal antiretroviral prophylaxis to prevent postnatal HIV transmission and in those not receiving antiretroviral prophylaxis. Provision of an LNS may benefit HIV-infected, breastfeeding women in resource-limited settings. This trial was registered at clinicaltrials.gov as NCT00164762.

Exploring the feasibility of engaging Traditional Birth Attendants in a prevention of mother to child HIV transmission program in Lilongwe, Malawi.

OBJECTIVE: To investigate the willingness of Traditional Birth Attendants (TBAs) to provide single dose antiretroviral prophylaxis to infants born to mothers with HIV and the feasibility of providing the TBAs with antiretroviral medication. DESIGN: 2 focus groups with a total of 17 registered TBAs. SETTING: Lilongwe, Malawi. METHODS: TBAs were recruited by local health workers and participated in focus groups assessing their attitudes towards participation in a PMTCT program. RESULTS: TBAs were willing to participate in this prevention of mother-to-child HIV transmission (PMTCT) program and helped identify barriers to their participation. CONCLUSIONS: Given appropriate support and training, TBAs' participation in PMTCT programs could be an additional way to deliver medication to mothers and neonates who might otherwise miss crucial doses of medication.

The acceptance and feasibility of replacement feeding at 6 months as an HIV prevention method in Lilongwe, Malawi: results from the BAN study.

International guidelines recommend EBF to age 6 months among HIV-infected mothers choosing to breast-feed and cessation thereafter if replacement feeding is acceptable, feasible, affordable, sustainable, and safe. When mothers wean, they are challenged to provide an adequate replacement diet. This study investigates the use and acceptability of a lipid-based nutrient supplement (LNS) as a breast-milk substitute when provided to infants (6-12 mo) of HIV-positive mothers, as part of the Breast-feeding, Antiretroviral, and Nutrition (BAN) Study. A sub-sample of mothers (n = 45) participated in interviews that explored EBF, weaning, and strategies to feed LNS. Mothers reported several weaning strategies, including gradual reduction of breast-feeding, expressing breast-milk into a cup, and separation of mother and child. LNS, a peanut-based micronutrient fortified paste, was highly accepted and incorporated into the traditional diet. Weaning is a feasible HIV prevention method among this population in Malawi when supported by the provision of LNS as a breast-milk substitute.

Inadequate coordination of maternal and infant HIV services detrimentally affects early infant diagnosis outcomes in Lilongwe, Malawi.

OBJECTIVE: To assess the continuity of care and outcome of pediatric HIV prevention, testing, and treatment services, focusing on early infant diagnosis with DNA polymerase chain reaction (PCR). DESIGN: A retrospective observational cohort. METHODS: Maternal HIV antibody, infant HIV DNA PCR test results, and outcome data from HIV-infected infants from the prevention of mother-to-child transmission, early infant diagnosis, and pediatric HIV treatment programs operating in Lilongwe, Malawi, between 2004 and 2008 were collected, merged, and analyzed. RESULTS: Of the 14,669 pregnant women who tested HIV antibody positive, 7875 infants (53.7%) received HIV DNA PCR testing. One thousand eighty-four infants (13.8%) were HIV infected. Three hundred twenty (29.5%) children enrolled into pediatric HIV care, with 202 (63.1%) at the Baylor Center of Excellence. Among these, antiretroviral therapy was initiated on 110 infants (54.5%) whose median age was 9.1 months (interquartile range, 5.4-13.8) and a median of 2.5 months (interquartile range, 1.4-5.2) after HIV clinic registration. Sixty-nine HIV-infected infants (34.2%) died or were lost by December 2008. Initiation of antiretroviral therapy increased the likelihood of survival 7-fold (odds ratio, 7.1; 95% confidence interval, 3.68 to 13.70). CONCLUSIONS: Separate programs for maternal and infant HIV prevention and care services demonstrated high attrition rates of HIV-exposed and HIV-infected infants, elevated levels of mother-to-child transmission, late infant diagnosis, delayed pediatric antiretroviral therapy initiation, and high HIV-infected infant mortality. Antiretroviral therapy increased HIV-infected infant survival, emphasizing the urgent need for improved service coordination and strategies that increase access to infant HIV diagnosis, improve patient retention, and reduce antiretroviral therapy initiation delays.

Modifications of a large HIV prevention clinical trial to fit changing realities: a case study of the Breastfeeding, Antiretroviral, and Nutrition (BAN) protocol in Lilongwe, Malawi.

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, on-going, randomized breastfeeding intervention trial of HIV-infected 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.

Involving communities in the design of clinical trial protocols: the BAN Study in Lilongwe, Malawi.

OBJECTIVE: To learn the attitudes and concerns of the local community on participating in research, infant feeding practices, and maternal nutrition in order to inform the design of a clinical trial in Lilongwe, Malawi on the safety and efficacy of antiretroviral and nutrition interventions to reduce postnatal transmission of HIV. DESIGN: Formative research methods were used, including semi-structured interviews, focus group discussions, home observations, and taste trials. Data were collected, analyzed, and incorporated into the protocol within 3 months. RESULTS: Participants were supportive of the clinical trial, although their overall understanding of research was limited. Mothers agreed that infants' blood could be drawn by venipuncture, yet concern was raised about the amount of blood proposed to be collected from both infants and mothers. Data demonstrated that rapid breastfeeding cessation would be difficult and malnutrition could be a risk if infants were weaned early. Mothers selected a maternal supplement suitable for use in the clinical trial. CONCLUSIONS: The protocol was rapidly modified to achieve cultural acceptability while maintaining study objectives. Without the formative research, several significant areas would have been undetected and may have jeopardized the implementation of the trial. Additional research was carried out to develop a meaningful informed consent process, the amount of blood collected was reduced to acceptable levels, and the protocol was modified to reduce the risk of malnutrition. Researchers who conduct clinical trials are encouraged to incorporate formative research into their protocol design to ensure participant understanding of the research, to safeguard participants, and to increase feasibility and acceptance of the clinical research in the community.