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1.  Revisiting Pneumonia and Exposure Status in Infants Born to HIV-Infected Mothers 
The Pediatric infectious disease journal  2014;33(1):10.1097/INF.0b013e31829f0ade.
HIV-exposed uninfected infants are an increasing population. Past analyses have often categorized these infants as uninfected leading to inaccurate conclusions. We present a HIV exposure, rather than infection, based reanalysis of treatment failure among children with pneumonia to show that failure odds among HIV-exposed uninfected infants are intermediate between their unexposed and infected counterparts. Additional prospective studies aimed at better understanding this population are needed.
doi:10.1097/INF.0b013e31829f0ade
PMCID: PMC3868946  PMID: 24352190
HIV-exposed uninfected; pneumonia
2.  Finding a Needle in the Haystack: The Costs and Cost-Effectiveness of Syphilis Diagnosis and Treatment during Pregnancy to Prevent Congenital Syphilis in Kalomo District of Zambia 
PLoS ONE  2014;9(12):e113868.
Background
In March 2012, The Elizabeth Glaser Pediatric AIDS Foundation trained maternal and child health workers in Southern Province of Zambia to use a new rapid syphilis test (RST) during routine antenatal care. A recent study by Bonawitz et al. (2014) evaluated the impact of this roll out in Kalomo District. This paper estimates the costs and cost-effectiveness from the provider's perspective under the actual conditions observed during the first year of the RST roll out.
Methods
Information on materials used and costs were extracted from program records. A decision-analytic model was used to evaluate the costs (2012 USD) and cost-effectiveness. Basic parameters needed for the model were based on the results from the evaluation study.
Results
During the evaluation study, 62% of patients received a RST, and 2.8% of patients tested were positive (and 10.4% of these were treated). Even with very high RST sensitivity and specificity (98%), true prevalence of active syphilis would be substantially less (estimated at <0.7%). For 1,000 new ANC patients, costs of screening and treatment were estimated at $2,136, and the cost per avoided disability-adjusted-life year lost (DALY) was estimated at $628. Costs change little if all positives are treated (because prevalence is low and treatment costs are small), but the cost-per-DALY avoided falls to just $66. With full adherence to guidelines, costs increase to $3,174 per 1,000 patients and the cost-per-DALY avoided falls to $60.
Conclusions
Screening for syphilis is only useful for reducing adverse birth outcomes if patients testing positive are actually treated. Even with very low prevalence of syphilis (a needle in the haystack), cost effectiveness improves dramatically if those found positive are treated; additional treatment costs little but DALYs avoided are substantial. Without treatment, the needle is essentially found and thrown back into the haystack.
doi:10.1371/journal.pone.0113868
PMCID: PMC4257564  PMID: 25478877
3.  Human Milk Galectin-3 Binding Protein and Breastfeeding-Associated HIV Transmission 
Analysis of milk from 247 HIV-infected Zambian mothers showed that Galectin-3 Binding Protein (Gal3BP) concentrations were significantly higher among HIV-infected mothers who transmitted HIV through breastfeeding (6.51±2.12 ug/mL) than among non-transmitters but were also correlated with higher milk and plasma HIV RNA copies/ml and lower CD4+ cell counts. The association between Gal3BP and postnatal transmission was attenuated after adjustment for milk and plasma HIV load and CD4+ cell counts. This suggests that although milk Gal3BP is a marker of advanced maternal disease, it does not independently modify transmission risk.
doi:10.1097/INF.0b013e3182a6e0a8
PMCID: PMC3907473  PMID: 23899964
HIV transmission; breastfeeding; Galectin-3 Binding Protein; oral transmission
4.  Childhood Anemia at High Altitude: Risk Factors for Poor Outcomes in Severe Pneumonia 
Pediatrics  2013;132(5):e1156-e1162.
BACKGROUND:
Pneumonia is the leading cause of mortality in young children globally, and factors that affect tissue delivery of oxygen may affect outcomes of pneumonia. We studied whether altitude and anemia influence disease severity and outcomes in young children with World Health Organization–defined severe pneumonia.
METHODS:
We analyzed data from the SPEAR (Severe Pneumonia Evaluation Antimicrobial Research) study, a World Health Organization– and USAID-sponsored multinational randomized controlled trial of antibiotics for severe pneumonia among children aged 2 to 59 months in resource-poor settings. The trial enrolled 958 children in 8 sites at varying elevations, classified as high (≥2000 m) or low (<2000 m) altitude. We compared illness severity and assessed the effect of anemia on treatment outcome at high and low altitudes, adjusting for potential confounders and study site.
RESULTS:
Children at high altitudes had significantly lower oxygen saturation on presentation, more cyanosis, lower systolic blood pressure, and higher hemoglobin. After adjusting for potential confounders, anemia predicted treatment failure in children living at high altitude (relative risk: 4.07; 95% confidence interval: 2.60–6.38) but not at low altitude (relative risk: 1.12; 95% confidence interval: 0.96–1.30). Children at high altitude took longer to reach normoxemia than did children at lower altitudes (5.25 vs 0.75 days; P < .0001).
CONCLUSIONS:
Children at high altitude present with more severe disease, and children with anemia at high altitude are at greater risk of poor outcome when being treated for severe pneumonia. Given the high global prevalence of anemia among young children, prevention and treatment of anemia should be a priority in children living at high altitude and could improve outcomes of pneumonia.
doi:10.1542/peds.2013-0761
PMCID: PMC3812558  PMID: 24101768
pneumonia; anemia; high altitude; international child health
5.  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
6.  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
8.  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
9.  Post-Weaning Breast Milk HIV-1 Viral Load, Blood Prolactin Levels and Breast Milk Volume 
AIDS (London, England)  2006;20(11):1539-1547.
Background:
The effect of abrupt weaning, advocated as a safe transition from exclusive breastfeeding in HIV-exposed children, on the quantity of HIV viral load in breast milk (BMVL) is not known.
Objectives:
To determine the effect of abrupt cessation of breastfeeding on serum prolactin, pumped breast milk volume and BMVL obtained 2 weeks after rapid weaning in HIV-infected women.
Methods:
Women enrolled in a prospective study (ZEBS) were randomized to abruptly wean at 20 weeks postpartum or continue exclusive breastfeeding. Breast milk was obtained at 22 weeks by electric breast pump over 10 min from 222 women who had either weaned or continued to breastfeed. Pre- and post-pumping prolactin was measured. BMVL was measured at 20 and 22 weeks in 71 randomly selected women from both groups.
Results:
Baseline prolactin and breast milk volume was significantly lower among women who had weaned. Detectable (68 versus 42%; P 0.03) and median BMVL (448 versus < 50 copies/ml; P = 0.005) was significantly higher = among those who had weaned in comparison with those who were still breastfeeding and was significantly higher in the same women after weaning compared with 2 weeks earlier (P = 0.001). Conclusions: BMVL is substantially higher after rapid weaning and this may pose an increased risk of HIV transmission if children resume breastfeeding after a period of cessation. Increases in BMVL with differing degrees of mixed feeding needs to be assessed.
doi:10.1097/01.aids.0000237370.49241.dc
PMCID: PMC1773053  PMID: 16847409
HIV; breastfeeding; breast milk; viral load; weaning; prolactin mother-to-child transmission; postnatal HIV transmission
10.  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
11.  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
12.  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
13.  Quality and safety of integrated community case management of malaria using rapid diagnostic tests and pneumonia by community health workers 
Pathogens and Global Health  2012;106(1):32-39.
Objectives
To assess the quality and safety of having community health workers (CHWs) in rural Zambia use rapid diagnostic tests (RDTs) and provide integrated management of malaria and pneumonia.
Design/methods
In the context of a cluster-randomized controlled trial of two models for community-based management of malaria and/or non-severe pneumonia in children under 5 years old, CHWs in the intervention arm were trained to use RDTs, follow a simple algorithm for classification and treat malaria with artemether–lumefantrine (AL) and pneumonia with amoxicillin. CHW records were reviewed to assess the ability of the CHWs to appropriately classify and treat malaria and pneumonia, and account for supplies. Patients were also followed up to assess treatment safety.
Results
During the 12-month study, the CHWs evaluated 1017 children with fever and/or fast/difficult breathing and performed 975 RDTs. Malaria and/or pneumonia were appropriately classified 94–100% of the time. Treatment based on disease classification was correct in 94–100% of episodes. Supply management was excellent with over 98% of RDTs, amoxicillin, and AL properly accounted for. The use of RDTs, amoxicillin, and AL was associated with few minor adverse events. Most febrile children (90%) with negative RDT results recovered after being treated with an antipyretic alone.
Conclusions
Volunteer CHWs in rural Zambia are capable of providing integrated management of malaria and pneumonia to children safely and at high quality.
doi:10.1179/1364859411Y.0000000042
PMCID: PMC4001509  PMID: 22595272
Malaria; Pneumonia; Children; Rapid diagnostic test; Community health worker; Amoxicillin; Artemether–umefantrine; Zambia
14.  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
15.  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
16.  Effects of Early, Abrupt Weaning on HIV-free Survival of Children in Zambia 
The New England journal of medicine  2008;359(2):130-141.
Background
In low-resource settings, many programs recommend that women who are infected with the human immunodeficiency virus (HIV) stop breast-feeding early. We conducted a randomized trial to evaluate whether abrupt weaning at 4 months as compared with the standard practice has a net benefit for HIV-free survival of children.
Methods
We enrolled 958 HIV-infected women and their infants in Lusaka, Zambia. All the women planned to breast-feed exclusively to 4 months; 481 were randomly assigned to a counseling program that encouraged abrupt weaning at 4 months, and 477 to a program that encouraged continued breast-feeding for as long as the women chose. The primary outcome was either HIV infection or death of the child by 24 months.
Results
In the intervention group, 69.0% of the mothers stopped breast-feeding at 5 months or earlier; 68.8% of these women reported the completion of weaning in less than 2 days. In the control group, the median duration of breast-feeding was 16 months. In the overall cohort, there was no significant difference between the groups in the rate of HIV-free survival among the children; 68.4% and 64.0% survived to 24 months without HIV infection in the intervention and control groups, respectively (P = 0.13). Among infants who were still being breast-fed and were not infected with HIV at 4 months, there was no significant difference between the groups in HIV-free survival at 24 months (83.9% and 80.7% in the intervention and control groups, respectively; P = 0.27). Children who were infected with HIV by 4 months had a higher mortality by 24 months if they had been assigned to the intervention group than if they had been assigned to the control group (73.6% vs. 54.8%, P = 0.007).
Conclusions
Early, abrupt cessation of breast-feeding by HIV-infected women in a low-resource setting, such as Lusaka, Zambia, does not improve the rate of HIV-free survival among children born to HIV-infected mothers and is harmful to HIV-infected infants. (ClinicalTrials.gov number, NCT00310726.)
doi:10.1056/NEJMoa073788
PMCID: PMC2577610  PMID: 18525036
17.  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
18.  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
19.  The Pneumonia Etiology Research for Child Health Project: A 21st Century Childhood Pneumonia Etiology Study 
The Pneumonia Etiology Research for Child Health (PERCH) project is a 7-country, standardized, comprehensive evaluation of the etiologic agents causing severe pneumonia in children from developing countries. During previous etiology studies, between one-quarter and one-third of patients failed to yield an obvious etiology; PERCH will employ and evaluate previously unavailable innovative, more sensitive diagnostic techniques. Innovative and rigorous epidemiologic and analytic methods will be used to establish the causal association between presence of potential pathogens and pneumonia. By strategic selection of study sites that are broadly representative of regions with the greatest burden of childhood pneumonia, PERCH aims to provide data that reflect the epidemiologic situation in developing countries in 2015, using pneumococcal and Haemophilus influenzae type b vaccines. PERCH will also address differences in host, environmental, and/or geographic factors that might determine pneumonia etiology and, by preserving specimens, will generate a resource for future research and pathogen discovery.
doi:10.1093/cid/cir1052
PMCID: PMC3297546  PMID: 22403238
20.  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
21.  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
22.  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
23.  Community Case Management of Fever Due to Malaria and Pneumonia in Children Under Five in Zambia: A Cluster Randomized Controlled Trial 
PLoS Medicine  2010;7(9):e1000340.
In a cluster randomized trial, Kojo Yeboah-Antwi and colleagues find that integrated management of malaria and pneumonia in children under five by community health workers is both feasible and effective.
Background
Pneumonia and malaria, two of the leading causes of morbidity and mortality among children under five in Zambia, often have overlapping clinical manifestations. Zambia is piloting the use of artemether-lumefantrine (AL) by community health workers (CHWs) to treat uncomplicated malaria. Valid concerns about potential overuse of AL could be addressed by the use of malaria rapid diagnostics employed at the community level. Currently, CHWs in Zambia evaluate and treat children with suspected malaria in rural areas, but they refer children with suspected pneumonia to the nearest health facility. This study was designed to assess the effectiveness and feasibility of using CHWs to manage nonsevere pneumonia and uncomplicated malaria with the aid of rapid diagnostic tests (RDTs).
Methods and Findings
Community health posts staffed by CHWs were matched and randomly allocated to intervention and control arms. Children between the ages of 6 months and 5 years were managed according to the study protocol, as follows. Intervention CHWs performed RDTs, treated test-positive children with AL, and treated those with nonsevere pneumonia (increased respiratory rate) with amoxicillin. Control CHWs did not perform RDTs, treated all febrile children with AL, and referred those with signs of pneumonia to the health facility, as per Ministry of Health policy. The primary outcomes were the use of AL in children with fever and early and appropriate treatment with antibiotics for nonsevere pneumonia. A total of 3,125 children with fever and/or difficult/fast breathing were managed over a 12-month period. In the intervention arm, 27.5% (265/963) of children with fever received AL compared to 99.1% (2066/2084) of control children (risk ratio 0.23, 95% confidence interval 0.14–0.38). For children classified with nonsevere pneumonia, 68.2% (247/362) in the intervention arm and 13.3% (22/203) in the control arm received early and appropriate treatment (risk ratio 5.32, 95% confidence interval 2.19–8.94). There were two deaths in the intervention and one in the control arm.
Conclusions
The potential for CHWs to use RDTs, AL, and amoxicillin to manage both malaria and pneumonia at the community level is promising and might reduce overuse of AL, as well as provide early and appropriate treatment to children with nonsevere pneumonia.
Trial registration
ClinicalTrials.gov NCT00513500
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Every year, about 11 million children die before their fifth birthday. Most of these deaths are in developing countries and most are due to a handful of causes—pneumonia (lung inflammation usually caused by an infection), malaria (a parasitic disease spread by mosquitoes), measles, diarrhea, and birth-related problems. In sub-Saharan Africa, pneumonia and malaria alone are responsible for nearly a third of deaths in young children. Both these diseases can be treated if caught early—pneumonia with antibiotics such as amoxicillin and malaria with artemisinin-based combination therapy (ACT), a treatment that contains several powerful antimalarial drugs. Unfortunately, parents in rural areas in sub-Saharan Africa rarely have easy access to health facilities and sick children are often treated at home by community health workers (CHWs, individuals with some medical training who provide basic health care to their communities), drug sellers, and traditional healers. This situation means that ongoing global efforts to reduce child mortality will require innovative community level interventions if they are to succeed.
Why Was This Study Done?
One community level intervention that the World Health Organization (WHO) and the United Nations Children's Fund (UNICEF) recently recommended is integrated management of malaria and pneumonia in countries where these diseases are major childhood killers. One such country is Zambia. In rural areas of Zambia, CHWs treat suspected cases of uncomplicated (mild) malaria with artemether-lumefantrine (AL, an ACT) or with sulfadoxine-pyrimethamine (a non-ACT antimalarial drug combination) and refer children with suspected pneumonia to the nearest health facility. However, because uncomplicated malaria and pneumonia both cause fever, many children are treated inappropriately. This misdiagnosis is worrying because giving antimalarial drugs to children with pneumonia delays their treatment with more appropriate drugs and increases the risk of drug-resistant malaria emerging. The use of rapid diagnostic tests (RDTs) for malaria might be one way to improve the treatment of malaria and pneumonia by CHWs in Zambia. Here, the researchers investigate the feasibility and effectiveness of this approach in a cluster randomized controlled trial, a study that compares the outcomes of groups (clusters) of patients randomly allocated to different interventions.
What Did the Researchers Do and Find?
The researchers randomly allocated 31 community health posts (fixed locations where CHWs provide medical services to several villages) to the study's intervention and control arms. CHWs in the intervention arm did RDTs for malaria on all the children under 5 years old who presented with fever and/or difficult or fast breathing (symptoms of pneumonia), treated test-positive children with AL, and treated those with nonsevere pneumonia (an increased breathing rate) with amoxicillin. CHWs in the control arm did not use RDTs but treated all children with fever with AL and referred those with signs of pneumonia to the nearest health facility. About 3,000 children with fever were treated during the 12-month study. 99.1% of the children in the control arm received AL compared with 27.5% of the children in the intervention arm, a 4-fold reduction in treatment for malaria. Importantly, the CHWs in the intervention arm adhered to treatment guidelines and did not give AL to children with negative RDT results. Of the children classified with nonsevere pneumonia, 13.3% of those in the control arm received early and appropriate treatment with amoxicillin compared to 68.2% of those in the intervention arm, a 5-fold increase in the timely treatment for pneumonia.
What Do These Findings Mean?
These findings indicate that CHWs in Zambia are capable of using RDTs, AL, and amoxicillin to manage malaria and pneumonia. They show that the intervention tested in this study has the potential to reduce the overuse of AL and to provide early and appropriate treatment for nonsevere pneumonia. Although this approach needs to be tested in other settings, these findings suggest that the use of CHWs might be a feasible and effective way to provide integrated management of pneumonia and malaria at the community level in developing countries. Importantly, these results also support the evaluation of the treatment by CHWs of other major childhood diseases and raise the possibility of saving the lives of many children in sub-Saharan Africa and other developing regions of the world through community level interventions.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000340.
WHO provides information on malaria, on rapid diagnostic tests for malaria, on artemisinin-combination therapy, and on global child mortality and efforts to reduce it (in several languages); WHO also provides a country health profile for Zambia
The US Centers for Disease Control and Prevention provide information on malaria (in English and Spanish)
Kidshealth, a resource maintained by the not-for-profit Nemours Foundation (a not-for-profit organization for children's health), provides information for parents on pneumonia (in English and Spanish)
MedlinePlus provides links to additional information on malaria and on pneumonia (in English and Spanish)
More information about the Zambia Integrated Management of Malaria and Pneumonia Study is available
doi:10.1371/journal.pmed.1000340
PMCID: PMC2943441  PMID: 20877714
24.  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
25.  Restriction of HIV-1 Genotypes in Breast Milk Does Not Account for the Population Transmission Genetic Bottleneck That Occurs following Transmission 
PLoS ONE  2010;5(4):e10213.
Background
Breast milk transmission of HIV-1 remains a major route of pediatric infection. Defining the characteristics of viral variants to which breastfeeding infants are exposed is important for understanding the genetic bottleneck that occurs in the majority of mother-to-child transmissions. The blood-milk epithelial barrier markedly restricts the quantity of HIV-1 in breast milk, even in the absence of antiretroviral drugs. The basis of this restriction and the genetic relationship between breast milk and blood variants are not well established.
Methodology/Principal Findings
We compared 356 HIV-1 subtype C gp160 envelope (env) gene sequences from the plasma and breast milk of 13 breastfeeding women. A trend towards lower viral population diversity and divergence in breast milk was observed, potentially indicative of clonal expansion within the breast. No differences in potential N-linked glycosylation site numbers or in gp160 variable loop amino acid lengths were identified. Genetic compartmentalization was evident in only one out of six subjects in whom contemporaneously obtained samples were studied. However, in samples that were collected 10 or more days apart, six of seven subjects were classified as having compartmentalized viral populations, highlighting the necessity of contemporaneous sampling for genetic compartmentalization studies. We found evidence of CXCR4 co-receptor using viruses in breast milk and blood in nine out of the thirteen subjects, but no evidence of preferential localization of these variants in either tissue.
Conclusions/Significance
Despite marked restriction of HIV-1 quantities in milk, our data indicate intermixing of virus between blood and breast milk. Thus, we found no evidence that a restriction in viral genotype diversity in breast milk accounts for the genetic bottleneck observed following transmission. In addition, our results highlight the rapidity of HIV-1 env evolution and the importance of sample timing in analyses of gene flow.
doi:10.1371/journal.pone.0010213
PMCID: PMC2857876  PMID: 20422033

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