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1.  Early Childhood Infection of Kaposi’s Sarcoma-associated Herpesvirus in Zambian Households: a Molecular Analysis 
Sub-Saharan Africa is endemic for Kaposi’s sarcoma-associated herpesvirus (KSHV) and there is a high rate of early childhood infection; however, the transmission sources are not well characterized. We examined household members as potential KSHV transmission sources to young children in the KSHV-endemic country of Zambia. To this end, we enrolled and followed Zambian households with at least one KSHV-seropositive child and collected longitudinal buccal swab samples. KSHV burden was evaluated and K1 sequences from the children were determined and analyzed for differences to K1 sequences from household members. The K1 sequences were also analyzed for evolution over time. We generated K1 sequences from 31 individuals across 16 households. Nine households contained multiple KSHV-positive members, including at least one child. In 6 of 9 households, the child had 100% sequence identity to all household members. However, in two households the child and mother had distinct K1 sequences. In the remaining household, the children were the only KSHV-infected individuals. Furthermore, we report that 1 of 18 individuals had K1 sequence variation within the timespan analyzed. In the present study, we provide evidence that (1) early childhood KSHV transmission occurs from both within and outside the household, (2) intra-household transmission can occur via non-maternal sources, (3) viral shedding in the buccal cavity is highly variable, and (4) the dominant K1 sequence within an individual did not rapidly evolve over time. These results are important for developing KSHV intervention strategies.
doi:10.1002/ijc.27729
PMCID: PMC3535687  PMID: 22815207
Kaposi’s sarcoma-associated herpesvirus; children; households; Zambia; K1; transmission
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
3.  Pediatric Malignancies, Treatment Outcomes and Abandonment of Pediatric Cancer Treatment in Zambia 
PLoS ONE  2014;9(2):e89102.
Background
There exist significant challenges to the receipt of comprehensive oncologic treatment for children diagnosed with cancer in sub-Saharan Africa. To better define those challenges, we investigated treatment outcomes and risk factors for treatment abandonment in a cohort of children diagnosed with cancer at the University Teaching Hospital (UTH), the site of the only pediatric oncology ward in Zambia.
Methods
Using an established database, a retrospective cohort study was conducted of children aged 0–15 years admitted to the pediatric oncology ward between July 2008 and June 2010 with suspected cancer. Diagnosis, mode of diagnosis, treatment outcome, and risk factors for abandonment of treatment were abstracted from this database and clinical medical records.
Results
Among 162 children treated at the UTH during the study time period that met inclusion criteria, only 8.0% completed a treatment regimen with most of the patients dying during treatment or abandoning care. In multivariable analysis, shorter distance from home to the UTH was associated with a lower risk of treatment abandonment (Adjusted Odds Ratio [aOR] = 0.48 (95% confidence interval [CI] 0.23–0.97). Conversely maternal education less than secondary school was associated with increased risk for abandonment (aOR = 1.65; 95% CI 1.05–2.58).
Conclusions
Despite availability of dedicated pediatric oncology treatment, treatment completion rates are poor, due in part to the logistical challenges faced by families, low educational status, and significant distance from the hospital. Alternative treatment delivery strategies are required to bring effective pediatric oncology care to the patients in need, as their ability to come to and remain at a central tertiary care facility for treatment is limited. We suggest that the extensive system now in place in most of sub-Saharan Africa that sustains life-long antiretroviral therapy for children with human immunodeficiency virus (HIV) infection be adapted for pediatric cancer treatment to improve outcome.
doi:10.1371/journal.pone.0089102
PMCID: PMC3931678  PMID: 24586527
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.  Higher Levels of Neutralizing Antibodies against KSHV in KS Patients Compared to Asymptomatic Individuals from Zambia 
PLoS ONE  2013;8(8):e71254.
Kaposi sarcoma-associated herpesvirus (KSHV) is the etiologic agent for Kaposi Sarcoma (KS), the most common cancer diagnosed in HIV- infected patients. The role of neutralizing antibodies in KS pathogenesis and in KSHV infected individuals is not clearly understood. The goal of this study was to investigate and compare the prevalence and titers of neutralizing antibodies in plasma samples from KS patients and KSHV infected asymptomatic individuals from Zambia, a KS endemic region in sub-Saharan Africa. Plasma samples (N = 267) consisting of KS patients (group 1) and asymptomatic individuals (group 2) were collected from Lusaka, Zambia. A flow cytometry based quantitative neutralization assay utilizing recombinant KSHV expressing GFP was used to detect KSHV neutralizing antibodies. Our results show that the overall prevalence of neutralizing antibodies in KS patients (group 1) was 66.7% which was significantly higher than the prevalence of 6.5% present in KSHV infected asymptomatic individuals (group 2). Total antibody titers as well as neutralizing antibodies titers were found to be significantly higher among KS patients. It is likely that higher neutralizing antibodies prevalence and titers in KS patients result from higher levels of antigenic stimulation over time. This study is first to compare prevalence and titers of neutralizing antibodies in participants with and without disease from a KSHV endemic region.
doi:10.1371/journal.pone.0071254
PMCID: PMC3743886  PMID: 23967174
6.  Performance of modified WHO presumptive criteria for diagnosis of HIV infection in children <18 months admitted to University Teaching Hospital in Lusaka 
Medical journal of Zambia  2010;37(2):64-70.
Background
Making a diagnosis of HIV infection in children aged less than 18 months remains a challenge in low resource settings like Zambia due to the limited availability of gold standard testing with HIV DNA PCR. Clinicians in rural areas have to depend on clinical diagnosis to start HAART as they wait for the dry blood spot (DBS) for DNA PCR results sent from the urban centers.
Methods
This descriptive cross-sectional study was performed at the University Teaching Hospital, Lusaka, Zambia. 299 HIV-exposed children aged less than 18 months were enrolled following a consent procedure. Patients were evaluated for HIV infection based on the World Health Organization’s presumptive diagnostic criteria (WHO-PDC), integrated management of childhood illnesses (IMCI) criteria, select physical exam abnormalities, and CD4% and findings were compared with HIV-DNA PCR results.
Results
Of the 299 exposed patients analyzed, 111(37%) were found to be HIV-positive by DNA PCR. The median CD4% in the infected children was 18%. WHO-PDC used on its own had 23% sensitivity (95% CI 17–32%) and 93% specificity (88–96%), respectively, whereas IMCI criterion had 10% sensitivity (6–17%) and 97% specificity (94–99%), respectively. Multivariate analysis was used to identify the most sensitive predictors when combined with the WHO-PDC and IMCI criterion. WHO-PDC with CD4% improved the sensitivity to 77% (68–83%) with a specificity of 83% (77–88%), positive predictive value (PPV) of 73% (64–80%) and negative predictive value (NPV) of 86% (80–90%). IMCI with CD4% improved sensitivity to 80% (71–87%) with a specificity of 88% (82–92%), PPV 78% (69–85%) and NPV 89% (84–93%). The addition of individual physical exam findings without CD4% improved the sensitivity of WHO-PDC only modestly. When the WHO-PDC, weight<3rd percentile, hepatomegaly, splenomegaly, lymphadenopathy and CD4% were combined, the sensitivity improved to 85% (77–90%), specificity 63% (56–70%), PPV 58% (50–65%) and NPV of 88% (81–92%).
Conclusion
The WHO-PDC clinical algorithm can be improved when combined with a CD4% <25% in children less than 12 months of age and CD4% <20% in those between 12 and 18 months.
PMCID: PMC3500600  PMID: 23170039
HIV; early infant diagnosis; diagnosis; Zambia
7.  Lopinavir/Ritonavir versus Lamivudine peri-exposure prophylaxis to prevent HIV-1 transmission by breastfeeding: the PROMISE-PEP trial Protocol ANRS 12174 
BMC Infectious Diseases  2012;12:246.
Background
Postnatal transmission of HIV-1 through breast milk remains an unsolved challenge in many resource-poor settings where replacement feeding is not a safe alternative. WHO now recommends breastfeeding of infants born to HIV-infected mothers until 12 months of age, with either maternal highly active antiretroviral therapy (HAART) or peri-exposure prophylaxis (PEP) in infants using nevirapine. As PEP, lamivudine showed a similar efficacy and safety as nevirapine, but with an expected lower rate of resistant HIV strains emerging in infants who fail PEP, and lower restrictions for future HIV treatment. Lopinavir/ritonavir (LPV/r) is an attractive PEP candidate with presumably higher efficacy against HIV than nevirapine or lamivudine, and a higher genetic barrier to resistance selection. It showed an acceptable safety profile for the treatment of very young HIV-infected infants. The ANRS 12174 study aims to compare the risk of HIV-1 transmission during and safety of prolonged infant PEP with LPV/r (40/10 mg twice daily if 2-4 kg and 80/20 mg twice daily if >4 kg) versus Lamivudine (7,5 mg twice daily if 2-4 kg, 25 mg twice daily if 4-8 kg and 50 mg twice daily if >8 kg) from day 7 until one week after cessation of BF (maximum 50 weeks of prophylaxis) to prevent postnatal HIV-1 acquisition between 7 days and 50 weeks of age.
Methods
The ANRS 12174 study is a multinational, randomised controlled clinical trial conducted on 1,500 mother-infant pairs in Burkina Faso, South Africa, Uganda and Zambia. We will recommend exclusive breastfeeding (EBF) until 26th week of life and cessation of breastfeeding at a maximum of 49 weeks in both trial arms.
HIV-uninfected infants at day 7 (± 2 days) born to HIV-1 infected mothers not eligible for HAART who choose to breastfeed their infants.
The primary endpoint is the acquisition of HIV-1 (as assessed by HIV-1 DNA PCR) between day 7 and 50 weeks of age. Secondary endpoints are safety (including resistance, adverse events and growth) until 50 weeks and HIV-1-free survival until 50 weeks.
Discussion
This study will provide a new evidence-based intervention to support HIV-1-infected women not eligible for HAART to safely breastfeed their babies.
Trial registration number ( http://www.clinicaltrials.gov)
NCT00640263
doi:10.1186/1471-2334-12-246
PMCID: PMC3482558  PMID: 23039034
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.  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
11.  The Zambia Children's KS-HHV8 Study: Rationale, Study Design, and Study Methods 
American Journal of Epidemiology  2011;173(9):1085-1092.
The epidemic of human immunodeficiency virus in Zambia has led to a dramatic rise in the incidence of human herpesvirus-8 (HHV-8)–associated Kaposi's sarcoma in both adults and children. However, there is a paucity of knowledge about the routes of HHV-8 transmission to young children. The Zambia Children's KS-HHV8 Study, a large, prospective cohort study in Lusaka, Zambia, was launched in 2004 to investigate the role of household members as a source of HHV-8 infection in young children and social behaviors that may modify the risk of HHV-8 acquisition. This cohort is distinct from other epidemiologic studies designed to investigate HHV-8 incidence and transmission because it recruited and followed complete households in the urban central African context. Between July 2004 and March 2007, 1,600 households were screened; 368 households comprising 464 children and 1,335 caregivers and household members were enrolled. Follow-up of this population continued for 48 months postrecruitment, affording a unique opportunity to study horizontal transmission of HHV-8 and understand the routes and sources of transmission to young children in Zambia. The authors describe the study rationale, design, execution, and characteristics of this cohort, which provides critical data on the epidemiology and transmission of HHV-8 to young children in Zambia.
doi:10.1093/aje/kwq465
PMCID: PMC3121218  PMID: 21447476
cohort studies; herpesvirus 8, human; incidence; sarcoma, Kaposi; Zambia
12.  Multiple independent lineages of HIV-1 persist in breast milk and plasma 
AIDS (London, England)  2011;25(2):143-152.
Design
The origin and evolution of HIV-1 in breast milk is unclear, despite the continuing significance of this tissue as a transmitting compartment. To elucidate the evolutionary trajectory of viral populations in a transient mucosal compartment, longitudinal sequences of the envelope gp120 region from plasma and breast milk spanning the first year after delivery were analyzed in six women infected by HIV-1 subtype C.
Methods
Multiple phylogenetic algorithms were used to elucidate the evolutionary history and spatial structure of virus populations between tissues.
Results
Overall persistent mixing of viral sequences between plasma and breast milk indicated that breast milk is not a distinct genetic viral compartment. Unexpectedly, longitudinal phylogenies showed multiple lineages defined by long branches that included virus from both the breast milk and the plasma. Plasma was unlikely the anatomical origin of the most recent common ancestor (MRCA) in at least three of the subjects, while in other women, the temporal origin of the MRCA of the viral populations following delivery occurred well before the onset of breast milk production.
Conclusions
These findings suggest that during pregnancy/lactation, a viral variant distinct from the plasma virus initially seeds the breast milk, followed by subsequent gene flow between the plasma and breast milk tissues. This study indicates the potential for reactivation or re-introduction of distinct lineages during major immunological disruptions during the course of natural infection.
doi:10.1097/QAD.0b013e328340fdaf
PMCID: PMC3032216  PMID: 21173592
HIV-1; breast milk; evolution; phylogeny; compartment; reservoir
13.  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
14.  Effect of using HIV and infant feeding counselling cards on the quality of counselling provided to HIV positive mothers: a cluster randomized controlled trial 
Background
Counselling human immunodeficiency virus (HIV) positive mothers on safer infant and young child feeding (IYCF) options is an important component of programmes to prevent mother to child transmission of HIV, but the quality of counselling is often inadequate. The aim of this study was to determine the effect the World Health Organization HIV and infant feeding cards on the quality of counselling provided to HIV positive mothers by health workers about safer infant feeding options.
Method
This was a un-blinded cluster-randomized controlled field trial in which 36 primary health facilities in Kafue and Lusaka districts in Zambia were randomized to intervention (IYCF counselling with counselling cards) or non- intervention arm (IYCF counselling without counselling cards). Counselling sessions with 10 HIV positive women attending each facility were observed and exit interviews were conducted by research assistants.
Results
Totals of 180 women in the intervention group and 180 women in the control group were attended to by health care providers and interviewed upon exiting the health facility. The health care providers in the intervention facilities more often discussed the advantages of disclosing their HIV status to a household member (RR = 1.46, 95% CI [1.11, 1.92]); used visual aids in explaining the risk of HIV transmission through breast milk (RR = 4.65, 95% CI [2.28, 9.46]); and discussed the advantages and disadvantages of infant feeding options for HIV positive mothers (all p values < 0.05). The differences also included exploration of the home situation (p < 0.05); involving the partner in the process of choosing a feeding option (RR = 1.38, 95% CI [1.09, 1.75]); and exploring how the mother will manage to feed the baby when she is at work (RR = 2.82, 95% CI [1.70, 4.67]). The clients in the intervention group felt that the provider was more caring and understanding (RR = 1.81, 95% CI [1.19, 2.75]).
Conclusion
The addition of counselling cards to the IYCF counselling session for HIV positive mothers were a valuable aid to counselling and significantly improved the quality of the counselling session.
doi:10.1186/1746-4358-6-13
PMCID: PMC3189093  PMID: 21943308
infant feeding; breastfeeding; young children feeding; HIV; counselling cards
15.  Short Communication: Antiretroviral Therapy Resistance Mutations Present in the HIV Type 1 Subtype C pol and env Regions from Therapy-Naive Patients in Zambia 
Abstract
The prevalence of antiretroviral therapy (ART) resistance mutations present in HIV-1 subtype C pol and env regions of the proviral DNA was analyzed and compared from therapy-naive individuals before (Cohort A) and after (Cohort B) the availability of free ART in Zambia. Mutations present in sequences published in a previous study from Zambian ART-naive individuals infected with subtype C were analyzed using current parameters for the classification of ART drug resistance and compared with Cohorts A and B. No statistically significant differences were observed when comparing mutations present in the pol and env of these cohorts. However, an increase in the number of minor, borderline, or partial resistance mutations as well as the presence of major resistance mutations were observed in Cohort B. These results suggest there is an increasing trend of drug resistance-associated mutations that could be a result of the availability of free ART in Zambia. Moreover, the high prevalence of resistance mutations observed for maraviroc and vicriviroc in both cohorts may suggest a limited efficacy of entry inhibitors on HIV-1 subtype C.
doi:10.1089/aid.2009.0181
PMCID: PMC2932558  PMID: 20623996
16.  Cost of individual peer counselling for the promotion of exclusive breastfeeding in Uganda 
Background
Exclusive breastfeeding (EBF) for 6 months is the recommended form of infant feeding. Support of mothers through individual peer counselling has been proved to be effective in increasing exclusive breastfeeding prevalence. We present a costing study of an individual peer support intervention in Uganda, whose objective was to raise exclusive breastfeeding rates at 3 months of age.
Methods
We costed the peer support intervention, which was offered to 406 breastfeeding mothers in Uganda. The average number of counselling visits was about 6 per woman. Annual financial and economic costs were collected in 2005-2008. Estimates were made of total project costs, average costs per mother counselled and average costs per peer counselling visit. Alternative intervention packages were explored in the sensitivity analysis. We also estimated the resources required to fund the scale up to district level, of a breastfeeding intervention programme within a public health sector model.
Results
Annual project costs were estimated to be US$56,308. The largest cost component was peer supporter supervision, which accounted for over 50% of total project costs. The cost per mother counselled was US$139 and the cost per visit was US$26. The cost per week of EBF was estimated to be US$15 at 12 weeks post partum. We estimated that implementing an alternative package modelled on routine public health sector programmes can potentially reduce costs by over 60%. Based on the calculated average costs and annual births, scaling up modelled costs to district level would cost the public sector an additional US$1,813,000.
Conclusion
Exclusive breastfeeding promotion in sub-Saharan Africa is feasible and can be implemented at a sustainable cost. The results of this study can be incorporated in cost effectiveness analyses of exclusive breastfeeding promotion programmes in sub-Saharan Africa.
doi:10.1186/1478-7547-9-11
PMCID: PMC3135543  PMID: 21714877
17.  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
18.  Functional Properties of the HIV-1 Subtype C Envelope Glycoprotein Associated with Mother-to-Child Transmission 
Virology  2010;400(2):164-174.
Understanding the properties of viruses capable of establishing infection during perinatal transmission of HIV-1 is critical for designing effective means of limiting transmission. We previously demonstrated that the newly transmitted viruses (in infant) were more fit in growth, as imparted by their envelope glycoproteins, than those in their corresponding mothers. Here, we further characterized the viral envelope glycoproteins from six mother-infant transmission pairs and determined whether any specific envelope functions correlate with HIV-1 subtype C perinatal transmission. We found that most newly transmitted viruses were less susceptible to neutralization by their maternal plasma compared to contemporaneous maternal viruses. However, the newly transmitted variants were sensitive to neutralization by pooled heterologous plasma but in general were resistant to IgG1 b12. Neither Env processing nor incorporation efficiency was predictive of viral transmissibility. These findings provide further insight into the characteristics of perinatally transmissible HIV-1 and may have implications for intervention approaches.
doi:10.1016/j.virol.2009.12.019
PMCID: PMC2844456  PMID: 20096914
HIV-1 subtype C; perinatal transmission; envelope glycoproteins; neutralization; autologous or heterologous antibodies; envelope processing and incorporation
19.  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
20.  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
21.  Integration of Services for Victims of Child Sexual Abuse at the University Teaching Hospital One-Stop Centre 
Journal of Tropical Medicine  2010;2010:864760.
Objective. To improve care of sexually abused children by establishment of a “One Stop Centre” at the University Teaching Hospital. Methodology. Prior to opening of the One Stop Centre, a management team comprising of clinical departmental heads and a technical group of professionals (health workers, police, psychosocial counselors lawyers and media) were put in place. The team evaluated and identified gaps and weaknesses on the management of sexually abused children prevailing in Zambia. A manual was produced which would be used to train all professionals manning a One Stop Centre. A team of consultants from abroad were identified to offer need based training activities and a database was developed. Results. A multidisciplinary team comprising of health workers, police and psychosocial counselors now man the centre. The centre is assisted by lawyers as and when required. UTH is offering training to other areas of the country to establish similar services by using a Trainer of Trainers model. A comprehensive database has been established for Lusaka province. Conclusion. For establishment of a One Stop Centre, there needs to be a core group comprising of managers as well as a technical team committed to the management and protection of sexually abused children.
doi:10.1155/2010/864760
PMCID: PMC2913632  PMID: 20706671
22.  Mortality among HIV-1– and Human Herpesvirus Type 8–Affected Mother-Infant Pairs in Zambia 
Objective
To determine the respective trends in mortality of Zambian mother-infant pairs based on maternal infection with HIV-1 and human herpesvirus type 8 (HHV-8).
Methods
A prospective cohort study was done on Zambian mother-infant pairs, stratified by maternal serologic status and followed from 6 weeks postdelivery for 48 months. Statistical analysis of the differences in the calculated mortality rates among the four groups was done using Stata 7.0. Kaplan-Meier analysis and Cox proportional hazard models were used to measure subject survival time.
Results
Between September 1998 and March 2002, a total of 1,425 mother-infant pairs were enrolled. The crude mortality rate among children born to dually infected mothers was ~9 times higher (245.90 deaths per 1,000 live births) when compared with the death ratio of children born to seronegative mothers (24.63 deaths per 1,000 live births). The incidence rate for death was 0.34/1,000 in infants of co-infected mothers in comparison with 0.32/1,000 among HIV-1–infected mothers, 0.0336/1,000 among uninfected mothers, and 0.0403/1,000 among HHV-8–infected mothers (χ2 = 154.56; P < 0.01). Infants of co-infected mothers had a comparable risk of death in comparison with infants infected with HIV-1 alone {hazard ratio, 9.91 [95% confidence interval (95% CI), 5.08–19.37] for co-infected versus 9.26 [95% CI, 4.75–18.07] for HIV-1–infected alone}. Infants of mothers infected only with HHV-8 also had comparable survival in comparison with uninfected infants (hazard ratio, 1.21; 95% CI, 0.56–2.61).
Conclusion
Infants born to mothers dually infected with both HIV-1 and HHV-8 have comparable survival with infants exposed to HIV-1 alone. Infants born to mothers infected only with HHV-8 have comparable survival with uninfected infants.
doi:10.1158/1055-9965.EPI-08-0254
PMCID: PMC2892478  PMID: 18768489
23.  Primary gamma-herpesviral infection in Zambian children 
BMC Infectious Diseases  2010;10:115.
Background
HHV-8 is closely related to Epstein-Barr virus (EBV), but the clinical presentations of these two infections in early childhood are not well understood. Also, it is not known whether infection by one virus correlates with another. Here, we compare the natural history of infection by these two viruses along with the clinical manifestations and risk factors that are associated with early childhood infection in Zambia, which is an endemic area for HHV-8.
Methods
This study was conducted in a cohort of 12 month old Zambian children (N = 677). Data on socio-economic status and a wide range of clinical manifestations were collected. Logistic regression was used to test for significant associations between the collected variables and HHV-8 or EBV serostatus at 12 months of age.
Results
We observed a significantly higher seroprevalence for EBV (58.9%) as compared to HHV-8 (13.4%). HIV-1 infected children had at a significantly higher risk of being infected with HHV-8 (Odds ratio [OR] 3.69, 95% confidence interval [CI] 1.64 - 8.32). HIV-1 infection of the mothers was a significant risk factor for increased acquisition of EBV but not HHV-8 by children (OR 1.86, 05% CI 1.20 - 2.87). Self reported rash was marginally associated with primary infection for HHV-8 and EBV.
Conclusions
These results suggest that there is no correlation between EBV and HHV-8 infections. Infection by one does not increase the susceptibility for the second virus. Primary HHV-8 and EBV infection in early childhood may clinically present as rash but remains largely asymptomatic and may remain undetected in this population. HIV infection in the mother or child are important risk factors that contribute to EBV or HHV-8 infection.
doi:10.1186/1471-2334-10-115
PMCID: PMC2881090  PMID: 20462453
24.  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
25.  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

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