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1.  Low Rates of Treatment Failure in Children Aged 2–59 Months Treated for Severe Pneumonia: A Multisite Pooled Analysis 
Low rates of treatment failure and death in >6000 cases of children treated for severe pneumonia with oral antibiotics support supports the shift to management of severe pneumonia to outpatients and in the community.
Background. Despite advances in childhood pneumonia management, it remains a major killer of children worldwide. We sought to estimate global treatment failure rates in children aged 2–59 months with World Health Organization–defined severe pneumonia.
Methods. We pooled data from 4 severe pneumonia studies conducted during 1999–2009 using similar methodologies. We defined treatment failure by day 6 as death, danger signs (inability to drink, convulsions, abnormally sleepy), fever (≥38°C) and lower chest indrawing (LCI; days 2–3), LCI (day 6), or antibiotic change.
Results. Among 6398 cases of severe pneumonia from 10 countries, 564 (cluster adjusted: 8.5%; 95% confidence interval [CI], 5.9%–11.5%) failed treatment by day 6. The most common reasons for clinical failure were persistence of fever and LCI or LCI or fever alone (75% of failures). Seventeen (0.3%) children died. Danger signs were uncommon (<1%). Infants 6–11 months and 2–5 months were 2- and 3.5-fold more likely, respectively, to fail treatment (adjusted OR [AOR], 1.8 [95% CI, 1.4–2.3] and AOR, 3.5 [95% CI, 2.8–4.3]) as children aged 12–59 months. Failure was increased 7-fold (AOR, 7.2 [95% CI, 5.0–10.5]) when comparing infants 2–5 months with very fast breathing to children 12–59 months with normal breathing.
Conclusions. Our findings demonstrate that severe pneumonia case management with antibiotics at health facilities or in the community is associated with few serious morbidities or deaths across diverse geographic settings and support moves to shift management of severe pneumonia with oral antibiotics to outpatients in the community.
doi:10.1093/cid/cis1201
PMCID: PMC3657495  PMID: 23264361
severe pneumonia; amoxicillin; meta-analysis; treatment failure; mortality
2.  Dynamics of breast milk HIV-1 RNA with unilateral mastitis or abscess 
Background
Mastitis and abscess in HIV-infected women increase risk of breastfeeding transmission of HIV. Guidelines encourage women to stop breastfeeding on the affected breast and feed on the contralateral breast. However, impact of breast pathology on breast milk HIV dynamics is unknown.
Methods
HIV RNA was quantified in 211 breast milk samples collected before, during and after a clinical mastitis or abscess diagnosis from 38 HIV-infected women participating in a Zambian breastfeeding study. HIV RNA quantity was compared between affected and unaffected breasts over time using generalized estimating equation models. A sample of 115 women without breast pathology was selected as a control group.
Results
In the affected breast, breast milk HIV RNA quantity increased from the pre- to during-pathology period by log10 0.45 copies/mL (95% CI: 0.16, 0.74) and after symptom resolution, HIV RNA levels were no different from pre-pathology levels (log10 -0.04 copies/mL 95%CI: -0.33, 0.25). In the contralateral unaffected breast, HIV RNA quantity did not significantly increase (log10 0.15 copies/mL, 95% CI: -0.41, 0.10). Increase was more marked in women with abscess or with a greater number of mastitis symptoms. HIV RNA was not significantly different between affected and unaffected women, except at the time of diagnosis.
Conclusions
Breast milk HIV RNA increased modestly in the affected breast with unilateral mastitis or abscess and returned to pre-pathology levels with symptom resolution. Contralateral HIV RNA was not affected. Results support guidelines encouraging feeding from the contralateral breast to minimize risk of HIV transmission associated with unilateral breast pathology.
doi:10.1097/QAI.0b013e31827e64d4
PMCID: PMC3647002  PMID: 23202812
Infant feeding; HIV; Exclusive breastfeeding; Breast problem; Mastitis; Abscess
4.  Coverage of primary mother-to-child HIV transmission isolates by second-generation broadly neutralizing antibodies 
AIDS (London, England)  2013;27(3):10.1097/QAD.0b013e32835cadd6.
Objectives and design
A vaccine capable of providing cross-clade, sterilizing protection has been the holy grail of HIV-1 prevention and control since the beginning of the pandemic. A major component of this effort has been the identification and characterization of broadly neutralizing antibodies (bNAbs). Recent advances in bNAb isolation, structure-based engineering, and vector-mediated gene transfer have led to increased interest in bypassing the immune system by expressing neutralizing antibodies directly in muscle. To assess the neutralization potency and coverage of a panel of second-generation bNAbs, we cloned and phenotypically characterized 227 primary HIV-1 envelopes from 23 mother-to-child transmission (MTCT) pairs.
Methods
Viral envelopes were tested for in-vitro neutralization sensitivity using a standard pseudotype assay system. A 50% inhibitory concentration (IC50) at least 10 μg/ml was used to define neutralization resistance.
Results
The combination of antibodies PG16 and NIH45–46G54W had the broadest activity with the highest neutralization potency, achieving full coverage of 87% of transmission pairs (at a median sampling depth of 10 envelopes per pair) and 96% of recently infected infants in a very conservative analysis.
Conclusions
Our data strongly support the inclusion of NIH45–46G54W, or a more extensively modified variant, in future proof-of-principle immunoprophylaxis or gene therapy-based trials. Furthermore, until robust sequence-based resistance detection becomes available, it will be necessary to conduct deeper phenotypic screening of primary isolates in order to determine the prevalence of minor resistant variants to help in selecting the best reagents for clinical trials.
doi:10.1097/QAD.0b013e32835cadd6
PMCID: PMC3863550  PMID: 23296195
AIDS; antibodies; HIV; neutralization; paediatrics; prevention of mother-to-child transmission; vaccine
5.  Developing a Career in Global Health: Considerations for Physicians-in-Training and Academic Mentors 
Background
Global health is an expansive field, and global health careers are as diverse as the practice of medicine, with new paths being forged every year. Interest in global health among medical students, residents, and fellows has never been higher. As a result, a greater number of these physicians-in-training are participating in global health electives during their training. However, there is a gap between the level of trainee interest and the breadth and depth of educational opportunities that prepare them for a career in global health.
Objective
Global health experiences can complement and enhance each step of traditional physician training, from medical school through residency and fellowship. Global health experiences can expose trainees to patients with diverse pathologies, improve physical exam skills by decreasing reliance on laboratory tests and imaging, enhance awareness of costs and resource allocation in resource-poor settings, and foster cultural sensitivity. The aim of this article is to describe issues faced by physicians-in-training and the faculty who mentor them as trainees pursue careers in global health.
Methods
We conducted a narrative review that addresses opportunities and challenges, competing demands on learners' educational schedules, and the need for professional development for faculty mentors.
Conclusions
A widening gap between trainee interest and the available educational opportunities in global health may result in many medical students and residents participating in global health experiences without adequate preparation and mentorship. Without this essential support, global health training experiences may have detrimental consequences on both trainees and the communities hosting them. We discuss considerations at each training level, options for additional training, current career models in global health, and challenges and potential solutions during training and early career development.
doi:10.4300/JGME-D-11-00299.1
PMCID: PMC3444181  PMID: 23997872
6.  Frequency and Trajectory of Abnormalities in Respiratory Rate, Temperature and Oxygen Saturation in Severe Pneumonia in Children 
The frequency or trajectory of vital sign abnormalities in children with pneumonia has not been described. In a cohort of 2,714 patients with severe pneumonia identified and treated as per the World Health Organization definition and recommendations, tachypnea, fever and hypoxia were found in 68.9%, 23.6% and 15.5% of children, respectively. Median oxygen saturation returned to a normal range by 10 hours following initiation of treatment, followed by temperature at 12 hours and respiratory rate at 22 hours for subjects less than 12 months and at 48 hours for those greater than or equal to 12 months of age.
doi:10.1097/INF.0b013e318257f8ec
PMCID: PMC3399926  PMID: 22531236
pneumonia; vital signs; tachypnea; hypoxia; trajectory
7.  Cluster Randomized Trial of Community Case Management of Severe Pneumonia with Oral Amoxicillin in Children 2-59 Months of Age in Haripur District, Pakistan 
Lancet  2011;378(9805):1796-1803.
Background
First dose oral cotrimoxazole and referral is the recommended treatment for WHO-defined severe pneumonia. Difficulties with referral compliance are reported from many low resource settings resulting in low access to appropriate treatment.
Methods
In a cluster-randomized equivalence trial in Haripur District, Pakistan 28 clusters were randomized equally to intervention and control clusters. In 14 intervention clusters children 2-59 months of age with severe pneumonia were treated with oral amoxicillin by community-based Lady Health Workers (LHW). In 14 control clusters LHWs gave first dose of oral cotrimoxazole and referred to a health facility for appropriate treatment, which was standard of care. The objective was to determine whether community case-management (CCM) of severe pneumonia by LHW using oral amoxicillin was equivalent to current standard of care. Primary outcome was treatment failure on day 6 of treatment. Participants, care givers, and assessors were not blinded to study therapy. Per-protocol analysis was conducted adjusting for clustering within arms using generalized estimating equations.
Findings
1995 children were randomized to intervention and 1477 to control clusters. We analysed 1857 children randomized to intervention and 1354 randomized to control clusters. They were similar in sex, age, and clinical characteristics. Treatment failure was 8·9% (165/1857) in intervention and 17·8% (241/1354) in control clusters. Cluster adjusted failure rates, the primary outcome, were significantly reduced in intervention clusters (risk difference (RD) -8·9%; 95% CI:-12.4% to -5.4%) by day 6. Further adjusting for baseline covariates made little difference (RD: -7·3%, CI: -10·1% to -4·5%). Three deaths occurred, only one in the intervention arm. Two deaths were before day 6, while one occurred between day 6 and 14. Most reduction in risk was in fever and lower chest indrawing on day 3 (RD -6·38%; 95% CI: -8·3% to -4·5%). Age, gender and very fast breathing were predictive of treatment failure.
Interpretation
CCM of severe pneumonia by LHWs resulted in reduced treatment failure versus current standard of care. CCM could result in standardized therapy for severe pneumonia, reduce delay in treatment initiation and costs for families and health systems.
Funding
United States Agency for International Development.
doi:10.1016/S0140-6736(11)61140-9
PMCID: PMC3685294  PMID: 22078721
8.  Exclusive breastfeeding, maternal HIV disease, and the risk of clinical breast pathology in HIV-infected, breastfeeding women 
Objective
To examine the relationship between breastfeeding patterns, markers of maternal HIV disease, and woman’s breast pathology.
Study Design
Secondary data analysis from a randomized breastfeeding trial including 947 HIV-infected women (n=5,982 visits) from breastfeeding initiation until: 6 months post-partum; 1 month after breastfeeding cessation; or loss-to-follow-up/death. Generalized estimating equations assessed the effects of breastfeeding pattern and maternal HIV status on breast pathology.
Results
190 (20.1%) women had a breast problem; 86 (9.1%) had mastitis and 31 (3.3%) had abscess. After confounder adjustment, non-exclusively breastfeeding women increased risk of breast problems (OR: 1.98 95% CI: 1.33, 2.95) and mastitis (OR: 2.87 95% CI: 1.69, 4.88) compared to exclusive breastfeeders. Women with CD4 count <200 cells/uL tended to have increased risk of abscess.
Conclusions
Non-exclusive breastfeeding significantly increased the risk of breast pathology. Exclusive breastfeeding is not only optimal for infant health; it benefits mothers by reducing breast problems.
doi:10.1016/j.ajog.2011.06.021
PMCID: PMC3217158  PMID: 21784403
Abscess; CD4 count; Exclusive breastfeeding; HIV; Mastitis
9.  Pregnancy loss and role of infant HIV status on perinatal mortality among HIV-infected women 
BMC Pediatrics  2012;12:138.
Background
HIV-infected women, particularly those with advanced disease, may have higher rates of pregnancy loss (miscarriage and stillbirth) and neonatal mortality than uninfected women. Here we examine risk factors for these adverse pregnancy outcomes in a cohort of HIV-infected women in Zambia considering the impact of infant HIV status.
Methods
A total of 1229 HIV-infected pregnant women were enrolled (2001–2004) in Lusaka, Zambia and followed to pregnancy outcome. Live-born infants were tested for HIV by PCR at birth, 1 week and 5 weeks. Obstetric and neonatal data were collected after delivery and the rates of neonatal (<28 days) and early mortality (<70 days) were described using Kaplan-Meier methods.
Results
The ratio of miscarriage and stillbirth per 100 live-births were 3.1 and 2.6, respectively. Higher maternal plasma viral load (adjusted odds ratio [AOR] for each log10 increase in HIV RNA copies/ml = 1.90; 95% confidence interval [CI] 1.10–3.27) and being symptomatic were associated with an increased risk of stillbirth (AOR = 3.19; 95% CI 1.46–6.97), and decreasing maternal CD4 count by 100 cells/mm3 with an increased risk of miscarriage (OR = 1.25; 95% CI 1.02–1.54). The neonatal mortality rate was 4.3 per 100 increasing to 6.3 by 70 days. Intrauterine HIV infection was not associated with neonatal morality but became associated with mortality through 70 days (adjusted hazard ratio = 2.76; 95% CI 1.25–6.08). Low birth weight and cessation of breastfeeding were significant risk factors for both neonatal and early mortality independent of infant HIV infection.
Conclusions
More advanced maternal HIV disease was associated with adverse pregnancy outcomes. Excess neonatal mortality in HIV-infected women was not primarily explained by infant HIV infection but was strongly associated with low birth weight and prematurity. Intrauterine HIV infection contributed to mortality as early as 70 days of infant age. Interventions to improve pregnancy outcomes for HIV-infected women are needed to complement necessary therapeutic and prophylactic antiretroviral interventions.
doi:10.1186/1471-2431-12-138
PMCID: PMC3480840  PMID: 22937874
Perinatal mortality; Infant mortality; Risk factors; Adverse pregnancy outcome; HIV infection; Vertical transmission
10.  Outpatient treatment of children with severe pneumonia with oral amoxicillin in 4 countries: The MASS study 
Summary
Objective
A recent RCT demonstrated home-based treatment of WHO-defined severe pneumonia with oral amoxicillin was equivalent to hospital-based therapy and parenteral antibiotics. We aimed to determine whether this finding is generalizable across four countries.
Methods
Multi-centre observational study in Bangladesh, Egypt, Ghana and Vietnam between November 2005 and May 2008. Children aged 3 to 59 months with WHO-defined severe pneumonia were enrolled at participating health centers and managed at home with oral amoxicillin (80–90 mg/kg/day) for 5 days. Children were followed-up at home on days 1, 2, 3 and 6 and at a facility on day 14 to look for cumulative treatment failure through day 6 and relapse between days 6–14.
Results
Of 6,582 children screened, 873 were included, of whom 823 had an outcome ascertained. There was substantial variation in presenting characteristics by site. Bangladesh and Ghana had fever (97%) as a more common symptom than Egypt (74%) and Vietnam (66%), while in Vietnam audible wheeze was more common (49%) than at other sites (range 2%–16%). Treatment failure by day 6 was 9.2% (95% CI: 7.3%–11.2%) across all sites, varying from 6.4% (95% CI: 3.1%–9.8%) in Ghana to 13.2% (95% CI: 8.4%–18.0%) in Vietnam. 2.7% (95% CI: 1.5%–3.9%) of the 733 children well on day 6 relapsed by day 14. The most common causes of treatment failure were persistence of LCI at day 6 (3.8%; 95% CI: 2.6%–5.2%), abnormal sleepy or difficult to wake (1.3%; 95% CI: 0.7%–2.3%), and central cyanosis (1.3%; 95% CI: 0.7%–2.3%). All children survived and only one adverse drug reaction occurred. Treatment was more frequent in young infants and those presenting with rapid respiratory rates.
Conclusions
Clinical treatment failure and adverse event rates among children with severe pneumonia treated at home with oral amoxicillin did not substantially differ across geographic areas. Thus home-based therapy of severe pneumonia can be applied to a wide variety of settings.
doi:10.1111/j.1365-3156.2011.02787.x
PMCID: PMC3154370  PMID: 21545381
pneumonia; developing countries; integrated management of childhood illness; amoxicillin; effectiveness
11.  Early Weaning Increases Diarrhea Morbidity and Mortality Among Uninfected Children Born to HIV-infected Mothers in Zambia 
The Journal of Infectious Diseases  2011;203(9):1222-1230.
Background. Early weaning may reduce human immunodeficiency virus (HIV) transmission but may have deleterious consequences for uninfected children. Here we evaluate effects of early weaning on diarrhea morbidity and mortality of uninfected children born to HIV-infected mothers.
Methods. HIV-infected women in Lusaka, Zambia, were randomly assigned to breastfeeding for 4 months only or to continue breastfeeding until the mother decided to stop. Replacement and complementary foods were provided and all women were counseled around feeding and hygiene. Diarrhea morbidity and mortality were assessed in 618 HIV-uninfected singletons alive and still breastfeeding at 4 months. Intent-to-treat analyses and comparisons based on actual feeding practices were conducted using regression methods.
Results. Between 4 and 6 months, diarrheal episodes were 1.8-fold (95% confidence interval (CI), 1.3–2.4) higher in the short compared with long breastfeeding group. Associations were stronger based on actual feeding practices and persisted after adjustment for confounding. At older ages, only more severe outcomes, including diarrhea-related hospitalization or death (relative hazard [RH], 3.2, 95% CI, 2.1–5.1 increase 4–24 months), were increased among weaned children.
Conclusions. Continued breastfeeding is associated with reduced risk of diarrhea-related morbidity and mortality among uninfected children born to HIV-infected mothers in this low-resource setting despite provision of replacement and complementary food and counseling.
 Clinical Trials Registration. NCT00310726.
doi:10.1093/infdis/jir019
PMCID: PMC3069726  PMID: 21459815
12.  Lactation-associated postpartum weight changes among HIV-infected women in Zambia 
Background There are concerns about effects of lactation on postpartum weight changes among HIV-infected women because low weight may increase risks of HIV-related disease progression.
Methods This analysis of postpartum maternal weight change is based on a trial evaluating the effects of shortened breastfeeding on postpartum mother-to-child transmission of HIV in Lusaka, Zambia, in which 958 HIV-infected women were randomized to breastfeed for a short duration (4 months) or for a duration of their own informed choosing (median 16 months). Among 768 women who met inclusion criteria, we compared across the two groups change in weight (kg) and the percent underweight [body mass index (BMI) <18.5] through 24 months. We also examined the effect of breastfeeding in two high-risk groups: those with low BMI and those with low CD4 counts.
Results Overall, women in the long-duration group gained less weight compared with those in the short-duration group from 4–24 months {1.0 kg [95% confidence interval (CI): 0.3–1.7] vs 2.3 kg (95% CI: 1.6–2.9), P = 0.01}. No association was found between longer breastfeeding and being underweight (odds ratio 1.1; 95% CI: 0.8–1.6; P = 0.40). Effects of lactation in underweight women and women with low CD4 counts were similar to the effects in women with higher BMI and higher CD4 counts. Women with low baseline BMI tended to gain more weight from 4 to 24 months than those with higher BMI, regardless of breastfeeding duration (2.1 kg, 95% CI: 1.3–2.9; P < 0.01).
Conclusions In this study of HIV-infected breastfeeding women in a low-resource setting, the average change in weight from 4 to 24 months postpartum was a net gain rather than loss. Although longer duration breastfeeding was associated with less weight gain, breastfeeding duration was not associated with being underweight (BMI < 18.5). Weight change associated with longer breastfeeding may be metabolically regulated so that women with low BMI and at risk of wasting are protected from excess weight loss.
doi:10.1093/ije/dyq065
PMCID: PMC2972438  PMID: 20484334
Breast feeding; lactation; HIV infections; weight loss; metabolism; body mass index
13.  Potential impact of new World Health Organization criteria for antiretroviral treatment for prevention of mother-to-child HIV transmission 
AIDS (London, England)  2010;24(9):1374-1377.
We reviewed the potential impact of new World Health Organization criteria for antiretroviral therapy using data from 1025 HIV-infected women and infants followed through 24 months in Lusaka, Zambia. The new criteria require initiating therapy among 68% of pregnant women and, if fully effective, would prevent 92% of maternal deaths and 88% of perinatal and postnatal infections. Using CD4 <350 cells/uL, irrespective of clinical stage, is more efficient and stricter CD4 cut-offs would be counter-productive.
PMCID: PMC2946203  PMID: 20568677
14.  Elevations in mortality due to weaning persist into the second year of life among uninfected children born to HIV-infected mothers 
Background
Early weaning has been recommended to reduce postnatal HIV transmission. We evaluated the safety of stopping breastfeeding at different ages for mortality of uninfected children born to HIV-infected mothers.
Methods
During a trial of early weaning, 958 HIV-infected mothers and their infants were recruited and followed from birth to 24 months in Lusaka, Zambia. Half of the cohort was randomized to wean abruptly at 4 months and the other half to continue breastfeeding. We examined associations between uninfected child mortality and actual breastfeeding duration investigating possible confounding and effect modification.
Results
The mortality rate among 749 uninfected children was 9.4% by 12 months and 13.6% by 24 months. Weaning during the interval encouraged by the protocol (4-5 months) was associated with a 2.03-fold increased risk of mortality (95% CI: 1.13 - 3.65), weaning 6-11 months a 3.54-fold increase (95% CI: 1.68 - 7.46) and 12-18 months a 4.22-fold increase (95% CI: 1.59 - 11.24). Significant effect modification was detected such that risks associated with weaning were stronger among infants born to mothers with higher CD4 counts (>350 cells/mL).
Conclusion
Shortening the normal duration of breastfeeding for uninfected children born to HIV-infected mothers living in low resource settings is associated with significant increases mortality extending into the second year of life. Intensive nutritional and counseling interventions reduce, but do not eliminate, this excess mortality.
doi:10.1086/649886
PMCID: PMC2805776  PMID: 20047479
15.  Mortality and virologic outcomes following access to antiretroviral therapy among a cohort of HIV-infected women who received single-dose nevirapine in Lusaka, Zambia 
Objectives
Single-dose nevirapine (SDNVP) for prevention of mother-to-child HIV transmission selects mutations conferring resistance to non-nucleoside reverse transcriptase inhibitor (NNRTI)-based therapy. We investigated mortality and virologic and clinical outcomes following introduction of antiretroviral treatment (ART) among a cohort of women given SDNVP.
Methods
When ART programs were introduced in 2004 in Lusaka, Zambia, we were completing a trial of infant feeding which involved following HIV-infected women who received SDNVP between 2001 and 2005. Women still in follow-up or who could be contacted were evaluated for eligibility for ART (CD4 count <200 or <350 and WHO stage ≥ 3) and started on NNRTI-based therapy if eligible. We compared mortality in the cohort of women before and after ART access, and examined, among women initiating ART, whether virologic response was better allowing a longer time to elapse between SDNVP and treatment initiation.
Results
In the cohort of 872 women, mortality more than halved after ART became available (relative hazard [RH] = 0.46 95% CI: 0.23–0.91 p=0.03). Of 161 SDNVP-exposed women followed on NNRTI-based ART, 70.8% suppressed (viral load <400 copies/ml). Only 3/8 (37.5%) women SDNVP-exposed <6 months of starting therapy suppressed compared to 13/22 (59.1%) who started 6–12 months, 44/61 (72.1 %) 12–24 months, and 54/70 (77.1%) >24 months post-exposure (chi-square trend p=0.01).
Conclusions
Most SDNVP-exposed women respond well to NNRTI-based therapy but there was an attenuation of therapy efficacy that persisted to 12 months after exposure. Women should be screened for ART eligibility during pregnancy and started on effective regimens before delivery.
doi:10.1097/QAI.0b013e3181ab6d5e
PMCID: PMC2782481  PMID: 19506483
16.  Role of breastfeeding cessation in mediating the relationship between maternal HIV disease stage and increased child mortality among HIV-exposed uninfected children 
Background Maternal CD4 count predicts child mortality in HIV-uninfected children born to HIV-infected women.
Methods To explore the mediating role of breastfeeding cessation in this relationship, we compared marginal structural models of maternal CD4 count on child death with and without adjustment for breastfeeding.
Results In crude analyses, children of mothers with CD4 < 200 during pregnancy were 3.2 times more likely to die by 18 months (CI 1.3–8.1) as children whose mothers had CD4 > 500. Earlier breastfeeding cessation was also associated with low CD4 (HR 1.8; CI 1.2–2.7). After adjusting for breastfeeding and low birth weight using a marginal structural model, the low CD4 count-child mortality association through 18 months was reduced 17%. The change was overestimated using a traditional Cox proportional hazards model (35% reduction in HR from 3.4 to 2.5).
Conclusions Our analysis suggests that only a small part of the effect of low vs high CD4 count on child mortality through 18 months is mediated through breastfeeding cessation. Our results must be taken into account when deciding whether or not to recommend breastfeeding for infants of HIV-infected mothers.
doi:10.1093/ije/dyn249
PMCID: PMC2734073  PMID: 19047077
HIV; infant mortality; direct and indirect effects; marginal structural model; Africa; breastfeeding
17.  Detection of Low Levels of Human Immunodeficiency Virus (HIV) May Be Critical for Early Diagnosis of Pediatric HIV Infection by Use of Dried Blood Spots▿  
Journal of Clinical Microbiology  2009;47(9):2989-2991.
We compared a DNA-based assay with a total nucleic acid-based assay for early detection of infant human immunodeficiency virus (HIV) infection. The codetection of DNA and RNA did not result in an overall higher sensitivity compared to that of DNA alone. Discordant results were associated with low levels of HIV DNA, indicating that the sample amount may be critical.
doi:10.1128/JCM.02453-08
PMCID: PMC2738105  PMID: 19625479
18.  Temporal and Lateral Dynamics of HIV Shedding and Elevated Sodium in Breast Milk Among HIV-Positive Mothers During the First 4 Months of Breast-Feeding 
Objective
To better understand the dynamics of breast milk HIV shedding and its relation to postnatal HIV transmission, we investigated the temporal and lateral relations of breast milk viral shedding and sodium concentrations in HIV-positive women.
Design
This was a longitudinal cohort study in Lusaka, Zambia.
Method
We examined patterns of HIV shedding in breast milk over the first 4 months of breast-feeding and their correlations with postnatal HIV transmission among 138 breast-feeding mothers. Sodium concentration in breast milk was also examined in the same samples and in breast milk from 23 HIV-negative controls.
Results
Higher breast milk viral load at 1 week, 1 month, and 4 months and consistent viral shedding in breast milk were significantly associated with increased risk of HIV transmission. Elevated breast milk sodium concentration ($13 mmol/L) at 4 months was associated with HIV transmission, low maternal CD4 cell count, and high maternal plasma viral load. Elevated sodium concentration at 1 week postpartum was common and was not associated with any of these parameters.
Conclusions
Consistent viral shedding and high breast milk viral load are strong predictors of mother-to-child HIV transmission. Although sodium concentrations later in breast-feeding correlate with breast milk viral load, increased breast milk sodium is normal in early lactation and does not predict HIV transmission.
PMCID: PMC2821877  PMID: 18398972
breast-feeding; breast milk sodium; HIV; lactation; mastitis; mother-to-child transmission; viral load
19.  Barriers to acceptance and adherence of antiretroviral therapy in urban Zambian women: a qualitative study 
AIDS care  2009;21(1):78.
Sub-Saharan Africa contains over 60% of the world’s HIV infections and Zambia is among the most severely affected countries in the region. As antiretroviral programs have been rapidly expanding, the long-term success of these programs depends on a good understanding of the behavioral determinants of acceptance and adherence to antiretroviral therapy (ART). The study used qualitative methods to gain local insight into potentially important factors affecting HIV-infected women’s decision to accept or continue with ART. Some of the barriers identified by this study are consistent with factors cited in the existing adherence literature from both developed and developing nations such as side effects, hunger and stigma; other factors have not been previously reported. One major theme was unfamiliarity with the implications of having a chronic, potentially deadly disease. Other emerging themes from this study include the complicated effect of ART on interpersonal relationship, particularly between husbands and wives, the presence of depression and hopelessness, and lack of accurate information. The results suggest that the reasons for non-uptake of treatment include issues related to local cultural frameworks (e.g., illness ideology), mental and behavioral health (e.g., depression and/or interpersonal challenges), stigma, and motivating factors (e.g., values of church or marriage) of different cultures that affect the ability and willingness to take life-saving medicine for a long period of time. Qualitative studies are critical to better understand why ART eligible individuals are choosing not to initiate or continue treatment to achieve needed adherence levels.
doi:10.1080/09540120802032643
PMCID: PMC2821879  PMID: 19085223
ART adherence; Africa; qualitative; HIV
20.  Reduced Mortality Associated With Breast-Feeding–Acquired HIV Infection and Breast-Feeding Among HIV-Infected Children in Zambia 
Objectives
In developing countries, where mother-to-child transmission of HIV through breast-feeding is common, little is known about the impact of postpartum transmission on child survival. This study assessed whether children infected postpartum have longer survival from time of infection versus those infected during gestation or delivery.
Design
We used a prospective cohort study to analyze data from 213 HIV-infected children enrolled in a breast-feeding intervention trial in Lusaka, Zambia (2001 to 2004).
Methods
We compared mortality 1 year after HIV infection in children stratified by age of infection: 0 to 3 days (intrauterine [IU] group), 4 to 40 days (intrapartum/early postpartum [IP/EPP] group), and >40 days (postpartum [PP] group).
Results
A total of 61, 71, and 81 children were infected in the IU, IP/EPP, and PP groups, respectively. Children with intrauterine or intrapartum/early postpartum transmission had higher mortality over the first 12 months after infection than children with postpartum transmission (P = 0.001 and P = 0.006, respectively); no differences were detected between children with intrauterine and intrapartum/early postpartum transmission. Nearly 20% of the IU and IP/EPP groups died by 100 days after infection, whereas nearly 10% of the PP group had died by this time. After adjusting for birth weight, maternal CD4 cell count, breast-feeding, and maternal death, children infected postpartum had one quarter the mortality rate (hazard ratio [HR] = 0.27, 95% confidence interval [CI]: 0.15 to 0.50) of those infected in utero. Stopping breast-feeding increased mortality in infected children (HR = 3.1, 95% CI: 1.8 to 5.3).
Conclusions
This study demonstrates a survival benefit among children infected postpartum versus children infected during pregnancy or delivery and a benefit to increased breast-feeding duration among infected children. Testing children for HIV early may provide a means to allow for earlier intervention.
doi:10.1097/QAI.0b013e31816e39a3
PMCID: PMC2814597  PMID: 18344878
Africa; breast-feeding; HIV; infant mortality; mother-to-child transmission; pediatric HIV
21.  High Concentrations of Interleukin 15 in Breast Milk Are Associated with Protection against Postnatal HIV Transmission 
The Journal of infectious diseases  2009;200(10):1498-1502.
Given the central role that interleukin 15 (IL-15) plays in human immunodeficiency virus (HIV) immunity, we hypothesized that IL-15 in breast milk may protect against postnatal HIV transmission. In a nested case-control study, we compared breast milk IL-15 levels in 22 HIV-infected women who transmitted HIV to their infants to those in 72 nontransmitters. Samples were collected in the first month of life, prior to HIV infection. IL-15 concentrations were associated with a decreased risk of HIV transmission in unadjusted analysis and after adjusting for milk viral load, CD4 cell count, and other cytokines in breast milk. IL-15–mediated immunity may protect against HIV transmission during breast-feeding.
doi:10.1086/644603
PMCID: PMC2811259  PMID: 19835475
22.  Violence and Abuse Among HIV-Infected Women and Their Children in Zambia 
HIV and violence are two major public health problems increasingly shown to be connected and relevant to international mental health issues and HIV-related services. Qualitative research is important due to the dearth of literature on this association in developing countries, cultural influences on mental health syndromes and presentations, and the sensitive nature of the topic. The study presented in this paper sought to investigate the mental health issues of an HIV-affected population of women and children in Lusaka, Zambia, through a systematic qualitative study. Two qualitative methods resulted in the identification of three major problems for women: domestic violence (DV), depression-like syndrome, and alcohol abuse; and children: defilement, DV, and behavior problems. DV and sexual abuse were found to be closely linked to HIV and alcohol abuse. This study shows the local perspective of the overlap between violence and HIV. Results are discussed in relation to the need for violence and abuse to be addressed as HIV services are implemented in sub-Saharan Africa.
doi:10.1097/01.nmd.0000230662.01953.bc
PMCID: PMC2811255  PMID: 16909070
Violence/abuse; HIV/AIDS; qualitative; women; children
23.  Bystander Effects 
doi:10.1097/QAI.0b013e31814d6600
PMCID: PMC2803759  PMID: 18043311
24.  Low and Undetectable Breast Milk Interleukin-7 Concentrations Are Associated With Reduced Risk of Postnatal HIV Transmission 
Objective
To investigate if breast milk interleukin [IL]-7 concentrations are associated with postnatal HIV transmission.
Design
A case-control study nested within a cohort of women recruited in Lusaka, Zambia.
Methods
IL-7 breast milk concentrations were measured in samples from 24 HIV-infected breast-feeding women who transmitted HIV to their child after the neonatal period and from 47 women who did not transmit. Samples were frequency-matched by the time of sample collection (1 week and 1 month postpartum). Logistic regression was used to adjust for possible confounders. For comparison, samples from 18 HIV-uninfected women from the same community were included in the analysis, and plasma IL-7 was determined.
Results
Breast milk IL-7 concentrations were significantly higher than plasma IL-7 concentrations in all 3 groups. In contrast to levels among transmitters and HIV-uninfected women, breast milk IL-7 concentrations exhibited a bimodal distribution among nontransmitters. Breast milk IL-7 concentrations undetectable or less than 30 pg/mL were significantly associated with less HIV transmission (odds ratio = 0.13, 95% confidence interval: 0.03 to 0.64). The association remained strong after adjustment for breast milk viral load and sodium, maternal CD4 cell counts, parity, and time of sample collection.
Conclusion
Breast milk IL-7 may be necessary for effective HIV transmission.
doi:10.1097/QAI.0b013e318141f942
PMCID: PMC2803758  PMID: 17667336
breast milk; cell activation; interleukin-7; postnatal HIV transmission
25.  Differential Effects of Early Weaning for HIV-Free Survival of Children Born to HIV-Infected Mothers by Severity of Maternal Disease 
PLoS ONE  2009;4(6):e6059.
Background
We previously reported no benefit of early weaning for HIV-free survival of children born to HIV-infected mothers in intent-to-treat analyses. Since early weaning was poorly accepted, we conducted a secondary analysis to investigate whether beneficial effects may have been hidden.
Methods
958 HIV-infected women in Lusaka, Zambia, were randomized to abrupt weaning at 4 months (intervention) or to continued breastfeeding (control). Children were followed to 24 months with regular HIV PCR tests and examinations to determine HIV infection or death. Detailed behavioral data were collected on when all breastfeeding ended. Most participants were recruited before antiretroviral treatment (ART) became available. We compared outcomes among mother-child pairs who weaned earlier or later than intended by study design adjusting for potential confounders.
Results
Of infants alive, uninfected and still breastfeeding at 4 months in the intervention group, 16.1% who weaned as instructed acquired HIV or died by 24 months compared to 16.0% who did not comply (p = 0.98). Children of women with less severe disease during pregnancy (not eligible for ART) had worse outcomes if their mothers weaned as instructed (RH = 2.60 95% CI: 1.06–6.36) compared to those who continued breastfeeding. Conversely, children of mothers with more severe disease (eligible for ART but did not receive it) who weaned early had better outcomes (p-value interaction = 0.002). In the control group, weaning before 15 months was associated with 3.94-fold (95% CI: 1.65–9.39) increase in HIV infection or death among infants of mothers with less severe disease.
Conclusion
Incomplete adherence did not mask a benefit of early weaning. On the contrary, for women with less severe disease, early weaning was harmful and continued breastfeeding resulted in better outcomes. For women with more advanced disease, ART should be given during pregnancy for maternal health and to reduce transmission, including through breastfeeding.
Trial Registration
Clinical trials.gov NCT00310726
doi:10.1371/journal.pone.0006059
PMCID: PMC2698120  PMID: 19557167

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