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1.  Neurobehavioral and Developmental Traiectories Associated with Level of Prenatal Cocaine Exposure 
Introduction
In experimental models, prenatal cocaine exposure has been found to perturb GABA and dopamine development. Clinically, abnormalities in tone, posture and state regulation are noted in early infancy but the evolution of these findings over time is not well described. The current study assesses the longitudinal effects of prenatal cocaine exposure in dose-dependent fashion on developmental & behavioral and neurological trajectories over the first 2 years of life.
Methods
Three hundred and eighty infants, 113 cocaine-exposed, were enrolled at birth from an urban hospital from 2000 to 2004. Exposure was determined by maternal interview, segmental hair analyses (RIAH™) in all, and meconium and urine in a subset. Developmental, behavioral and neurological assessments were carried out blind to drug exposure at 6, 12 and 24 months of age in the 306 children who returned in follow-up. Mixed-effects linear modeling (developmental growth curve) assessed change in outcome over time.
Results
The mental developmental growth curve showed a negative slope (2.2 points) in adjusted analyses among cocaine-exposed children over the first 2 years of life. (p=.04), while the slope of the motor development growth curve did not. Adjusting for microcephaly at 6 months diminished the strength of the association between cocaine exposure and mental developmental growth curve (effect modification). Cocaine exposure was marginally associated with behavioral outcomes in adjusted analyses. Total Behavior scores and Orientation/Engagement scores improved with age. At 1 year of age, prenatal cocaine exposure was significantly associated with lower motor development scores. High rates of hypertonia (global and diparesis) identified at the 6-month visit dropped dramatically in the first 2 years of life: cocaine-exposed children showed a more rapid rate of resolution of hypertonia than unexposed children, with hypertonia improving 2.2 times faster among those with heavy cocaine exposure.
Conclusion
We found differences in mental performance over the first 2 years of life associated with prenatal cocaine exposure that was mediated by microcephaly implying that cocaine exerts a sustained teratogenic effect on brain development. Early neurological (hypertonia) and behavioral findings associated with prenatal cocaine exposure improved over time. Hypertonia did not predict long-term development impairments. Conceivably, the transient nature of neurobehavioral manifestations reflects postnatally a tendency towards homeostasis of cocaine-related embryopathic perturbations of GABA and dopaminergic systems.
doi:10.13188/2332-3469.1000015
PMCID: PMC4318507  PMID: 25664330
Perinatal; Cocaine exposure; Behavior; Drug use; Hypertonia; Neurologic; Child development
2.  Prenatal Cocaine Exposures and Dose-Related Cocaine Effects on Infant Tone and Behavior 
Neurotoxicology and teratology  2006;29(3):323-330.
Background
In experimental models, prenatal cocaine exposure has been found to perturb monoaminergic development. In humans, numerous studies have sought clinical correlates, but few have focused on dose-related effects, especially as regards neurologic function beyond the neonatal period.
Objective
To assess whether prenatal cocaine exposure has adverse effects on infant neurologic, developmental and behavioral outcomes and whether any effects are dose-dependent.
Design/Methods
Infants (398) were enrolled at birth from an urban hospital. Drug exposure was ascertained with biomarkers in hair (n=395), urine (n=170) and meconium (n=109). Children were followed prospectively and 286 (72%) were evaluated blind to drug exposure at 6 months of age with the Bayley scales, Fagan Scale of Infant Intelligence and a standardized neurological examination.
Results
Certain neurological findings increased significantly by the amount of cocaine detected in maternal hair, e.g. abnormality of tone, as indicated by extensor posture was detected among 28% of cocaine-unexposed infants, 43% of infants exposed to lower and 48% exposed to higher cocaine levels in maternal hair (p<0.009). Persistent fisting increased in a similar dose-dependent manner. These associations persisted in adjusted analyses. Prenatal cocaine exposure was not associated with developmental scores (mental, motor or novelty preference) but was associated with lower orientation scores in adjusted analyses.
Conclusions
At 6 months of age, prenatal cocaine exposure was associated with abnormalities of tone and posture and with lower orientation scores. Perturbations in monoaminergic systems by cocaine exposure during fetal development may explain the observed neurological and behavioral symptoms. Whether such findings in infancy increase the risk of later neurobehavioral problems requires further study.
doi:10.1016/j.ntt.2006.12.002
PMCID: PMC4307783  PMID: 17234383
perinatal; cocaine exposure; drug use; hypertonia; child development
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.  Plasma lopinavir concentrations predict virological failure in a cohort of South African children initiating a protease-inhibitor-based regimen 
Antiviral therapy  2014;19(4):399-406.
Background
Poor adherence to antiretroviral therapy contributes to pharmacokinetic variability and is the major determinant of virological failure. However, measuring treatment adherence is difficult, especially in children. We investigated the relationship between plasma lopinavir concentrations, pretreatment characteristics and viral load >400 copies/ml.
Methods
A total of 237 HIV-infected children aged 4–42 months on lopinavir/ritonavir oral solution were studied prospectively and followed for up to 52 weeks. Viral load and lopinavir concentration were measured at clinic visits 12, 24, 36 and 52 weeks after starting treatment. Cox multiple failure events models were used to estimate the crude and adjusted effect of lopinavir concentrations on the hazard of viral load >400 copies/ml.
Results
The median (IQR) pretreatment CD4+ T-lymphocyte percentage was 18.80% (12.70–25.35) and 53% of children had a pretreatment viral load >750,000 copies/ml. The median (IQR) weight-for-age and height-for-age z-scores were −2.17 (−3.35–−2.84) and −3.34 (−4.57–−3.41), respectively. Median (IQR) lopinavir concentrations were 8.00 mg/l (4.11–12.42) at median (IQR) 3.50 h (2.67–4.25) after the dose. The hazard of viral load >400 copies/ml was increased with lopinavir concentrations <1 mg/l versus ≥1 mg/l (adjusted hazard ratio 2.3 [95% CI 1.63, 3.26]) and lower height-for-age z-scores.
Conclusions
Low lopinavir concentrations (<1 mg/l) are associated with viraemia in children. This measure could be used as a proxy for adherence and to determine which children are more likely to fail.
doi:10.3851/IMP2749
PMCID: PMC4229495  PMID: 24518130
6.  Impact of Antiretroviral Drugs in Pregnant Women and Their Children in Africa: HIV Resistance and Treatment Outcomes 
The Journal of Infectious Diseases  2013;207(Suppl 2):S93-S100.
The global community has committed itself to eliminating new pediatric HIV infections by 2015 and improving maternal, newborn, and child health and survival in the context of HIV. Such objectives require regimens to prevent mother-to-child transmission (pMTCT) which, while being highly efficacious, protect the efficacy of future first-line antiretroviral therapy (ART). Major obstacles to eliminating vertical transmissions globally include low rates of adherence to ART and non-completion of the ‘pMTCT cascade’ due to programmatic and structural challenges faced by healthcare systems in low-income countries. Providing all pregnant women with lifelong ART regardless of CD4 count/disease stage (Option B+) could be the most effective option to prevent both HIV transmission and resistance, assuming adherence is successfully maintained. This strategy is more likely to achieve sustained undetectable HIV viremia, does not involve ART interruptions, is simpler to implement, and is cost-effective. Where Option B+ is not available, options A (short course zidovudine with single-dose nevirapine and an ARV “tail”) and B (combination ART during pregnancy and breastfeeding, with ART cessation after weaning in women not qualifying for ART for their own health) are also efficacious, highly cost-effective and associated with infrequent resistance selection if taken properly.
doi:10.1093/infdis/jit110
PMCID: PMC3657116  PMID: 23687295
mother-to-child transmission; HIV; prophylaxis; antiretroviral therapy; resistance
7.  Initiation of Antiretroviral Therapy Before 6 Months of Age is Associated with Faster Growth Recovery in South African Children Perinatally infected with HIV 
The Journal of pediatrics  2013;162(6):1138-1145.e2.
Objective
To describe the effects of age at ART initiation on growth outcomes among children infected with HIV followed for 48 months after treatment initiation.
Study design
This secondary analysis describes anthropometric changes in children infected with HIV in Johannesburg, South Africa who initiated ritonavir-boosted lopinavir (LPV/r)-based ART before 24 months of age and were randomized to continue LPV/r or to receive nevirapine after achieving and maintaining virologic suppression. Weight, height, and head circumference were measured at visits over 48 months post-ART initiation. Growth patterns including z-scores for weight for age (WAZ), height for age (HAZ), BMI for age, and head circumference for age (HCAZ) were compared between children initiating ART <6 months, 6–12 months, and 12–24 months of age.
Results
195 children (mean±SD age 10.7±5.9 months), including 54(27.7%) <6 months, 69(35.4%) 6–12 months, and 72(36.9%) 12–24 months of age at ART initiation, were evaluated. In the first 12 months on treatment, children <6 months of age at ART initiation experienced more rapid improvement in WAZ (1.98 vs. 1.44, p=0.084) and HCAZ (1.24 vs. 0.45, p=0.004) than children who initiated ART between 12–24 months of age. By 48 months on ART, growth outcomes were similar, regardless of age at ART initiation. WAZ approached population norms by 12 months on ART. Although improving, HAZ remained on average 1.0 z-score below population norms at 48 months of therapy.
Conclusions
Initiation of ART before 6 months of age results in more rapid growth recovery in children infected with HIV. These data provide further evidence for the importance of prompt diagnosis and early initiation of ART for infants infected with HIV.
doi:10.1016/j.jpeds.2012.11.025
PMCID: PMC3640753  PMID: 23312691
height; weight; BMI; head circumference
8.  Adherence and Viral Suppression among Infants and Young Children Initiating Protease Inhibitor-Based Antiretroviral Therapy 
Background
High levels of adherence to antiretroviral therapy (ART) are considered necessary to achieve viral suppression. We analyzed data from a cohort of HIV-infected children who were less than 2 years of age receiving protease inhibitor (PI)-based ART to investigate associations between viral suppression and adherence ascertained using different methods.
Methods
Data were from the pre-randomization phase of a clinical trial in South Africa of HIV-infected children initiating either ritonavir-boosted lopinavir (LPV/r)- or ritonavir-based ART. At scheduled visits during the first 24 weeks of enrollment, study pharmacists measured quantities of medications returned (MR) to the clinic. Caregivers answered questionnaires on missed doses and adherence barriers. Associations between adherence and viral suppression (HIV-1 RNA <400 copies/mL) were investigated by regimen.
Results
By 24 weeks, 197/269 (73%) children achieved viral suppression. There was no association between viral suppression and caregiver reported missed doses or adherence barriers. For children receiving the LPV/r-based regimen, MR adherence to each of the three drugs in the regimen (LPV/r, lamivudine or stavudine) individually or together was associated with viral suppression at different adherence thresholds. For example, <85% adherence to any of the three medications significantly increased odds of lack of viral suppression (Odds Ratio [OR] 2.30 [95% CI: 1.30–4.07], p=.004). In contrast, for children receiving the ritonavir-based regimen, there was no consistent pattern of association between MR and viral suppression.
Conclusions
Caregiver reports of missed doses did not predict virologic response to treatment. Pharmacist medication reconciliation correlated strongly with virologic response for children taking a LPV/r-based regimen and appears to be a valid method for measuring pediatric adherence.
doi:10.1097/INF.0b013e31827e84ba
PMCID: PMC3624073  PMID: 23249913
adherence; pediatric ART; HIV; measurement
9.  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
10.  Sex differences in responses to antiretroviral treatment in South African HIV-infected children on ritonavir-boosted lopinavir- and nevirapine-based treatment 
BMC Pediatrics  2014;14:39.
Background
While studies of HIV-infected adults on antiretroviral treatment (ART) report no sex differences in immune recovery and virologic response but more ART-associated complications in women, sex differences in disease progression and response to ART among children have not been well assessed. The objective of this study was to evaluate for sex differences in response to ART in South African HIV-infected children who were randomized to continue ritonavir-boosted lopinavir (LPV/r)-based ART or switch to nevirapine-based ART.
Methods
ART outcomes in HIV-infected boys and girls in Johannesburg, South Africa from 2005–2010 were compared. Children initiated ritonavir-boosted lopinavir (LPV/r)-based ART before 24 months of age and were randomized to remain on LPV/r or switch to nevirapine-based ART after achieving viral suppression. Children were followed for 76 weeks post-randomization and then long-term follow up continued for a minimum of 99 weeks and maximum of 245 weeks after randomization. Viral load, CD4 count, lipids, anthropometrics, drug concentrations, and adherence were measured at regular intervals. Outcomes were compared between sexes within treatment strata.
Results
A total of 323 children (median age 8.8 months, IQR 5.1-13.5), including 168 boys and 155 girls, initiated LPV/r-based ART and 195 children were randomized. No sex differences in risk of virological failure (confirmed viral load >1000 copies/mL) by 156 weeks post-randomization were observed within either treatment group. Girls switched to nevirapine had more robust CD4 count improvement relative to boys in this group through 112 weeks post-randomization. In addition, girls remaining on LPV/r had higher plasma concentrations of ritonavir than boys during post-randomization visits. After a mean of 3.4 years post-randomization, girls remaining on LPV/r also had a higher total cholesterol:HDL ratio and lower mean HDL than boys on LPV/r.
Conclusions
Sex differences are noted in treated HIV-infected children even at a young age, and appear to depend on treatment regimen. Future studies are warranted to determine biological mechanisms and clinical significance of these differences.
Trial registration
ClinicalTrials.gov Identifier: NCT00117728
doi:10.1186/1471-2431-14-39
PMCID: PMC3927631  PMID: 24521425
HIV; Children; Sex differences; Antiretroviral treatment outcomes; Pharmacokinetics
12.  Distribution of Human Papillomavirus Genotypes among HIV-Positive and HIV-Negative Women in Cape Town, South Africa 
Objective: HIV-positive women are known to be at high-risk of human papillomavirus (HPV) infection and its associated cervical pathology. Here, we describe the prevalence and distribution of HPV genotypes among HIV-positive and -negative women in South Africa, with and without cervical intraepithelial neoplasia (CIN).
Methods: We report data on 1,371 HIV-positive women and 8,050 HIV-negative women, aged 17–65 years, recruited into three sequential studies in Cape Town, South Africa, conducted among women who had no history of cervical cancer screening recruited from the general population. All women were tested for HIV. Cervical samples were tested for high-risk HPV DNA (Hybrid Capture 2) with positive samples tested to determine the specific genotype (Line Blot). CIN status was determined based on colposcopy and biopsy.
Results: The HPV prevalence was higher among HIV-positive women (52.4%) than among HIV-negative women (20.8%) overall and in all age groups. Younger women, aged 17–19 years, had the highest HPV prevalence regardless of HIV status. HIV-positive women were more likely to have CIN 2 or 3 than HIV-negative women. HPV 16, 35, and 58 were the most common high-risk HPV types with no major differences in the type distribution by HIV status. HPV 18 was more common in older HIV-positive women (40–65 years) with no or low grade disease, but less common in younger women (17–29 years) with CIN 2 or 3 compared to HIV-negative counterparts (p < 0.03). Infections with multiple high-risk HPV types were more common in HIV-positive than HIV-negative women, controlling for age and cervical disease status.
Conclusion: HIV-positive women were more likely to have high-risk HPV than HIV-negative women; but, among those with HPV, the distribution of HPV types was similar by HIV status. Screening strategies incorporating HPV genotyping and vaccination should be effective in preventing cervical cancer in both HIV-positive and -negative women living in sub-Saharan Africa.
doi:10.3389/fonc.2014.00048
PMCID: PMC3953716  PMID: 24672770
HIV-infections; HPV; genotype; HPV vaccine; cervical cancer screening
13.  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
14.  HPV infection and increased risk of HIV acquisition. A systematic review and meta-analysis 
AIDS (London, England)  2012;26(17):10.1097/QAD.0b013e328358d908.
doi:10.1097/QAD.0b013e328358d908
PMCID: PMC3831022  PMID: 22874522
papillomavirus infections; HIV; meta-analysis; human papillomavirus; risk factors
15.  Changes in paediatric HIV-related hospital admissions and mortality in Soweto, South Africa 1996–2011: light at the end of the tunnel? 
Background
With widespread availability of paediatric ART and improved access to PMTCT, it is important to monitor the impact on paediatric HIV-related hospital admissions and in-hospital mortality in South Africa.
Methods
Over a 15 year period, 4 independant surveillance studies were conducted in the paediatric wards at Chris Hani Baragwanath Hospital in Soweto, South Africa (1996, 2005, 2007 and late 2010 to early 2011). Trends in HIV prevalence and HIV-related mortality were evaluated.
Results
HIV prevalence was similar during the first 3 time periods: 26.2% (1996), 31.7% (2005) and 29.5% (2007) p>0.10, but was lower in 2010–11 (19.3%; p=0.0005). Median age of the children admitted with HIV increased in the latter time periods from 9.13 (IQR 3.6 – 28.8), to 10.0 (3.0 – 44.5) (p>0.10) and 18.0 (6.2 – 69.8) months (p=0.048). Median admission WAZ-scores were similar (<−3 SD) for the latter 3 time periods. Admission CD4 percentage increased from 0.0% (0.0 – 9.4) 2005, to 15.0% (8.2 – 22.8) 2007 (p<0.0001) and was 18.7% (9.6 – 24.7) in 2010–11 (p>0.10). Mortality among all vs. HIV-infected admissions was 63/565 (11.2%) and 43/179 (24.0%) in 2005, 91/1510 (6.0%) and 53/440 (12.0%) in 2007 and 18/429 (4.2%) and 9/73 (12.3%) in 2010–11.
Conclusion
HIV-prevalence and mortality among paediatric admissions is decreasing. This is likely a result of improved PMTCT and wider ART coverage. Continued effort to improve PMTCT coverage and identify and treat younger and older HIV-infected children is required to further reduce HIV-related morbidity and mortality.
doi:10.1097/QAI.0b013e318256b4f8
PMCID: PMC3404242  PMID: 22487588
16.  Lipid Profiles in Young HIV-infected Children Initiating and Changing Antiretroviral Therapy 
Background
Both HIV infection and antiretroviral therapy are associated with dyslipidemias in adults but there are fewer data on outcomes in young children. Here we examined lipid profile changes in a cohort of young children before and after suppression on an initial ritonavir-boosted lopinavir (LPV/r)-based regimen and after switch to a nevirapine (NVP)-based regimen.
Methods
195 HIV-infected children who initiated LPV/r-based therapy when <24 months of age at one site in Johannesburg, South Africa, and who achieved viral suppression (<400copies/ml sustained for ≥ 3 months) were randomised to either continue on the LPV/r-based regimen (n=99) or to switch to a NVP-based regimen (n=96). Non-fasting concentrations of total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL) and triglycerides (TG) were measured pre-treatment, at randomization when suppressed, and at 9, 20 and 31 months post-randomization.
Results
Median age at treatment initiation was 9 months and the initial regimen was maintained for an average of 9 months before randomization. TC, LDL and HDL increased from pre-treatment to randomization (p<0.0001) and TC/HDL ratio and TG decreased (p<0.0001). After switching to NVP, HDL was significantly higher (p<0.02) and TC/HDL and TG significantly lower (p<0.0001) through 31 months post-switch relative to remaining on the LPV/r-based regimen.
Conclusion
Initiating antiretroviral therapy was associated with changes to a more favorable lipid profile in young children. Switching from a LPV/r-based regimen to a NVP-based regimen accentuated and continued these improvements. Investigation of safe and effective methods for managing dyslipidemias in children of different ages in resource-limited settings is warranted.
doi:10.1097/QAI.0b013e318243760b
PMCID: PMC3341506  PMID: 22134152
perinatal HIV infection; dyslipidaemia; nevirapine; ritonavir boosted lopinavir
17.  Influence of intragenic CCL3 haplotypes and CCL3L copy number in HIV-1 infection in a sub-Saharan African population 
Genes and immunity  2012;14(1):42-51.
Two CCL3 haplotypes (HapA1 and Hap-A3) and two polymorphic positions shared by the haplotypes (Hap-2SNP) were investigated together with CCL3L copy number (CN), for their role in HIV-1 disease. Hap-A1 was associated with protection from in utero HIV-1 infection: exposed-uninfected infants had higher representation of WT/Hap-A1 than infected infants (excluding intrapartum-infected infants), which maintained significance post maternal Nevirapine (mNVP) and viral load (MVL) correction (P=0.04; OR=0.33). Mother-infant pair analyses showed the protective effect of Hap-A1 is dependent on its presence in the infant. Hap-A3 was associated with increased intrapartum transmission: WT/Hap-A3 was increased in intrapartum vs. non-transmitting mothers, and remained significant post mNVP and MVL correction (P=0.02; OR=3.50). This deleterious effect of Hap-A3 seemed dependent on its presence in the mother. Hap-2SNP was associated with lower CD4 count in the non-transmitting mothers (P=0.03). CCL3 Hap-A1 was associated with high CCL3L CN in total (P=0.001) and exposed-uninfected infants (P=0.006); the effect was not additive, however having either Hap-A1 or high CCL3L CN was more significantly (P=0.0008) associated with protection from in utero infection than Hap-A1 (P=0.028) or high CCL3L CN (P=0.002) alone. Linkage disequilibrium between Hap-A1 and high CCL3L CN appears unlikely given that a Nigerian population showed an opposite relationship.
doi:10.1038/gene.2012.51
PMCID: PMC3554858  PMID: 23151487
CCL3; CCL3L; HIV-1; Haplotypes; SNPs; Mother-to-child-transmission
18.  Influence of intragenic CCL3 haplotypes and CCL3L copy number in HIV-1 infection in a sub-Saharan African population 
Genes and immunity  2012;14(1):42-51.
Two CCL3 haplotypes (HapA1 and Hap-A3) and two polymorphic positions shared by the haplotypes (Hap-2SNP) were investigated together with CCL3L copy number (CN), for their role in HIV-1 disease. Hap-A1 was associated with protection from in utero HIV-1 infection: exposed-uninfected infants had higher representation of WT/Hap-A1 than infected infants (excluding intrapartum-infected infants), which maintained significance post maternal Nevirapine (mNVP) and viral load (MVL) correction (P=0.04; OR=0.33). Mother-infant pair analyses showed the protective effect of Hap-A1 is dependent on its presence in the infant. Hap-A3 was associated with increased intrapartum transmission: WT/Hap-A3 was increased in intrapartum vs. non-transmitting mothers, and remained significant post mNVP and MVL correction (P=0.02; OR=3.50). This deleterious effect of Hap-A3 seemed dependent on its presence in the mother. Hap-2SNP was associated with lower CD4 count in the non-transmitting mothers (P=0.03). CCL3 Hap-A1 was associated with high CCL3L CN in total (P=0.001) and exposed-uninfected infants (P=0.006); the effect was not additive, however having either Hap-A1 or high CCL3L CN was more significantly (P=0.0008) associated with protection from in utero infection than Hap-A1 (P=0.028) or high CCL3L CN (P=0.002) alone. Linkage disequilibrium between Hap-A1 and high CCL3L CN appears unlikely given that a Nigerian population showed an opposite relationship.
doi:10.1038/gene.2012.51
PMCID: PMC3554858  PMID: 23151487
CCL3; CCL3L; HIV-1; Haplotypes; SNPs; Mother-to-child-transmission
19.  Antiretroviral Therapy Responses among Children Attending a Large Public Clinic in Soweto, South Africa 
Background
Antiretroviral therapy access with successful outcomes for children is expanding in resource limited countries. The aim of this study was to determine treatment responses of children in a routine setting where first line therapy with lopinavir/ritonavir is routinely included for young children.
Methods
Outpatient records of children who initiated ART between April 2004 and March 2008 at a government clinic in Soweto were reviewed. Children <3 years initiated ART with lopinavir/ritonavir- and those ≥ 3 years efavirenz-containing regimens
Results
ART was initiated at median age 4.3 years, 28.6% also received TB treatment. During 3155 child-years of follow-up (median follow-up 17 months), 132 (6%) children died giving a mortality rate of 4.2 (95%CI: 3.5, 5.0) deaths per 100 child-years. By 12 and 24 months, 84% and 96% of children achieved virologic suppression. The proportion of children with viral rebound rose from 5.4% to 16.3% at 24 and 36 months from start of ART. Younger children (receiving lopinavir/ritonavir-based first-line therapy) with higher viral loads, suppressed more slowly and were more likely to die. Children given TB treatment at the time of viral suppression were more likely to have virologic rebound.
Conclusion
Despite good treatment outcomes overall, children with advanced disease at ART initiation had poorer outcomes, particularly those < 3 years of age, most of whom were treated with LPV/r-containing therapy. The increasing risk of viral rebound over time for the whole cohort is concerning given currently limited available treatment options for children.
doi:10.1097/INF.0b013e31822539f6
PMCID: PMC3193588  PMID: 21734620
Children; HIV treatment outcomes; South Africa
20.  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
21.  Distribution of High-Risk Human Papillomavirus Genotypes among HIV-Negative Women with and without Cervical Intraepithelial Neoplasia in South Africa 
PLoS ONE  2012;7(9):e44332.
Objective
Large studies describing the profile of high-risk Human papillomavirus (hrHPV) genotypes among women in sub-Saharan Africa are lacking. Here we describe the prevalence and distribution of hrHPV genotypes among HIV-negative women in South Africa, with and without cervical intraepithelial neoplasia (CIN).
Methods
We report data on 8,050 HIV-negative women, aged 17–65 years, recruited into three sequential studies undertaken in Cape Town, South Africa. Women had no history of previous cervical cancer screening. Cervical samples were tested for hrHPV DNA using the Hybrid Capture 2 (HC2) assay and all positive samples were genotyped using a PCR-based assay (Line Blot). Women underwent colposcopy and biopsy/endocervical curettage to determine CIN status. The prevalence and distribution of specific hrHPV genotypes were examined by age and CIN status.
Results
Overall, 20.7% (95% CI, 19.9–21.6%) of women were hrHPV-positive by HC2, with women with CIN having the highest rates of positivity. Prevalence decreased with increasing age among women without CIN; but, a bimodal age curve was observed among women with CIN. HPV 16 and 35 were the most common hrHPV genotypes in all age and CIN groups. HPV 45 became more frequent among older women with CIN grade 2 or 3 (CIN2,3). Younger women (17–29 years) had more multiple hrHPV genotypes overall and in each cervical disease group than older women (40–65 years).
Conclusion
HPV 16, 35, and 45 were the leading contributors to CIN 2,3. The current HPV vaccines could significantly reduce HPV-related cervical disease; however, next generation vaccines that include HPV 35 and 45 would further reduce cervical disease in this population.
doi:10.1371/journal.pone.0044332
PMCID: PMC3435398  PMID: 22970201
22.  Rapid Development of Antiretroviral Drug Resistance Mutations in HIV-Infected Children Less Than Two Years of Age Initiating Protease Inhibitor-Based Therapy in South Africa 
Abstract
Data on the development of antiretroviral drug resistance in HIV-1-infected children receiving protease inhibitor (PI)-based antiretroviral therapy (ART) are limited. We examined antiretroviral resistance among a cohort of 323 South African HIV-infected children <2 years old exposed to nevirapine for prevention of mother-to-child transmission. Ritonavir (RTV) was used initially for 138 children who were <6 months old or receiving antimycobacterial therapy; otherwise children received lopinavir/ritonavir (LPV/r)-based ART. HIV-1 population sequencing of the pol gene was conducted on all pretreatment samples and on posttreatment samples for children who did not achieve HIV-1 plasma RNA <400 copies/ml by 52 weeks. Among children in the cohort, 38 died, 22 had <24 weeks follow-up, 209 achieved virologic suppression, and 54 did not. Of 41 children without virologic suppression with posttreatment HIV genotype data available, major resistance mutations were found in 32 (78%): 14 (36%) had PI mutations including V82A, M46I, and L90M; 29 (71%) had M184V/I; and three had NNRTI mutations (K103N, Y181C, and G190A). Among the children who did not achieve virologic suppression, none of the seven children treated exclusively with LPV/r developed PI-related mutations, compared with 14 of 32 (44%) who received RTV-based regimens (p=0.036); PI genotypes were unavailable for two children. Seventy-eight percent of children without virologic suppression developed resistance mutations that impact second-line ART options. Only children who received RTV-based ART developed major PI-related resistance mutations, and use of this regimen should be avoided.
doi:10.1089/aid.2010.0205
PMCID: PMC3161115  PMID: 21345162
23.  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
24.  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
25.  Infant feeding practices at routine PMTCT sites, South Africa: results of a prospective observational study amongst HIV exposed and unexposed infants - birth to 9 months 
Background
We sought to investigate infant feeding practices amongst HIV-positive and -negative mothers (0-9 months postpartum) and describe the association between infant feeding practices and HIV-free survival.
Methods
Infant feeding data from a prospective observational cohort study conducted at three (of 18) purposively-selected routine South African PMTCT sites, 2002-2003, were analysed. Infant feeding data (previous 4 days) were gathered during home visits at 3, 5, 7, 9, 12, 16, 20, 24, 28, 32 and 36 weeks postpartum. Four feeding groups were of interest, namely exclusive breastfeeding, mixed breastfeeding, exclusive formula feeding and mixed formula feeding. Cox proportional hazards models were fitted to investigate associations between feeding practices (0-12 weeks) and infant HIV-free survival.
Results
Six hundred and sixty five HIV-positive and 218 HIV-negative women were recruited antenatally and followed-up until 36 weeks postpartum. Amongst mothers who breastfed between 3 weeks and 6 months postpartum, significantly more HIV-positive mothers practiced exclusive breastfeeding compared with HIV-negative: at 3 weeks 130 (42%) versus 33 (17%) (p < 0.01); this dropped to 17 (11%) versus 1 (0.7%) by four months postpartum. Amongst mothers practicing mixed breastfeeding between 3 weeks and 6 months postpartum, significantly more HIV-negative mothers used commercially available breast milk substitutes (p < 0.02) and use of these peaked between 9 and 12 weeks. The probability of postnatal HIV or death was lowest amongst infants living in the best resourced site who avoided breastfeeding, and highest amongst infants living in the rural site who stopped breastfeeding early (mean and standard deviations: 10.7% ± 3% versus 46% ± 11%).
Conclusions
Although feeding practices were poor amongst HIV-positive and -negative mothers, HIV-positive mothers undertake safer infant feeding practices, possibly due to counseling provided through the routine PMTCT programme. The data on differences in infant outcome by feeding practice and site validate the WHO 2009 recommendations that site differences should guide feeding practices amongst HIV-positive mothers. Strong interventions are needed to promote exclusive breastfeeding (to 6 months) with continued breastfeeding thereafter amongst HIV-negative motherswho are still the majority of mothers even in high HIV prevalence setting like South Africa.
doi:10.1186/1746-4358-7-4
PMCID: PMC3348038  PMID: 22472507
PMTCT; HIV and Infant Feeding; Breastfeeding; HIV-free survival; Formula Feeding

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