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1.  Tuberculosis incidence is high in HIV-infected African children but is reduced by co-trimoxazole and time on antiretroviral therapy 
BMC Medicine  2016;14:50.
There are few data on tuberculosis (TB) incidence in HIV-infected children on antiretroviral therapy (ART). Observational studies suggest co-trimoxazole prophylaxis may prevent TB, but there are no randomized data supporting this. The ARROW trial, which enrolled HIV-infected children initiating ART in Uganda and Zimbabwe and included randomized cessation of co-trimoxazole prophylaxis, provided an opportunity to estimate the incidence of TB over time, to explore potential risk factors for TB, and to evaluate the effect of stopping co-trimoxazole prophylaxis.
Of 1,206 children enrolled in ARROW, there were 969 children with no previous TB history. After 96 weeks on ART, children older than 3 years were randomized to stop or continue co-trimoxazole prophylaxis; 622 were eligible and included in the co-trimoxazole analysis. Endpoints, including TB, were adjudicated blind to randomization by an independent endpoint review committee (ERC). Crude incidence rates of TB were estimated and potential risk factors, including age, sex, center, CD4, weight, height, and initial ART strategy, were explored in multivariable Cox proportional hazards models.
After a median of 4 years follow-up (3,632 child-years), 69 children had an ERC-confirmed TB diagnosis. The overall TB incidence was 1.9/100 child-years (95 % CI, 1.5–2.4), and was highest in the first 12 weeks following ART initiation (8.8/100 child-years (5.2–13.4) versus 1.2/100 child-years (0.8–1.6) after 52 weeks). A higher TB risk was independently associated with younger age (<3 years), female sex, lower pre-ART weight-for-age Z-score, and current CD4 percent; fewer TB diagnoses were observed in children on maintenance triple nucleoside reverse transcriptase inhibitor (NRTI) ART compared to standard non-NRTI + 2NRTI.
Over the median 2 years of follow-up, there were 20 ERC-adjudicated TB cases among 622 children in the co-trimoxazole analysis: 5 in the continue arm and 15 in the stop arm (hazard ratio (stop: continue) = 3.0 (95 % CI, 1.1–8.3), P = 0.028). TB risk was also independently associated with lower current CD4 percent (P <0.001).
TB incidence varies over time following ART initiation, and is particularly high during the first 3 months post-ART, reinforcing the importance of TB screening prior to starting ART and use of isoniazid preventive therapy once active TB is excluded. HIV-infected children continuing co-trimoxazole prophylaxis after 96 weeks of ART were diagnosed with TB less frequently, highlighting a potentially important role of co-trimoxazole in preventing TB.
Electronic supplementary material
The online version of this article (doi:10.1186/s12916-016-0593-7) contains supplementary material, which is available to authorized users.
PMCID: PMC4804479  PMID: 27004529
Antiretroviral therapy; HIV; Incident tuberculosis; Pediatric
3.  CSF-contacting neurons regulate locomotion by relaying mechanical stimuli to spinal circuits 
Nature Communications  2016;7:10866.
Throughout vertebrates, cerebrospinal fluid-contacting neurons (CSF-cNs) are ciliated cells surrounding the central canal in the ventral spinal cord. Their contribution to modulate locomotion remains undetermined. Recently, we have shown CSF-cNs modulate locomotion by directly projecting onto the locomotor central pattern generators (CPGs), but the sensory modality these cells convey to spinal circuits and their relevance to innate locomotion remain elusive. Here, we demonstrate in vivo that CSF-cNs form an intraspinal mechanosensory organ that detects spinal bending. By performing calcium imaging in moving animals, we show that CSF-cNs respond to both passive and active bending of the spinal cord. In mutants for the channel Pkd2l1, CSF-cNs lose their response to bending and animals show a selective reduction of tail beat frequency, confirming the central role of this feedback loop for optimizing locomotion. Altogether, our study reveals that CSF-cNs constitute a mechanosensory organ operating during locomotion to modulate spinal CPGs.
CSF-contacting neurons are known to project to locomotor CPGs although their relevance to active locomotion is unclear. Here, the authors show that these cells constitute a mechanosensory organ relying on PKD2L1 channels to detect spinal cord curvature and modulate locomotor frequency in freely moving animals.
PMCID: PMC4786674  PMID: 26946992
4.  Acute Illness Is Associated with Suppression of the Growth Hormone Axis in Zimbabwean Infants 
Frequent infections contribute to childhood stunting in developing countries but the causal pathways are uncertain. We tested the hypothesis that intercurrent illnesses suppress the growth hormone axis through reductions in insulin-like growth factor 1 (IGF-1). In a birth cohort of 202 HIV-unexposed Zimbabwean infants, we analyzed data on 7-day illness recall and measured plasma interleukin-6, C-reactive protein, alpha-1-acid glycoprotein, and IGF-1 by enzyme-linked immunosorbent assay, at age 6 weeks, and then 3, 6, 12, and 18 months. Children with recent acute illness had lower IGF-1 concentrations than healthy children and IGF-1 correlated inversely (P < 0.05) with inflammatory biomarkers at most time points between 3 and 18 months. Using path analysis, we showed that cough and fever had a predominantly indirect effect on suppressing IGF-1, through the acute-phase response, whereas diarrhea had a predominantly direct effect on IGF-1. Acute illness may therefore impact the growth hormone axis through both direct and indirect pathways.
PMCID: PMC4347356  PMID: 25535308
7.  Assessment of Environmental Enteric Dysfunction in the SHINE Trial: Methods and Challenges 
Environmental enteric dysfunction (EED) is a virtually ubiquitous, but poorly defined, disorder of the small intestine among people living in conditions of poverty, which begins early in infancy and persists. EED is characterized by altered gut structure and function, leading to reduced absorptive surface area and impaired intestinal barrier function. It is hypothesized that recurrent exposure to fecal pathogens and changes in the composition of the intestinal microbiota initiate this process, which leads to a self-perpetuating cycle of pathology. We view EED as a primary gut disorder that drives chronic systemic inflammation, leading to growth hormone resistance and impaired linear growth. There is currently no accepted case definition or gold-standard biomarker of EED, making field studies challenging. The Sanitation Hygiene Infant Nutrition Efficacy (SHINE) trial in Zimbabwe is evaluating the independent and combined effects of a package of infant feeding and/or water, sanitation, and hygiene interventions on stunting and anemia. SHINE therefore provides an opportunity to longitudinally evaluate EED in a well-characterized cohort of infants, using a panel of biomarkers along the hypothesized causal pathway. Our aims are to describe the evolution of EED during infancy, ascertain its contribution to stunting, and investigate the impact of the randomized interventions on the EED pathway. In this article, we describe current concepts of EED, challenges in defining the condition, and our approach to evaluating EED in the SHINE trial.
PMCID: PMC4657593  PMID: 26602300
infants; stunting; environmental enteric dysfunction; inflammation; IGF-1
8.  The Potential Role of Mycotoxins as a Contributor to Stunting in the SHINE Trial 
Children in developing countries experience multiple exposures that are harmful to their growth and development. An emerging concern is frequent exposure to mycotoxins that contaminate a wide range of staple foods, including maize and groundnuts. Three mycotoxins are suspected to contribute to poor child health and development: aflatoxin, fumonisin, and deoxynivalenol. We summarize the evidence that mycotoxin exposure is associated with stunting, and propose that the causal pathway may be through environmental enteric dysfunction (EED) and disturbance of the insulin-like growth factor 1 (IGF-1) axis. The objectives of this substudy are to assess the relationship between agricultural and harvest practices and mycotoxin exposure; to evaluate associations between mycotoxin exposure and child stunting; and to investigate EED as a potential pathway linking mycotoxin exposure to child stunting, to inform potential areas for intervention.
PMCID: PMC4657594  PMID: 26602301
stunting; aflatoxin; fumonisin; deoxynivalenol; mycotoxin
9.  Assessing the Intestinal Microbiota in the SHINE Trial 
Advances in DNA sequencing technology now allow us to explore the dynamics and functions of the microbes that inhabit the human body, the microbiota. Recent studies involving experimental animal models suggest a role of the gut microbiota in growth. However, the specific changes in the human gut microbiota that contribute to growth remain unclear, and studies investigating the gut microbiota as a determinant of environmental enteric dysfunction (EED) and child stunting are lacking. In this article, we review the evidence for a link between the developing infant gut microbiota, infant feeding, EED, and stunting, and discuss the potential causal pathways relating these variables. We outline the analytic approaches we will use to investigate these relationships, by capitalizing on the longitudinal design and randomized interventions of the Sanitation Hygiene Infant Nutrition Efficacy trial in Zimbabwe.
PMCID: PMC4657595  PMID: 26602302
microbiota; stunting; infant; environmental enteric dysfunction
10.  Rotavirus-associated mild encephalopathy with a reversible splenial lesion (MERS)—case report and review of the literature 
BMC Infectious Diseases  2015;15:446.
Rotavirus is the most common cause of severe gastroenteritis in children under the age of 5 years worldwide. It is well recognised that rotavirus can cause signs and symptoms beyond the gastrointestinal tract, including neurological manifestations such as encephalopathy. Mild encephalopathy with a reversible splenial lesion (MERS) is a clinico-radiological syndrome that has been associated with rotavirus. We report a case of a 4-year-old boy with clinically mild encephalopathy, who had an isolated splenial lesion in the corpus callosum on neuroimaging, and rotavirus RNA detected in faeces. We use this case as an opportunity to review the literature on rotavirus-associated MERS.
Case presentation
A previously healthy 4-year-old boy presented with a 2-day history of vomiting, diarrhoea, and fever, complicated by reduced level of consciousness. Magnetic resonance imaging of the brain showed a marked hyperintensity in the splenium of the corpus callosum on T2 and diffusion-weighted images. Rotavirus genome was detected by polymerase chain reaction in a stool specimen, but not in the cerebrospinal fluid. The genotype was identified as G1P8. His clinical condition improved with gradual resolution of his symptoms. No neurological complications were evident upon discharge and the patient had no recurring symptoms or significant residual defects when followed up 2 months later.
MERS is a novel clinic-radiological syndrome first described in Japan. A transient splenial lesion with reduced diffusion that appears as a high signal intensity in diffusion-weighted MRI is the main diagnostic feature. Rotavirus is one of the most common agents associated with MERS, although to our knowledge only one previous case has been reported from Europe. The majority of patients appear to achieve full recovery following rotavirus-associated MERS, irrespective of treatment. This case, together with other published reports, supports the hypothesis that rotavirus-associated MERS is unlikely to be the result of direct viral invasion of the CNS. It has been suggested that MERS may be caused by intra-myelinic axonal oedema or local inflammatory cell infiltration; however, the pathogenesis remains incompletely understood.
PMCID: PMC4619335  PMID: 26499987
Rotavirus; Encephalopathy; Central Nervous System Infection; Corpus Callosum; MERS; Paediatrics
11.  Management and outcome of Bacille Calmette-Guérin vaccine adverse reactions 
Vaccine  2015;33(41):5470-5474.
•BCG vaccine is the one of the most widely used vaccines globally.•Local complications are commonly seen but approach to management varies.•Injection site reactions and non-suppurative lymphadenitis can be managed conservatively.•Aspiration may be beneficial in suppurative lymphadenitis.•Antimicrobials and surgery are rarely required except for non-resolving cases.
Bacille Calmette-Guérin (BCG) vaccine is one of the most widely used vaccines globally. Management of local BCG complications (injection site reactions and suppurative or non-suppurative lymphadenitis) varies between clinicians, and the optimal approach remains uncertain.
To determine the clinical features, management and outcome of BCG complications at two large acute hospitals in London, United Kingdom.
All children presenting with complications of BCG vaccination between January 2008 and December 2013 were included in this observational study. Medical and electronic laboratory records were reviewed to determine clinical features, treatment and outcome.
Sixty children presented with adverse reactions. Two-thirds (65%) presented with BCG lymphadenitis, one-third (30%) presented with injection site complications and two children (3%) presented with both injection site reaction and lymphadenitis; only one child (2%) had disseminated BCG disease. The majority (88%) of children with injection site reactions were managed conservatively; overall, 95% showed complete resolution within 6 months. Among children with lymphadenitis, 46% were managed conservatively, whilst 54% had anti-tuberculous therapy and/or a procedure (aspiration mostly, or surgery); complete resolution was seen in 59% of cases.
Injection site reactions and non-suppurative lymphadenitis were generally managed conservatively, with good outcomes. There was more variation in management and outcome of suppurative lymphadenitis and the optimal approach remains uncertain.
PMCID: PMC4582770  PMID: 26275478
BCG vaccine; Lymphadenitis; Complications; Treatment; Outcome
AIDS (London, England)  2015;29(5):609-618.
To estimate age at attaining Tanner stages in Ugandan/Zimbabwean HIV-infected children initiating antiretroviral therapy (ART) in older childhood, and investigate predictors of delayed puberty, particularly age at ART initiation.
Observational analysis within a randomised trial.
Tanner staging was assessed every 24 weeks from 10 years of age, menarche every 12 weeks and height every 4-6 weeks. Age at attaining different Tanner stages was estimated using normal interval regression, considering predictors using multivariable regression. Growth was estimated using multi-level models with child-specific intercepts and trajectories.
Median age at ART initiation was 9.4 years (IQR 7.8,11.3) (n=582). At the first assessment, the majority (80.2%) were in Tanner stage 1; median follow-up with staging was 2.8 years. There was a strong delaying effect of older age at ART initiation on age at attaining all Tanner stages (p<0.05) and menarche (p=0.02); in boys the delaying effect generally weakened with older age. There were additional significant delays associated with greater impairments in pre-ART height-for-age Z-score (p<0.05) in both sexes and pre-ART BMI-for-age in girls (p<0.05). There was no evidence that pre-ART immuno-suppression independently delayed puberty or menarche. However, older children/adolescents had significant growth spurts in intermediate Tanner stages, and were still significantly increasing their height when in Tanner stage 5 (p<0.01).
Delaying ART initiation until older childhood substantially delays pubertal development and menarche, independently of immuno-suppression. This highlights that factors other than CD4, such as pubertal development, need consideration when making decisions about timing of ART initiation in older children.
PMCID: PMC4342414  PMID: 25710288
HIV; Africa; children; antiretroviral therapy; puberty
13.  Plasma Concentrations of Hepcidin in Anemic Zimbabwean Infants 
PLoS ONE  2015;10(8):e0135227.
Anemia in infancy is a global public health problem. We evaluated the relative contributions of iron deficiency and inflammation to infant anemia.
We measured plasma hepcidin, ferritin, soluble transferrin receptor (sTfR), alpha-1-acid glycoprotein and C-reactive protein (CRP) by ELISA on archived plasma from 289 HIV-unexposed anemic or non-anemic Zimbabwean infants at ages 3mo, 6mo and 12mo. Among anemic infants, we determined the proportion with iron-deficiency anemia (IDA) and anemia of inflammation (AI). We undertook regression analyses of plasma hepcidin and anemia status, adjusting for sex, age and birthweight.
Anemic infants at 3mo were more stunted and had higher CRP (median 0.45 vs 0.21mg/L; P = 0.037) and hepcidin (median 14.7 vs 9.7ng/mL; P = 0.022) than non-anemic infants, but similar levels of ferritin and sTfR; 11% infants had IDA and 15% had AI. Anemic infants at 6mo had higher hepcidin (median 7.9 vs 4.5ng/mL; P = 0.016) and CRP (median 2.33 vs 0.32mg/L; P<0.001), but lower ferritin (median 13.2 vs 25.1μg/L; P<0.001) than non-anemic infants; 56% infants had IDA and 12% had AI. Anemic infants at 12mo had lower ferritin (median 3.2 vs 22.2μg/L; P<0.001) and hepcidin (median 0.9 vs 1.9ng/mL; P = 0.019), but similar CRP levels; 48% infants had IDA and 8% had AI. Comparing anemic with non-anemic infants, plasma hepcidin was 568% higher, 405% higher and 64% lower at 3mo, 6mo and 12mo, respectively, after adjusting for sex and birthweight (all p<0.01). Plasma hepcidin declined significantly with age among anemic but not non-anemic infants. Girls had 61% higher hepcidin than boys, after adjusting for age, anemia and birthweight (p<0.001).
Anemia is driven partly by inflammation early in infancy, and by iron deficiency later in infancy, with plasma hepcidin concentrations reflecting the relative contribution of each. However, there is need to better characterize the drivers of hepcidin during infancy in developing countries.
PMCID: PMC4529326  PMID: 26252205
14.  Sex Differences in Antiretroviral Therapy Initiation in Pediatric HIV Infection 
PLoS ONE  2015;10(7):e0131591.
The incidence and severity of infections in childhood is typically greater in males. The basis for these observed sex differences is not well understood, and potentially may facilitate novel approaches to reducing disease from a range of conditions. We here investigated sex differences in HIV-infected children in relation to antiretroviral therapy (ART) initiation and post-treatment outcome. In a South African cohort of 2,101 HIV-infected children, we observed that absolute CD4+ count and CD4% were significantly higher in ART-naïve female, compared to age-matched male, HIV-infected children. Absolute CD4 count and CD4% were also significantly higher in HIV-uninfected female versus male neonates. We next showed that significantly more male than female children were initiated on ART (47% female); and children not meeting criteria to start ART by >5yrs were more frequently female (59%; p<0.001). Among ART-treated children, immune reconstitution of CD4 T-cells was more rapid and more complete in female children, even after adjustment for pre-ART absolute CD4 count or CD4% (p=0.011, p=0.030, respectively). However, while ART was initiated as a result of meeting CD4 criteria less often in females (45%), ART initiation as a result of clinical disease in children whose CD4 counts were above treatment thresholds occurred more often in females (57%, p<0.001). The main sex difference in morbidity observed in children initiating ART above CD4 thresholds, above that of TB disease, was as a result of wasting and stunting observed in females with above-threshold CD4 counts (p=0.002). These findings suggest the possibility that optimal treatment of HIV-infected children might incorporate differential CD4 treatment thresholds for ART initiation according to sex.
PMCID: PMC4494714  PMID: 26151555
15.  T-Cell Subsets Predict Mortality in Malnourished Zambian Adults Initiating Antiretroviral Therapy 
PLoS ONE  2015;10(6):e0129928.
To estimate the prognostic value of T-cell subsets in Zambian patients initiating antiretroviral therapy (ART), and to assess the impact of a nutritional intervention on T-cell subsets.
This was a sub-study of a randomised clinical trial of a nutritional intervention for malnourished adults initiating ART. Participants in a randomised controlled trial (NUSTART trial) were enrolled between April and December 2012. Participants received lipid-based nutritional supplement either with or without additional vitamins and minerals. Immunophenotyping was undertaken at baseline and, in survivors, after 12 weeks of ART to characterize T-cell subsets using the markers CD3, CD4, CD8, CD45RA, CCR7, CD28, CD57, CD31, α4β7, Ki67, CD25 and HLA-DR. Univariate and multivariate survival analysis was performed, and responses to treatment were analysed using the Wicoxon rank-sum test.
Among 181 adults, 36 (20%) died by 12 weeks after starting ART. In univariate analysis, patients who died had fewer proliferating, more naïve and fewer gut homing CD4+ T-cells compared to survivors; and more senescent and fewer proliferating CD8+ T-cells. In a multivariate Cox regression model high naïve CD4+, low proliferating CD4+, high senescent CD8+ and low proliferating CD8+ subsets were independently associated with increased risk of death. Recent CD4+ thymic emigrants increased less between recruitment and 12 weeks of ART in the intervention group compared to the control group.
Specific CD4+ T-cell subsets are of considerable prognostic significance for patients initiating ART in Zambia, but only thymic output responded to this nutritional intervention.
PMCID: PMC4470912  PMID: 26083409
16.  Discordant Impact of HLA on Viral Replicative Capacity and Disease Progression in Pediatric and Adult HIV Infection 
PLoS Pathogens  2015;11(6):e1004954.
HLA class I polymorphism has a major influence on adult HIV disease progression. An important mechanism mediating this effect is the impact on viral replicative capacity (VRC) of the escape mutations selected in response to HLA-restricted CD8+ T-cell responses. Factors that contribute to slow progression in pediatric HIV infection are less well understood. We here investigate the relationship between VRC and disease progression in pediatric infection, and the effect of HLA on VRC and on disease outcome in adult and pediatric infection. Studying a South African cohort of >350 ART-naïve, HIV-infected children and their mothers, we first observed that pediatric disease progression is significantly correlated with VRC. As expected, VRCs in mother-child pairs were strongly correlated (p = 0.004). The impact of the protective HLA alleles, HLA-B*57, HLA-B*58:01 and HLA-B*81:01, resulted in significantly lower VRCs in adults (p<0.0001), but not in children. Similarly, in adults, but not in children, VRCs were significantly higher in subjects expressing the disease-susceptible alleles HLA-B*18:01/45:01/58:02 (p = 0.007). Irrespective of the subject, VRCs were strongly correlated with the number of Gag CD8+ T-cell escape mutants driven by HLA-B*57/58:01/81:01 present in each virus (p = 0.0002). In contrast to the impact of VRC common to progression in adults and children, the HLA effects on disease outcome, that are substantial in adults, are small and statistically insignificant in infected children. These data further highlight the important role that VRC plays both in adult and pediatric progression, and demonstrate that HLA-independent factors, yet to be fully defined, are predominantly responsible for pediatric non-progression.
Author Summary
HLA plays a central role in determining disease outcome in adult HIV infection. A principal mechanism by which this HLA effect is mediated is via viral replicative capacity (VRC), protective HLA alleles such as HLA-B*57 driving the selection of viral escape mutants that reduce VRC. The factors contributing to the diverse disease progression rates observed in infected children, however, remain uncertain. We here address the role of HLA and VRC in pediatric disease progression in a large cohort in Kimberley, South Africa. The findings highlight the consistent and important role of VRC in both adult and pediatric progression. However, the impact of key HLA molecules in shaping disease outcome in adult infection is notably absent in pediatric infection. Further studies of pediatric infection therefore provide the potential to gain critical new insights into HLA-independent mechanisms of HIV disease non-progression that predominate in HIV-infected but healthy, ART-naive children. Understanding these mechanisms remains of direct relevance to the development of future interventions to minimize HIV disease.
PMCID: PMC4468173  PMID: 26076345
17.  Linear growth faltering in infants is associated with Acidaminococcus sp. and community-level changes in the gut microbiota 
Microbiome  2015;3:24.
Chronic malnutrition, termed stunting, is defined as suboptimal linear growth, affects one third of children in developing countries, and leads to increased mortality and poor developmental outcomes. The causes of childhood stunting are unknown, and strategies to improve growth and related outcomes in children have only had modest impacts. Recent studies have shown that the ecosystem of microbes in the human gut, termed the microbiota, can induce changes in weight. However, the specific changes in the gut microbiota that contribute to growth remain unknown, and no studies have investigated the gut microbiota as a determinant of chronic malnutrition.
We performed secondary analyses of data from two well-characterized twin cohorts of children from Malawi and Bangladesh to identify bacterial genera associated with linear growth. In a case-control analysis, we used the graphical lasso to estimate covariance network models of gut microbial interactions from relative genus abundances and used network analysis methods to select genera associated with stunting severity. In longitudinal analyses, we determined associations between these selected microbes and linear growth using between-within twin regression models to adjust for confounding and introduce temporality. Reduced microbiota diversity and increased covariance network density were associated with stunting severity, while increased relative abundance of Acidaminococcus sp. was associated with future linear growth deficits.
We show that length growth in children is associated with community-wide changes in the gut microbiota and with the abundance of the bacterial genus, Acidaminococcus. Larger cohorts are needed to confirm these findings and to clarify the mechanisms involved.
Electronic supplementary material
The online version of this article (doi:10.1186/s40168-015-0089-2) contains supplementary material, which is available to authorized users.
PMCID: PMC4477476  PMID: 26106478
Microbiota; Microbiome; Intestinal; Stunting; Growth; Statistical learning; Networks
18.  Prevalence of Lipodystrophy and Metabolic Abnormalities in HIV-infected African Children after 3 Years on First-line Antiretroviral Therapy 
Most pediatric lipodystrophy data come from high-income/middle-income countries, but most HIV-infected children live in sub-Saharan Africa, where lipodystrophy studies have predominantly investigated stavudine-based regimens.
Three years after antiretroviral therapy (ART) initiation, body circumferences and skinfold thicknesses were measured (n = 590), and fasted lipid profile assayed (n = 325), in children from 2 ARROW trial centres in Uganda/Zimbabwe. Analyses compared randomization to long-term versus short-term versus no zidovudine from ART initiation [unadjusted; latter 2 groups receiving abacavir+lamivudine+non-nucleoside-reverse-transciptase-inhibitor (nNRTI) long-term], and nonrandomized (confounder-adjusted) receipt of nevirapine versus efavirenz.
Body circumferences and skinfold thicknesses were similar regardless of zidovudine exposure (P > 0.1), except for subscapular and supra-iliac skinfolds-for-age which were greater with long-term zidovudine (0.006 < P < 0.047). Circumferences/skinfolds were also similar with efavirenz and nevirapine (adjusted P > 0.09; 0.02 < P < 0.03 for waist/waist-hip-ratio). Total and high-density lipoprotein (HDL)-cholesterol, HDL/triglyceride-ratio (P < 0.0001) and triglycerides (P = 0.01) were lower with long-term zidovudine. Low-density lipoprotein (LDL)-cholesterol was higher with efavirenz than nevirapine (P < 0.001). Most lipids remained within normal ranges (75% cholesterol, 85% LDL and 100% triglycerides) but more on long-term zidovudine (3 NRTI) had abnormal HDL-cholesterol (88% vs. 40% short/no-zidovudine, P < 0.0001). Only 8/579(1.4%) children had clinical fat wasting (5 grade 1; 3 grade 2); 2(0.3%) had grade 1 fat accumulation.
Long-term zidovudine-based ART is associated with similar body circumferences and skinfold thicknesses to abacavir-based ART, with low rates of lipid abnormalities and clinical lipodystrophy, providing reassurance where national programs now recommend long-term zidovudine. Efavirenz and nevirapine were also similar; however, the higher LDL observed with efavirenz and lower HDL observed with zidovudine suggests that zidovudine+lamivudine+efavirenz should be investigated in future.
PMCID: PMC4369579  PMID: 25068287
HIV; Africa; children; antiretroviral therapy; lipodystrophy; lipids
20.  Pubertal development in HIV-infected African children on first-line antiretroviral therapy 
AIDS (London, England)  2015;29(5):609-618.
To estimate age at attaining Tanner stages in Ugandan/Zimbabwean HIV-infected children initiating antiretroviral therapy (ART) in older childhood and investigate predictors of delayed puberty, particularly age at ART initiation.
Observational analysis within a randomized trial.
Tanner staging was assessed every 24 weeks from 10 years of age, menarche every 12 weeks and height every 4–6 weeks. Age at attaining different Tanner stages was estimated using normal interval regression, considering predictors using multivariable regression. Growth was estimated using multilevel models with child-specific intercepts and trajectories.
Median age at ART initiation was 9.4 years (inter-quartile range 7.8, 11.3) (n = 582). At the first assessment, the majority (80.2%) were in Tanner stage 1; median follow-up with staging was 2.8 years. There was a strong delaying effect of older age at ART initiation on age at attaining all Tanner stages (P < 0.05) and menarche (P = 0.02); in boys the delaying effect generally weakened with older age. There were additional significant delays associated with greater impairments in pre-ART height-for-age Z-score (P < 0.05) in both sexes and pre-ART BMI-for-age in girls (P < 0.05). There was no evidence that pre-ART immuno-suppression independently delayed puberty or menarche. However, older children/adolescents had significant growth spurts in intermediate Tanner stages, and were still significantly increasing their height when in Tanner stage 5 (P < 0.01).
Delaying ART initiation until older childhood substantially delays pubertal development and menarche, independently of immuno-suppression. This highlights that factors other than CD4+, such as pubertal development, need consideration when making decisions about timing of ART initiation in older children.
PMCID: PMC4342414  PMID: 25710288
Africa; antiretroviral therapy; children; HIV; puberty
21.  Interactions between Zinc Deficiency and Environmental Enteropathy in Developing Countries1 
Advances in Nutrition  2014;5(1):1-6.
Zinc deficiency affects one-fifth of the world’s population and leads to substantial morbidity and mortality. Environmental enteropathy (EE), a subclinical pathology of altered intestinal morphology and function, is almost universal among people living in developing countries and affects long-term growth and health. This review explores the overlapping nature of these 2 conditions and presents evidence for their interaction. EE leads to impaired zinc homeostasis, predominantly due to reduced absorptive capacity arising from disturbed intestinal architecture, and zinc deficiency exacerbates several of the proposed pathways that underlie EE, including intestinal permeability, enteric infection, and chronic inflammation. Ongoing zinc deficiency likely perpetuates the adverse outcomes of EE by worsening malabsorption, reducing intestinal mucosal immune responses, and exacerbating systemic inflammation. Although the etiology of EE is predominantly environmental, zinc deficiency may also have a role in its pathogenesis. Given the impact of both EE and zinc deficiency on morbidity and mortality in developing countries, better understanding the relation between these 2 conditions may be critical for developing combined interventions to improve child health.
PMCID: PMC3884090  PMID: 24425714
22.  Congenital and Postnatal CMV and EBV Acquisition in HIV-Infected Zimbabwean Infants 
PLoS ONE  2014;9(12):e114870.
HIV-infected infants in sub-Saharan Africa have rapid disease progression. We hypothesized that co-infection with cytomegalovirus (CMV) or Epstein Barr virus (EBV) increases mortality in HIV-infected infants.
257 antiretroviral therapy-naïve HIV-infected Zimbabwean infants were tested for CMV and EBV at 6 weeks of age by real-time PCR; if positive, birth samples were retrieved where available to distinguish congenital and postnatal infection. The impact of co-infection on mortality through 6 months was estimated using Kaplan-Meier and Cox proportional hazards methods.
At 6 weeks, 203/257 (79%) HIV-infected infants were CMV-positive; 27 (11%) had congenital CMV, 108 (42%) postnatal CMV and 68 (26%) indeterminate timing of infection. By 6 months, 37/108 (34%) infants with postnatal CMV versus 16/54 (30%) CMV-negative infants died (adjusted hazard ratio (aHR) 1.1 [95%CI 0.6, 2.2]). At 6 weeks, 33/257 (13%) HIV-infected infants had EBV co-infection; 6 (2%) had congenital EBV, 18 (7%) postnatal EBV and 9 (4%) indeterminate timing of infection. By 6 months, 5/18 (28%) infants with postnatal EBV versus 72/224 (32%) EBV-negative infants died (aHR 0.8 [95%CI 0.3, 2.3]).
The vast majority of HIV-infants had acquired CMV by 6 weeks, and EBV co-infection occurred earlier than expected, with one in eight HIV-infected infants positive for EBV by 6 weeks. There was a high prevalence of congenital CMV infection and we identified 6 infants with congenital EBV infection, which has not previously been reported in Africa or in the context of HIV infection. Neither CMV nor EBV co-infection was associated with increased mortality.
PMCID: PMC4270791  PMID: 25522217
23.  A Randomized Trial of Prolonged Co-trimoxazole in HIV-Infected Children in Africa 
Co-trimoxazole (fixed-dose trimethoprim–sulfamethoxazole) prophylaxis administered before antiretroviral therapy (ART) reduces morbidity in children infected with the human immunodeficiency virus (HIV). We investigated whether children and adolescents receiving long-term ART in sub-Saharan Africa could discontinue co-trimoxazole.
We conducted a randomized, noninferiority trial of stopping versus continuing daily open-label co-trimoxazole in children and adolescents in Uganda and Zimbabwe. Eligible participants were older than 3 years of age, had been receiving ART for more than 96 weeks, were using insecticide-treated bed nets (in malaria-endemic areas), and had not had Pneumocystis jirovecii pneumonia. Coprimary end points were hospitalization or death and adverse events of grade 3 or 4.
A total of 758 participants were randomly assigned to stop or continue co-trimoxazole (382 and 376 participants, respectively), after receiving ART for a median of 2.1 years (interquartile range, 1.8 to 2.3). The median age was 7.9 years (interquartile range, 4.6 to 11.1), and the median CD4 T-cell percentage was 33% (interquartile range, 26 to 39). Participants who stopped co-trimoxazole had higher rates of hospitalization or death than those who continued (72 participants [19%] vs. 48 [13%]; hazard ratio, 1.64; 95% confidence interval [CI], 1.14 to 2.37; P = 0.007; noninferiority not shown). There was no evidence of variation across ages (P = 0.93 for interaction). A total of 2 participants in the prophylaxis-stopped group (1%) died, as did 3 in the prophylaxis-continued group (1%). Most hospitalizations in the prophylaxis-stopped group were for malaria (49 events, vs. 21 in the prophylaxis-continued group) or infections other than malaria (53 vs. 25), particularly pneumonia, sepsis, and meningitis. Rates of adverse events of grade 3 or 4 were similar in the two groups (hazard ratio, 1.20; 95% CI, 0.83 to 1.72; P = 0.33), but more grade 4 adverse events occurred in the prophylaxis-stopped group (hazard ratio, 2.04; 95% CI, 0.99 to 4.22; P = 0.05), with anemia accounting for the largest number of events (12, vs. 2 with continued prophylaxis).
Continuing co-trimoxazole prophylaxis after 96 weeks of ART was beneficial, as compared with stopping prophylaxis, with fewer hospitalizations for both malaria and infection not related to malaria. (Funded by the United Kingdom Medical Research Council and others; ARROW Current Controlled Trials number, ISRCTN24791884.)
PMCID: PMC4264559  PMID: 24382064
24.  The stunting syndrome in developing countries 
Linear growth failure is the most common form of undernutrition globally. With an estimated 165 million children below 5 years of age affected, stunting has been identified as a major public health priority, and there are ambitious targets to reduce the prevalence of stunting by 40% between 2010 and 2025. We view this condition as a ‘stunting syndrome’ in which multiple pathological changes marked by linear growth retardation in early life are associated with increased morbidity and mortality, reduced physical, neurodevelopmental and economic capacity and an elevated risk of metabolic disease into adulthood. Stunting is a cyclical process because women who were themselves stunted in childhood tend to have stunted offspring, creating an intergenerational cycle of poverty and reduced human capital that is difficult to break. In this review, the mechanisms underlying linear growth failure at different ages are described, the short-, medium- and long-term consequences of stunting are discussed, and the evidence for windows of opportunity during the life cycle to target interventions at the stunting syndrome are evaluated.
PMCID: PMC4232245  PMID: 25310000
Stunting; Malnutrition; Mortality; Neurodevelopment; Infections
25.  Dosing of Praziquantel by Height in Sub-Saharan African Adults 
The cornerstone of schistosomiasis control is mass praziquantel treatment in high prevalence areas. Adults are an important target population, given increasing recognition of the burden of male and female genital schistosomiasis. However, use of weighing scales to calculate praziquantel dosing in rural areas can be challenging. For school-age children, the World Health Organization (WHO) has approved a dose pole to simplify praziquantel dosing based on height. We modified the pediatric dose pole by adding two height categories and incorporating a simple overweight/obesity adjustment, for simplified mass treatment of adults in sub-Saharan Africa. Using the rural Zimbabwean Demographic and Health Survey data, we show that the modified dose pole with body mass index adjustment would result in > 98% of adults receiving an acceptable dose (30–60 mg/kg), with only 1.4% and 0.3% receiving an inadequate dose (< 30 mg/kg) or high dose (> 60 mg/kg), respectively. An adult dose pole may provide a more feasible alternative to weighing scales in community-based praziquantel treatment programs.
PMCID: PMC3973506  PMID: 24591432

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