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1.  Frequent Nevirapine Resistance in Infants Infected by HIV-1 via Breastfeeding while on Nevirapine Prophylaxis: Results of the BAN Study 
AIDS (London, England)  2015;29(16):2131-2138.
Objective
Assess nevirapine (NVP) resistance in infants who became infected in the three arms of the Breastfeeding, Antiretrovirals, and Nutrition (BAN) study: daily infant NVP prophylaxis, triple maternal antiretrovirals (ARV), or no extra intervention for 28 weeks of breastfeeding.
Design
Prospective cohort study.
Methods
The latest available plasma or dried blood spot specimen was tested from infants who became HIV-positive between 3 and 48 weeks of age. Population sequencing was used to detect mutations associated with reverse transcriptase inhibitor resistance. Sequences were obtained from 22/25 transmissions in the infant-NVP arm, 23/30 transmissions in the maternal-ARV arm, and 33/38 transmissions in the control arm.
Results
HIV-infected infants in the infant-NVP arm were significantly more likely to have NVP resistance than infected infants in the other two arms of the trial, especially during breastfeeding through 28 weeks of age (56% in infant-NVP arm vs. 6% in maternal-ARV arm and 11% in control arm, p=0.004). There was a nonsignificant trend suggesting infants with NVP resistance tended to be infected earlier and exposed to NVP while infected for a greater duration than infants without resistance.
Conclusions
Infants on NVP prophylaxis during breastfeeding are at reduced risk of acquiring HIV, but are at increased risk of NVP resistance if they do become infected. These findings point to the need for frequent HIV testing of infants while on NVP prophylaxis, and for availability of antiretroviral regimens excluding NVP for treating infants who become infected while on such a prophylactic regimen.
doi:10.1097/QAD.0000000000000814
PMCID: PMC4715989  PMID: 26186128
antiretroviral; breastfeeding; HIV transmission; nevirapine resistance; PMTCT
2.  Impact of Daily Cotrimoxazole on Clinical Malaria and Asymptomatic Parasitemias in HIV-Exposed, Uninfected Infants 
Cotrimoxazole prophylaxis was associated with reduced malaria incidence among human immunodeficiency virus-exposed, uninfected infants. Cotrimoxazole's protective benefits were more pronounced on asymptomatic infections, potentially affecting the malaria reservoir responsible for transmission. Therefore, cotrimoxazole prophylaxis may have important individual and public health benefits.
Background. Cotrimoxazole preventive therapy (CPT) is recommended for all human immunodeficiency virus (HIV)–exposed infants to avoid opportunistic infections. Cotrimoxazole has antimalarial effects and appears to reduce clinical malaria infections, but the impact on asymptomatic malaria infections is unknown.
Methods. We conducted an observational cohort study using data and dried blood spots (DBSs) from the Breastfeeding, Antiretrovirals and Nutrition study to evaluate the impact of CPT on malaria infection during peak malaria season in Lilongwe, Malawi. We compared malaria incidence 1 year before and after CPT implementation (292 and 682 CPT-unexposed and CPT-exposed infants, respectively), including only infants who remained HIV negative by 36 weeks of age. Malaria was defined as clinical, asymptomatic (using DBSs at 12, 24, and 36 weeks), or a composite outcome of clinical or asymptomatic. Linear and binomial regression with generalized estimating equations were used to estimate the association between CPT and malaria. Differences in characteristics of parasitemias and drug resistance polymorphisms by CPT status were also assessed in the asymptomatic infections.
Results. CPT was associated with a 70% (95% confidence interval, 53%–81%) relative reduction in the risk of asymptomatic infection between 6 and 36 weeks of age. CPT appeared to provide temporary protection against clinical malaria and more sustained protection against asymptomatic infections, with no difference in parasitemia characteristics.
Conclusions. CPT appears to reduce overall malaria infections, with more prolonged impacts on asymptomatic infections. Asymptomatic infections are potentially important reservoirs for malaria transmission. Therefore, CPT prophylaxis may have important individual and public health benefits.
doi:10.1093/cid/civ309
PMCID: PMC4542924  PMID: 25900173
antifolate resistance; cotrimoxazole; HIV; infant; malaria
3.  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 (via 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 2004-2010. HIV-infected mothers (CD4>200 cells/ul) 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 (RR): 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-values>0.1).
Conclusions
Maternal ARV treatment with protease inhibitors is associated with maternal tissue iron depletion; but LNS mitigates adverse effects. ARVs do not appear to influence infant iron status; however, extended use needs to be evaluated.
doi:10.1097/QAI.0000000000000588
PMCID: PMC4506710  PMID: 25723140
4.  Cytomegalovirus IgG Level and Avidity in Breastfeeding Infants of HIV-Infected Mothers in Malawi 
Clinical and Vaccine Immunology : CVI  2015;22(12):1222-1226.
Cytomegalovirus (CMV) infection is common among infants of HIV-infected mothers in resource-limited settings. We examined the prevalence and timing of infant CMV infection during the first year of life using IgG antibody and avidity among HIV-exposed infants in Malawi and correlated the results with the presence of detectable CMV DNA in the blood. The Breastfeeding, Antiretrovirals and Nutrition (BAN) study randomized 2,369 mothers and their infants to maternal antiretrovirals, infant nevirapine, or neither for 28 weeks of breastfeeding, followed by weaning. Stored plasma specimens were tested for CMV IgG and antibody avidity from a random subset of infants who had been previously tested with blood CMV PCR and had available specimens at birth and at 24 and 48 weeks of age. Ninety-four of 127 infants (74.0%) tested at 24 weeks of age had CMV IgG of low or intermediate avidity, signifying primary CMV infections. An additional 22 infants (17.3%) had IgG of high avidity; 19 of them had CMV DNA detected in their blood, indicating infant infections. Taken together, these results show that the estimated prevalence of CMV infection at 24 weeks was 88.9%. By 48 weeks of age, 81.3% of infants had anti-CMV IgG; most of them (70.9%) had IgG of high avidity. The CMV serology and avidity testing, combined with the PCR results, confirmed a high rate of primary CMV infection by 6 months of life among breastfeeding infants of HIV-infected mothers. The CMV PCR in blood detected most, but not all, infant CMV infections.
doi:10.1128/CVI.00460-15
PMCID: PMC4658584  PMID: 26424831
5.  Effect of cytomegalovirus infection on breastfeeding transmission of HIV and on the health of infants born to HIV-infected mothers 
AIDS (London, England)  2015;29(7):831-836.
Background
Cytomegalovirus (CMV) infection can be acquired in utero or postnatally through horizontal transmission and breastfeeding. The effect of postnatal CMV infection on postnatal HIV transmission is unknown.
Methods
The Breastfeeding, Antiretrovirals and Nutrition study, conducted in Malawi, randomized 2369 mothers and their infants to three antiretroviral prophylaxis arms –mother (triple regimen), infant (nevirapine), or neither – for 28 weeks of breastfeeding, followed by weaning. Stored plasma and peripheral blood mononuclear cell specimens were available for 492 infants at 24 weeks and were tested with CMV PCR. Available samples from infants who were CMV PCR-positive at 24 weeks were also tested at birth (N = 242), and from infants PCR-negative at 24 weeks were tested at 48 weeks (N = 96). Cox proportional-hazards models were used to determine if CMV infection was associated with infant morbidity, mortality, or postnatal HIV acquisition.
Results
At 24 weeks of age, CMV DNA was detected in 345/492 infants (70.1%); the estimated congenital CMV infection rate was 2.3%, and the estimated rate of CMV infection at 48 weeks was 78.5%. CMV infection at 24 weeks was associated with subsequent HIV acquisition through breastfeeding or infant death between 24 and 48 weeks of age (hazard ratio 4.27, P = 0.05).
Conclusion
Most breastfed infants of HIV-infected mothers in this resource-limited setting are infected with CMV by 24 weeks of age. Early CMV infection may be a risk factor for subsequent infant HIV infection through breastfeeding, pointing to the need for comprehensive approaches in order to achieve elimination of breastfeeding transmission of HIV.
doi:10.1097/QAD.0000000000000617
PMCID: PMC4493887  PMID: 25985405
breastfeeding; cytomegalovirus; HIV; infant; mother-to-child transmission
6.  Reducing lost to follow-up in a large clinical trial of prevention of mother-to-child transmission of HIV: The Breastfeeding, Antiretrovirals and Nutrition (BAN) study experience 
Clinical trials (London, England)  2014;12(2):156-165.
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 (LTFU) rates have been reported. In this paper, we describe the effectiveness of methods used to encourage retention in the Breastfeeding, Antiretrovirals, and Nutrition (BAN) study and analyze factors associated with LTFU in the study.
Methods
The BAN clinical trial was designed to evaluate the efficacy of 3 different mother-to-child HIV transmission prevention strategies. Lower than expected participant retention prompted enhanced efforts to reduce LTFU during the conduct of the trial. Following study completion, we employed regression modeling to determine predictors of perfect attendance and variables associated with being LTFU.
Results
During the study, intensive tracing efforts were initiated after the first 1686 mother-infant pairs had been enrolled, and 327 pairs were missing. Sixty of these pairs were located and had complete data obtained. Among the 683 participants enrolling after initiation of intensive tracing efforts, the LTFU rate was 3.4%. At study's end, 290 (12.2%) of the 2369 mother-infant pairs were LTFU. 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 LTFU.
Conclusions
In this large HIV prevention trial, intensive tracing efforts centered on reaching study participants at their homes succeeded in finding a substantial proportion of LTFU participants, and were very effective in preventing further LTFU during the remainder of the trial. The association between food insecurity and lower rates of LTFU is likely related to the study's provision of nutritional support, including a family maize supplement, which may have contributed to patient retention.
doi:10.1177/1740774514562031
PMCID: PMC4355163  PMID: 25518956
Antiretroviral therapy; human immunodeficiency virus; lost to follow up; prevention of mother to child transmission; retention; tracing
7.  Adherence to extended postpartum antiretrovirals is associated with decreased breastmilk HIV-1 transmission: Results of the BAN study 
AIDS (London, England)  2014;28(18):2739-2749.
Objective
Estimate association between postpartum antiretroviral adherence and breastmilk HIV-1 transmission
Design
Prospective cohort study
Methods
Mother-infant pairs were randomized after delivery to immediately begin receiving 28 weeks of either triple maternal antiretrovirals (zidovudine, lamivudine, and either nevirapine, nelfinavir, or lopinavir-ritonavir) or daily infant nevirapine as part of the Breastfeeding, Antiretrovirals, and Nutrition study. Associations between postpartum antiretroviral adherence and rate of breastmilk HIV-1 transmission were estimated using Cox models. We measured adherence over four postpartum time intervals using pill count, suspension bottle weight, and maternal self-report. Adherence was categorized and lagged by one interval. Missing adherence measures were multiply imputed. Infant HIV-1 infection was determined by DNA PCR every 2-6 weeks. The primary endpoint was infant HIV-1 infection by 38 weeks of age among infants alive and uninfected at 5 weeks.
Results
Analyses included 1479 mother-infant pairs and 45 transmission events. Using pill count and bottle weight information, 22-40% of mother-infant pairs at any given interval were <90% adherent. Having ≥90% adherence was associated with a 52% (95% CI 3-76%) relative reduction in the rate of breastmilk HIV-1 transmission, compared with having <90% adherence when controlling for study arm, breastfeeding status, and maternal characteristics. Complete case analysis rendered similar results (n=501; relative reduction 59%, 95% CI 6-82%).
Conclusion
Non-adherence to extended postpartum ART regimens in ‘real world’ settings is likely to be higher than that seen in BAN. Identifying mothers with difficulty adhering to antiretrovirals, and developing effective adherence interventions, will help maximize benefits of ARV provision throughout breastfeeding.
doi:10.1097/QAD.0000000000000492
PMCID: PMC4397579  PMID: 25493600
adherence; antiretroviral; breastfeeding; HIV transmission; PMTCT
8.  Health outcomes of HIV-exposed uninfected African infants 
AIDS (London, England)  2013;27(5):749-759.
Objectives
To evaluate severe (grade 3/4) morbidity and mortality in HIV-exposed, uninfected infants.
Design
Secondary data analysis of The Breastfeeding, Antiretrovirals, and Nutrition (BAN) clinical trial.
Methods
BAN randomized 2369 mother–infant pairs to maternal, infant, or no extended antiretroviral prophylaxis during breastfeeding. Morbidity outcomes examined were pneumonia/serious febrile illness, diarrhea/growth faltering, and malaria. Infant death was defined as neonatal (≤ 30 days of life), and postneonatal (31 days to 48 weeks of life). Cox proportional hazards models were used to evaluate the effect of covariates on infant morbidity and mortality.
Results
The rate of pneumonia/serious febrile illness was highest in the first 12 weeks (0.83/100 person-weeks) before rapidly decreasing; rates of all morbidity outcomes increased after 24 weeks. Rates of pneumonia/serious febrile illness and diarrhea/growth faltering were higher during the rainy season. Prophylactic infant cotrimoxazole significantly decreased the rates of all morbidity outcomes. White blood cell (WBC) count less than 9000/μl at birth was associated with increased diarrhea/growth faltering [adjusted hazard ratio (aHR) 1.73, P = 0.04] and malaria (aHR 2.18, P = 0.02). Low birth weight (2000–2499 g) was associated with neonatal death (aHR 12.3, P <0.001). Factors associated with postneonatal death included rainy season (aHR 4.24, P = 0.002), infant cotrimoxazole (aHR 0.48, P = 0.03), and low infant WBC count at birth (aHR 2.53, P = 0.02).
Conclusion
Infant morbidity rates increased after 24 weeks, when BAN infants weaned. Introduction of prophylactic cotrimoxazole was associated with reduced rates of morbidity and mortality in HIV-exposed uninfected infants. Unexpectedly, a low WBC count at birth was significantly associated with later infant morbidity and mortality in this cohort.
doi:10.1097/QAD.0b013e32835ca29f
PMCID: PMC4493890  PMID: 23719347
Africa; HIV; HIV-exposed; infant; morbidity; mortality; pediatric
9.  Hepatitis B virus infection among HIV-infected pregnant women in Malawi and transmission to infants 
Journal of hepatology  2013;60(3):508-514.
Background & Aims
The extent of HBV infection to infants of HBV/HIV-coinfected pregnant women in sub-Saharan Africa is unknown. The aim of this study was to assess prevalence of HBV infection among antiretroviral-naïve, HIV-infected pregnant women in Malawi and examine HBV transmission to their infants.
Methods
Plasma from 2048 HIV-infected, Malawian women and their infants were tested for markers of HBV infection. Study participants were provided standard-of-care health services, which included administration of pentavalent vaccine to infants at 6, 10, and 14 weeks of age.
Results
One-hundred and three women (5%) were HBsAg-positive; 70 of these HBsAg-positive women were also HBV-DNA-positive. Sixteen women (0.8%) were HBV-DNA-positive but HBsAg-negative. Five of 51 infants (9.8%) born to HBsAg-positive and/or HBV-DNA-positive women were HBV-DNA-positive by 48 weeks of age. HBV DNA concentrations of two infants of mothers who received extended lamivudine-containing anti-HIV prophylaxis were <4 log10 IU/ml compared to ≥8 log10 IU/ml in three infants of mothers who did not.
Conclusions
HBV DNA was detected in nearly 10% of infants born to HBV/HIV-coinfected women. Antenatal testing for HIV and HBV, if instituted, can facilitate implementation of prophylactic measures against infant infection by both viruses. Published by Elsevier B.V. on behalf of the European Association for the Study of the Liver.
doi:10.1016/j.jhep.2013.10.029
PMCID: PMC4411040  PMID: 24211737
Hepatitis; HIV; Mother-to-child transmission; Sub-Saharan Africa; Antiviral therapy
10.  Antiretroviral pharmacokinetics in mothers and breastfeeding infants from 6 to 24 weeks post partum: results of the BAN Study 
Antiviral therapy  2014;19(6):587-595.
Background
An intensive, prospective, open-label pharmacokinetic (PK) study in a subset of HIV-infected mothers and their uninfected infants enrolled in the Breastfeeding, Antiretroviral, and Nutrition study was performed to describe drug exposure and antiviral response.
Methods
Women using Combivir®[zidovudine (ZDV)+ lamivudine (3TC)]+Aluvia®[lopinavir/ritonavir(LPV/RTV)] were enrolled. Breast milk (BM) and mother and infant plasma (MP, IP) samples were obtained over 6hrs after observed dosing at 6, 12, or 24wks post-partum for drug concentrations and HIV RNA.
Results
30 mother/infant pairs (10 each at 6, 12,and 24wks post-partum) were enrolled. Relative to MP, BM concentrations of ZDV and 3TC were 35% and 21% higher, while LPV and RTV were 80% lower. Only 3TC was detected in IP with concentrations 96% and 98% lower than MP and BM, respectively. Concentrations in all matrices were similar at 6-24wks. The majority (98.3%) of BM concentrations were >HIVwt IC50, with one having detectable virus. There was no association between PK parameters and MP or BM HIV RNA.
Conclusions
ZDV and 3TC concentrated in BM while LPV and RTV did not, possibly due to protein binding and drug transporter affinity. Undetectable to low ARV concentrations in IP suggests prevention of transmission while breast feeding may be due to ARV effects on systemic or BM HIV RNA in the mother. Low IP 3TC exposure may predispose an infected infant to HIV resistance, necessitating testing and treating infants early.
doi:10.3851/IMP2739
PMCID: PMC4110187  PMID: 24464632
11.  Role of Intestinal Mucosal Integrity in HIV Transmission to Infants Through Breast-feeding: The BAN Study 
The Journal of Infectious Diseases  2013;208(4):653-661.
Background. Increased intestinal permeability may be one of the mechanisms of transmission of human immunodeficiency virus (HIV) to infants through breast-feeding. Intestinal permeability correlates with microbial translocation, which can be measured through quantification of bacterial lipopolysaccharide (LPS).
Methods. We evaluated levels of plasma LPS (by the Limulus amebocyte lysate assay) and immune activation markers in serial specimens from infants exposed to but uninfected with HIV and infants infected with HIV from the Breastfeeding, Antiretrovirals, and Nutrition (BAN) study.
Results. Plasma LPS levels increased after infants in the BAN study were weaned from the breast, at 24 weeks of age. Cotrimoxazole prophylaxis was associated with higher plasma LPS levels (P = .004). Infants with HIV infection had higher LPS levels, compared with uninfected infants (P = .004). Higher preinfection plasma LPS levels were a significant predictor of infant HIV infection through breast-feeding (hazard ratio = 1.60 for every unit increase in plasma LPS level; P = .01) and of lower infant length-for-age z scores (P = .02).
Conclusions. These findings suggest that disruption in intestinal integrity is a mechanism of HIV transmission to infants through breast-feeding. Weaning from breast milk and use of antibiotic prophylaxis was associated with increased levels of microbial translocation, which could facilitate HIV entry through the intestine. Complementary approaches to enhance intestinal mucosal integrity in the infant may further reduce breast-feeding transmission of HIV.
doi:10.1093/infdis/jit221
PMCID: PMC3719904  PMID: 23687226
HIV; infant; breast-feeding; microbial translocation; immune activation; intestinal permeability
13.  The Health of HIV-exposed Children after Early Weaning 
Maternal & child nutrition  2011;9(2):217-232.
There are potential health risks associated with the use of early weaning to prevent mother-to-child transmission of HIV in resource-poor settings. Our objective was to examine growth and nutrient inadequacies among a cohort of children weaned early. Children participating in the Breastfeeding Antiretrovirals and Nutrition (BAN) Study in Lilongwe, Malawi, had HIV-infected mothers, were weaned at 6 months and fed LNS until 12 months. 40 HIV-negative, BAN-exited children were compared to 40 HIV-negative, community children matched on age, gender and local health clinic. Nutrient intake was calculated from 24-hour dietary recalls collected from BAN-exited children. Anthropometric measurements were collected from BAN-exited and matched community children at 15-16 months, and 2 months later. Longitudinal random effects sex-stratified models were used to evaluate anthropometric differences between the 2 groups. BAN-exited children consumed adequate energy, protein, and carbohydrates but inadequate amounts of fat. The prevalence of inadequate micronutrient intakes were: 46% for vitamin A; 20% for vitamin B6; 69% for folate; 13% for vitamin C; 19% for iron; 23% for zinc. Regarding growth, BAN-exited girls gained weight at a significantly lower rate (0.02g/kg/day [95%CI: 0.01, 0.03] than their matched comparison (0.05g/kg/day [95%CI: 0.03, 0.07]); BAN girls grew significantly slower (0.73cm/month [95%CI: 0.40,1.06]) than their matched comparison (1.55cm/month [95%CI: 0.98, 2.12]). Among this sample of BAN-exited children, early weaning was associated with dietary deficiencies and girls experienced reduced growth velocity. In resource-poor settings, HIV prevention programs must ensure that breastfeeding stop only once a nutritionally adequate and safe diet without breastmilk can be provided.
doi:10.1111/j.1740-8709.2011.00369.x
PMCID: PMC3787136  PMID: 22099216
LNS; early breastfeeding cessation; HIV; Malawi; child growth
14.  The Effects of Cotrimoxazole Prophylactic Treatment on Adverse Health Outcomes among Human Immunodeficiency Virus-Exposed, Uninfected Infants 
Background
The World Health Organization guidelines recommend cotrimoxazole prophylactic treatment (CPT) for all HIV-exposed infants from age 6 weeks to the cessation of breastfeeding and the exclusion of HIV infection. There are limited data about the effects of CPT among this population of infants. We examined the effects of CPT on adverse health outcomes among HIV-exposed infants during the first 36 weeks of life by using data from the Breastfeeding, Antiretrovirals, and Nutrition (BAN) study, a large clinical trial of antiretroviral drugs given to the mother or infant for prevention of HIV transmission during breastfeeding.
Methods
For the analysis, we assigned a status of CPT-exposed to infants who were participating in the study after the CPT program started. We estimated unadjusted and adjusted hazard ratios (HRs) for the effect of CPT status on time to incident malaria, severe illness or death, anemia, and weight-for-age Z score < −2.0. Participation in the study was limited to focus exclusively on HIV-exposed, uninfected infants.
Results
The HR for the effect of CPT on incident malaria was 0.35 (95% confidence interval [CI]: 0.21, 0.57) during the first 10 weeks of CPT exposure, and 0.93 (95% CI: 0.67, 1.29) for the remaining 20 weeks. CPT was not associated with the other outcomes examined.
Conclusions
CPT offered temporary protection against malaria among HIV-exposed, uninfected infants. However, CPT offered no protection against anemia, low weight for age, or the collapsed outcome of severe illness or death.
doi:10.1097/INF.0b013e31825c124a
PMCID: PMC3914144  PMID: 22801093
HIV; malaria; cotrimoxazole; infants
15.  The Effect of Cotrimoxazole Prophylactic Treatment on Malaria, Birth Outcomes, and Postpartum CD4 Count in HIV-Infected Women 
Background. Limited data exist on cotrimoxazole prophylactic treatment (CPT) in pregnant women, including protection against malaria versus standard intermittent preventive therapy with sulfadoxine-pyrimethamine (IPTp). Methods. Using observational data we examined the effect of CPT in HIV-infected pregnant women on malaria during pregnancy, low birth weight and preterm birth using proportional hazards, logistic, and log binomial regression, respectively. We used linear regression to assess effect of CPT on CD4 count. Results. Data from 468 CPT-exposed and 768 CPT-unexposed women were analyzed. CPT was associated with protection against malaria versus IPTp (hazard ratio: 0.35, 95% Confidence Interval (CI): 0.20, 0.60). After adjustment for time period this effect was not statistically significant (adjusted hazard ratio: 0.66, 95% CI: 0.28, 1.52). Among women receiving and not receiving CPT, rates of low birth weight (7.1% versus 7.6%) and preterm birth (23.5% versus 23.6%) were similar. CPT was associated with lower CD4 counts 24 weeks postpartum in women receiving (−77.6 cells/μL, 95% CI: −125.2, −30.1) and not receiving antiretrovirals (−33.7 cells/μL, 95% CI: −58.6, −8.8). Conclusions. Compared to IPTp, CPT provided comparable protection against malaria in HIV-infected pregnant women and against preterm birth or low birth weight. Possible implications of CPT-associated lower CD4 postpartum warrant further examination.
doi:10.1155/2013/340702
PMCID: PMC3865641  PMID: 24363547
16.  Patterns of body composition among HIV-infected, pregnant Malawians and the effects of famine season1 
Maternal and child health journal  2013;17(2):10.1007/s10995-012-0970-6.
We describe change in weight, midupper arm circumference (MUAC), arm muscle area (AMA) and arm fat area (AFA) in 1130 pregnant HIV-infected women with CD4 counts > 200 as part of the BAN Study (www.thebanstudy.org), a randomized, controlled clinical trialto evaluate antiretroviral and nutrition interventions to reducemother-to-child transmission of HIV during breast feeding. In a longitudinal analysis, we found a linear increase in weight with a mean rate of weight gain of 0.27 kgs/wk, from baseline (12 to 30 wks gestation) until the last follow-up visit (32 to 38 wks). Analysis of weight gain showed that 17.1% of the intervals between visits resulted in a weight loss. In unadjusted models, MUAC and AMA increased and AFA declined during late pregnancy. Based on multivariable regression analysis, exposure to the famine season resulted in larger losses in AMA [−0.08, 95%CI: −0.14, −0.02; p=0.01] while AFA losses occurred irrespective of season [−0.55, 95%: −0.95, −0.14, p=0.01]. CD4 was associated with AFA [0.21, 95%CI: 0.01, 0.41, p=.04]. Age was positively associated with MUAC and AMA. Wealth index was positively associated with MUAC, AFA, and weight. While patterns of anthropometric measures among HIV-infected, pregnant women were found to be similar to those reported for uninfected women in sub-Saharan Africa, effects of the famine season among undernourished, Malawian women are of concern. Strategies to optimize nutrition during pregnancy for these women appear warranted.
doi:10.1007/s10995-012-0970-6
PMCID: PMC3837416  PMID: 22395817
17.  Maternal mid-upper arm circumference is associated with birth weight among HIV-infected Malawians 
We examined the relationship of maternal anthropometry to fetal growth and birth weight among 1005 HIV-infected women in Lilongwe, Malawi, who consented to enrollment in the Breastfeeding, Antiretrovirals, and Nutrition (BAN) Study (www.thebanstudy.org). Anthropometric assessments of mid-upper arm circumference (MUAC), arm muscle area (AMA), and arm fat area (AFA) were collected at the baseline visit between 12 and 30 weeks gestation and in up to 4 follow-up prenatal visits. In longitudinal analysis, fundal height increased monotonically at an estimated rate of 0.92 cm/week and was positively and negatively associated with AMA and AFA, respectively. These latter relationships varied over weeks of follow-up. Baseline MUAC, AMA, and AFA were positively associated with birth weight [MUAC: 31.84 grams per cm increment, 95% CI: 22.18, 41.49 (p<0.01); AMA: 6.88 g/cm2, 95% CI: 2.51, 11.26 (p<0.01); AFA: 6.97 g/cm2, 95% CI: 3.53, 10.41 (p<0.01)]. In addition, MUAC and AMA were both associated with decreased odds for LBW (<2500 g) [MUAC: OR=0.85, 95% CI: 0.77, 0.94 (p<0.01); AMA: OR=0.95, 95% CI: 0.91, 0.99 (p<0.05)]. These findings support the use of MUAC as an efficient, cost effective screening tool for LBW in HIV-infected women, as in HIV-uninfected women.
doi:10.1177/0884533611435991
PMCID: PMC3753683  PMID: 22511656
18.  Maternal and infant antiretroviral regimens to prevent postnatal HIV-1 transmission: 48-week follow-up of the BAN randomised controlled trial 
Lancet  2012;379(9835):2449-2458.
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.
doi:10.1016/S0140-6736(12)60321-3
PMCID: PMC3661206  PMID: 22541418
19.  Prevalence of hepatitis C virus infection among human immunodeficiency virus-1-infected pregnant women in Malawi: The BAN study☆ 
Background
In Sub-Saharan Africa, prevalence estimates of hepatitis C virus (HCV) vary widely.
Objectives
To assess the prevalence of HCV infection among HIV-infected, pregnant women screened for a large clinical trial in Lilongwe, Malawi.
Study design
Plasma from 2041 HIV-infected, pregnant women was screened for anti-HCV IgG using a chemiluminiscent immunometric assay (CIA). Specimens with a signal-cut-off ratio ≥ 1.00 were considered reactive and those with S/Co ratio < 1.00 non-reactive. All CIA-reactive specimens were tested by a recombinant immunoblot assay (RIBA) for anti-HCV and by PCR for HCV RNA.
Results
Of 2041 specimens, 110 (5.3%, 95% CI: 4.5–6.5%) were CIA reactive. Of the 109 CIA reactive specimens available for RIBA testing, 2 (1.8%) were positive, 28 (25.7%) were indeterminate, and 79 (72.5%) were negative. All CIA-reactive specimens were HCV RNA negative (n = 110). The estimated HCV prevalence based on the screening assay alone was 5.3%; based on supplemental RIBA testing, the status of HCV infection remained indeterminate in 1.4% (28/2040, 95% CI: 0.1–2.0) and the prevalence of confirmed HCV infections was 0.1% (2/2040, 95% CI: 0–0.4%).
Conclusions
HCV seroprevalence among HIV-infected, pregnant women in Malawi confirmed by supplemental RIBA HCV 3.0 is low (0.1%); CIA showed a high false-reactivity rate in this population.
doi:10.1016/j.jcv.2012.05.003
PMCID: PMC3652577  PMID: 22658797
HIV; HCV; Pregnant women; Malawi
20.  Stopping the Control Arm in Response to the DSMB: Mother’s Choice of HIV Prophylaxis during Breastfeeding in the BAN Study 
Contemporary Clinical Trials  2011;33(1):55-59.
The Data and Safety Monitoring Board (DSMB) for the Breastfeeding, Antiretrovirals, and Nutrition study, a clinical trial aimed to prevent postnatal HIV transmission, recommended halting randomization to the enhanced standard-of-care (control) arm. The 67 mother-infant pairs on the control arm and less than 21 weeks postpartum at the time of the DSMB recommendation were read a script informing them of the DSMB decision and offering them the the maternal or infant antiretroviral interventions for the remainder of the 28-week breastfeeding period. This paper describes the BAN study response to the DSMB decision and what the women on the control arm chose, when given a choice to start the maternal or infant antiretroviral interventions.
doi:10.1016/j.cct.2011.10.006
PMCID: PMC3253884  PMID: 22041453
Postnatal HIV transmission; breastfeeding; antiretorival prophylaxis
21.  Maternal or Infant Antiretroviral Drugs to Reduce HIV-1 Transmission 
The New England journal of medicine  2010;362(24):2271-2281.
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.)
doi:10.1056/NEJMoa0911486
PMCID: PMC3440865  PMID: 20554982
22.  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 exclusive breastfeeding to 6 months among HIV-infected mothers choosing to breastfeed 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 breastmilk substitute when provided to infants (6-12mo) of HIV-positive mothers, as part of the Breastfeeding, Antiretroviral, and Nutrition (BAN) Study. A sub-sample of mothers (n=45) participated in interviews that explored exclusive breastfeeding, weaning, and strategies to feed LNS. Mothers reported several weaning strategies, including gradual reduction of breastfeeding, expressing breastmilk 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 breastmilk substitute.
doi:10.1521/aeap.2011.23.3.281
PMCID: PMC3197736  PMID: 21696245
HIV; infant feeding; breastfeeding; weaning; LNS

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