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Growth and Development of the HIV Exposed Uninfected Children below 5 Years in Developing Countries: Focus on Nutritional Challenges, Mortality and Neurocognitive Function  [PDF]
Patience Kuona, Gwendoline Kandawasvika, Felicity Gumbo, Kusum Nathoo, Babill Stray-Pedersen
Food and Nutrition Sciences (FNS) , 2014, DOI: 10.4236/fns.2014.520211
Abstract: The future of any population is children. Resource limited settings with a high prevalence of HIV infection notably also have an excessive burden of malnutrition. The advances in prevention of mother to child HIV transmission programmes have led to very effective combination antiretroviral regimens resulting in growing numbers of HIV exposed but uninfected children. The mortality of HIV exposed but uninfected children below 5 years is high in resource limited settings. It is also important to pay particular attention to their longitudinal growth and neurodevelopmental outcomes. In these settings, the contribution of feeding practices, choice of complementary foods and micronutrient deficiencies, to health outcomes of HIV exposed uninfected children are not clearly defined. This review highlights some gaps in research that need to be addressed in areas with increasing numbers of HIV exposed but uninfected children. Interventions to reduce mortality, improve growth and neurodevelopmental outcomes in HIV exposed uninfected children from resource limited areas should be prioritized.
Low Birth Weight in Perinatally HIV-Exposed Uninfected Infants: Observations in Urban Settings in Cameroon  [PDF]
Casimir Ledoux Sofeu, Josiane Warszawski, Francis Ateba Ndongo, Ida Calixte Penda, Suzie Tetang Ndiang, Georgette Guemkam, Nicaise Makwet, Félicité Owona, Anfumbom Kfutwah, Patrice Tchendjou, Ga?tan Texier, Maurice Tchuente, Albert Faye, Mathurin Cyrille Tejiokem, The ANRS-PEDIACAM study group
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0093554
Abstract: Background The consequences of maternal HIV infection for fetal growth are controversial. Here, we estimated the frequency of small for gestational age and gender (SGAG) among neonates born to HIV-infected or uninfected mothers and assessed the contribution, if any, of maternal HIV to the risk of SGAG. Methods The data used were obtained from the ANRS-Pediacam cohort in Cameroon. Pairs of newborns, one to a HIV-infected mother and the other to an uninfected mother, were identified during the first week of life, and matched on gender and recruitment site from 2007–2010. SGAG was defined in line with international recommendations as a birth weight Z-score adjusted for gestational age at delivery and gender more than two standard deviations below the mean (?2SD). Considering the matched design, logistic regression modeling was adjusted on site and gender to explore the effect of perinatal HIV exposure on SGAG. Results Among the 4104 mother-infant pairs originally enrolled, no data on birth weight and/or gestational age were available for 108; also, 259 were twins and were excluded. Of the remaining 3737 mother-infant pairs, the frequency of SGAG was 5.3% (95%CI: 4.6–6.0), and was significantly higher among HIV-infected infants (22.4% vs. 6.3%; p<.001) and lower among HIV-unexposed uninfected infants (3.5% vs. 6.3%; p<.001) than among HIV-exposed uninfected infants. Similarly, SGAG was significantly more frequent among HIV-infected infants (aOR: 4.1; 2.0–8.1) and less frequent among HIV-unexposed uninfected infants (aOR: 0.5; 0.4–0.8) than among HIV-exposed uninfected infants. Primiparity (aOR: 1.9; 1.3–2.7) and the presence of any disease during pregnancy (aOR: 1.4; 1.0–2.0) were identified as other contributors to SGAG. Conclusion Maternal HIV infection was independently associated with SGAG for HIV-exposed uninfected infants. This provides further evidence of the need for adapted monitoring of pregnancy in HIV-infected women, especially if they are symptomatic, to minimize additional risk factors for SGAG.
Leukocyte Telomere Length in HIV-Infected and HIV-Exposed Uninfected Children: Shorter Telomeres with Uncontrolled HIV Viremia  [PDF]
Hélène C. F. C?té, Hugo Soudeyns, Anona Thorne, Ariane Alimenti, Valérie Lamarre, Evelyn J. Maan, Beheroze Sattha, Joel Singer, Normand Lapointe, Deborah M. Money, John Forbes, the CIHR Emerging Team in HIV therapy, aging (CARMA)
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0039266
Abstract: Objectives Nucleoside reverse transcriptase inhibitors (NRTIs) used in HIV antiretroviral therapy can inhibit human telomerase reverse transcriptase. We therefore investigated whether in utero or childhood exposure to NRTIs affects leukocyte telomere length (LTL), a marker of cellular aging. Methods In this cross-sectional CARMA cohort study, we investigated factors associated with LTL in HIV -1-infected (HIV+) children (n = 94), HIV-1-exposed uninfected (HEU) children who were exposed to antiretroviral therapy (ART) perinatally (n = 177), and HIV-unexposed uninfected (HIV?) control children (n = 104) aged 0–19 years. Univariate followed by multivariate linear regression models were used to examine relationships of explanatory variables with LTL for: a) all subjects, b) HIV+/HEU children only, and c) HIV+ children only. Results After adjusting for age and gender, there was no difference in LTL between the 3 groups, when considering children of all ages together. In multivariate models, older age and male gender were associated with shorter LTL. For the HIV+ group alone, having a detectable HIV viral load was also strongly associated with shorter LTL (p = 0.007). Conclusions In this large study, group rates of LTL attrition were similar for HIV+, HEU and HIV? children. No associations between children’s LTL and their perinatal ART exposure or HIV status were seen in linear regression models. However, the association between having a detectable HIV viral load and shorter LTL suggests that uncontrolled HIV viremia rather than duration of ART exposure may be associated with acceleration of blood telomere attrition.
Outcome of HIV-exposed uninfected children undergoing surgery
Jonathan S Karpelowsky, Alastair JW Millar, Nelleke van der Graaf, Guido van Bogerijen, Heather J Zar
BMC Pediatrics , 2011, DOI: 10.1186/1471-2431-11-69
Abstract: A prospective study of children less than 60 months of age undergoing general surgery at a paediatric referral hospital from July 2004 to July 2008 inclusive. Children underwent age-definitive HIV testing and were followed up post operatively for the development of complications, length of stay and mortality.Three hundred and eighty children were enrolled; 4 died and 11 were lost to follow up prior to HIV testing, thus 365 children were included. Of these, 38(10.4%) were HIVe, 245(67.1%) were HIVn and 82(22.5%) were HIVi children.The overall mortality was low, with 2(5.2%) deaths in the HIVe group, 0 in the HIVn group and 6(7.3%) in the HIVi group (p = 0.0003). HIVe had a longer stay than HIVn children (3 (2-7) vs. 2 (1-4) days p = 0.02). There was no significant difference in length of stay between the HIVe and HIVi groups. HIVe children had a higher rate of complications compared to HIVn children, (9 (23.7%) vs. 14(5.7%) (RR 3.8(2.1-7) p < 0.0001) but a similar rate of complications compared to HIVi children 34 (41.5%) (RR = 0.6 (0.3-1.1) p = 0.06).HIVe children have a higher risk of developing complications and mortality after surgery compared to HIVn children. However, the risk of complications is lower than that of HIVi children.HIV-exposed uninfected (HIVe) children are a rapidly growing population. Programs for the prevention of mother to child transmission (PMTCT) have reduced the transmission rate of perinatal HIV infection to approximately 2% to 5% [1-3]. Such programs have therefore effectively reduced the number of HIV infected (HIVi)children but identified an increasing population of HIVe children [4].HIVe children have been overlooked as a group of children who may be at an increased risk of illness compared to HIV-unexposed (HIVn) children. Recently, increased morbidity and mortality in HIVe children compared to HIVn children has been reported [4-10]. Many factors may account for this including innate deficiencies in immunity [11-13], feeding practice
Cotrimoxazole Prophylaxis and Risk of Severe Anemia or Severe Neutropenia in HAART-Exposed, HIV-Uninfected Infants  [PDF]
Scott Dryden-Peterson, Oluwemimo Jayeoba, Michael D. Hughes, Haruna Jibril, Kenneth McIntosh, Taolo A. Modise, Aida Asmelash, Kathleen M. Powis, Max Essex, Roger L. Shapiro, Shahin Lockman
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0074171
Abstract: Background Prophylactic cotrimoxazole is recommended for infants born to HIV-infected mothers. However, cotrimoxazole may increase the risk of severe anemia or neutropenia. Methods We compared the proportion of HIV-exposed uninfected (HIV-EU) infants experiencing incident severe anemia (and separately, severe neutropenia) between a prospective cohort receiving prophylactic cotrimoxazole from 1 to 6 months vs. infants from two prior trials who did not receive cotrimoxazole. Infants were from rural and urban communities in southern Botswana. Results A total of 1705 HIV-EU infants were included. Among these 645 (37.8%) were fed with iron-supplemented formula from birth. Severe anemia developed in 87 (5.1%) infants, and severe neutropenia in 164 (9.6%) infants. In an analysis stratified by infant feeding method, there were no significant differences in the risk of severe anemia by prophylactic cotrimoxazole exposure–risk difference, ?0.69% (95% confidence interval [CI] ?2.1 to 0.76%). Findings were similar in multivariable analysis, adjusted odds ratio (aOR) 0.35 (95% CI 0.07 to 1.65). There were also no significant differences observed for severe neutropenia by cotrimoxazole exposure, risk difference 2.0% (95% CI ?1.3 to 5.2%) and aOR 0.80 (95% CI 0.33 to 1.93). Conclusions Severe anemia and severe neutropenia were infrequent among HIV-exposed uninfected infants receiving cotrimoxazole from 1–6 months of age. Concerns regarding hematologic toxicity should not limit the use of prophylactic cotrimoxazole in HIV-exposed uninfected infants. ClinicalTrials.gov Registration Numbers NCT01086878 (http://clinicaltrials.gov/show/NCT010868?78), NCT00197587 (http://clinicaltrials.gov/show/NCT001975?87), and NCT00270296 (http://clinicaltrials.gov/show/NCT002702?96).
Normal Thymic Size and Low Rate of Infections in Human Donor Milk Fed HIV-Exposed Uninfected Infants from Birth to 18 Months of Age  [PDF]
Dorthe Lisbeth Jeppesen,Annette Kj?r Ersb?ll,Tine Ursula Hoppe,Susanne Dam Nielsen,Niels Henrik Valerius
International Journal of Pediatrics , 2013, DOI: 10.1155/2013/373790
Abstract: Objective. To evaluate the immune function in HIV-exposed uninfected (HIV-EU) infants fed human donor milk. Methods. Ultrasound-obtained thymic index (Ti), T-lymphocyte subsets, and the number of infections were examined from birth to 18 months of age in 18 HIV-EU infants. The infants were compared to a cohort of 47 term, HIV-unexposed breastfed or formula-fed infants. Results. The thymic size at 12 months of age was not significantly different between the HIV-EU group and the control infants ( ). At 4 months of age, the HIV-EU infants had significantly fewer infections than the control infants ( ). Furthermore, in the control group, the infants exclusively breastfed at 4 months of age had significantly fewer infections at 8 months when compared to age-matched formula-fed infants ( ). Conclusion. HIV-EU infants fed human donor milk have normal growth of thymus and contract fewer infections than other healthy infants. This finding along with fewer infections in exclusively breastfed infants compared to formula-fed infants supports the beneficial effect of human milk on the immune system. We suggest, when breastfeeding is not possible, that providing human donor milk to vulnerable groups of infants will be beneficial for their maturing immune system. 1. Introduction Vertical transmission of HIV from HIV-positive mothers to their infants is, in industrialised countries, reduced to less than 1-2% [1–3]. Consequently, the number of HIV-exposed uninfected (HIV-EU) infants in the world is growing. Despite HIV-EU infants remaining uninfected, there have been reports of impaired immune function and reduced CD4 counts in HIV-EU newborns [4–8]. However, reports on the long-term impact of HIV exposure on the immune system have been conflicting and there have been very few studies of whether the infection burden in HIV-EU infants is higher than in HIV-unexposed infants [9, 10]. The thymus plays a key role in the development of a functional immune system, providing the environment for T-lymphocyte maturation and being a central organ for the development and maintenance of cell-mediated immunity. The thymus is also known to be a target organ in HIV-infection [11]. The transition of T-cell progenitors in the thymus has been extensively evaluated, but the significance of the size or alterations in the size of the thymus in infancy is still unclear [12–15]. The positive correlation between thymic size and weight and length at birth and during the first months of life is well known and infections are reported to result in decreasing thymic size [16–20]. We have also
Strong HIV-1-Specific T Cell Responses in HIV-1-Exposed Uninfected Infants and Neonates Revealed after Regulatory T Cell Removal  [PDF]
Fatema A. Legrand, Douglas F. Nixon, Christopher P. Loo, Erika Ono, Joan M. Chapman, Maristela Miyamoto, Ricardo S. Diaz, Amélia M.N. Santos, Regina C.M. Succi, Jacob Abadi, Michael G. Rosenberg, Maria Isabel de Moraes-Pinto, Esper G. Kallas
PLOS ONE , 2006, DOI: 10.1371/journal.pone.0000102
Abstract: Background In utero transmission of HIV-1 occurs on average in only 3%–15% of HIV-1-exposed neonates born to mothers not on antiretroviral drug therapy. Thus, despite potential exposure, the majority of infants remain uninfected. Weak HIV-1-specific T-cell responses have been detected in children exposed to HIV-1, and potentially contribute to protection against infection. We, and others, have recently shown that the removal of CD4+CD25+ T-regulatory (Treg) cells can reveal strong HIV-1 specific T-cell responses in some HIV-1 infected adults. Here, we hypothesized that Treg cells could suppress HIV-1-specific immune responses in young children. Methodology/Principal Findings We studied two cohorts of children. The first group included HIV-1-exposed-uninfected (EU) as well as unexposed (UNEX) neonates. The second group comprised HIV-1-infected and HIV-1-EU children. We quantified the frequency of Treg cells, T-cell activation, and cell-mediated immune responses. We detected high levels of CD4+CD25+CD127? Treg cells and low levels of CD4+ and CD8+ T cell activation in the cord blood of the EU neonates. We observed HIV-1-specific T cell immune responses in all of the children exposed to the virus. These T-cell responses were not seen in the cord blood of control HIV-1 unexposed neonates. Moreover, the depletion of CD4+CD25+ Treg cells from the cord blood of EU newborns strikingly augmented both CD4+ and CD8+ HIV-1-specific immune responses. Conclusions/Significance This study provides new evidence that EU infants can mount strong HIV-1-specific T cell responses, and that in utero CD4+CD25+ T-regulatory cells may be contributing to the lack of vertical transmission by reducing T cell activation.
Partial protective effect of CCR5-Delta 32 heterozygosity in a cohort of heterosexual Italian HIV-1 exposed uninfected individuals
Enrico M Trecarichi, Mario Tumbarello, Katleen Donati, Enrica Tamburrini, Roberto Cauda, Christina Brahe, Francesco D Tiziano
AIDS Research and Therapy , 2006, DOI: 10.1186/1742-6405-3-22
Abstract: In conclusion, our data show a significantly higher frequency of CCR5-Delta 32 heterozygous genotype (p = 0.04) among the Italian heterosexual ESN individuals compared to HIV-1 seropositive patients, suggesting a partial protective role of CCR5-Delta 32 heterozygosity in this cohort.Despite multiple sexual exposures to HIV-1 virus, some individuals remain HIV-1 seronegative (exposed seronegative, ESN). Although severe factors have been related to HIV-1 infection resistance, the possible genetic mechanisms underlying this resistance presently remain elusive [1,2]. The most investigated genetic factor associated with HIV-1 infection resistance is the homozygous presence of a 32 bp deletion in CCR5 gene (CCR5-Delta 32) [3], i.e. the main co-receptor used by the macrophage (M)-tropic strain of the virus to infect peripheral blood mononuclear cells. The 32 bp deletion leads to the synthesis of a truncated protein which does not allow the proper interaction between HIV-1 and the cell surface, thus preventing virion endocytosis. Only 1% of Caucasian individuals is homozygous for CCR5-Delta 32 allele and the frequency of this genotype has been reported to be slightly higher in anti HIV-1 seronegative individuals at high risk of HIV-1-infection [4,5].Other genetic factors have been reported to be involved in HIV-1 infection susceptibility. It has been suggested that the C77G variant in exon 4 of the CD45 gene (CD45-C77G) is more frequent in HIV-1 infected subjects, compared to uninfected individuals [6]. This transversion is responsible for an abnormal splicing of exon 4, leading to the production of a high molecular weight isoform of the protein, normally expressed in the naive T cells but not in the normal activated T cells [7]. Other mutations of this gene have been associated to severe forms of combined immunodeficiency in humans [7].In the present study we investigated the possible role of CCR5 and CD45 genic variants in the resistance to HIV-1 infection in a cohort of
Maternal Obesity Affects Fetal Neurodevelopmental and Metabolic Gene Expression: A Pilot Study  [PDF]
Andrea G. Edlow, Neeta L. Vora, Lisa Hui, Heather C. Wick, Janet M. Cowan, Diana W. Bianchi
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0088661
Abstract: Objective One in three pregnant women in the United States is obese. Their offspring are at increased risk for neurodevelopmental and metabolic morbidity. Underlying molecular mechanisms are poorly understood. We performed a global gene expression analysis of mid-trimester amniotic fluid cell-free fetal RNA in obese versus lean pregnant women. Methods This prospective pilot study included eight obese (BMI≥30) and eight lean (BMI<25) women undergoing clinically indicated mid-trimester genetic amniocentesis. Subjects were matched for gestational age and fetal sex. Fetuses with abnormal karyotype or structural anomalies were excluded. Cell-free fetal RNA was extracted from amniotic fluid and hybridized to whole genome expression arrays. Genes significantly differentially regulated in 8/8 obese-lean pairs were identified using paired t-tests with the Benjamini-Hochberg correction (false discovery rate of <0.05). Biological interpretation was performed with Ingenuity Pathway Analysis and the BioGPS gene expression atlas. Results In fetuses of obese pregnant women, 205 genes were significantly differentially regulated. Apolipoprotein D, a gene highly expressed in the central nervous system and integral to lipid regulation, was the most up-regulated gene (9-fold). Apoptotic cell death was significantly down-regulated, particularly within nervous system pathways involving the cerebral cortex. Activation of the transcriptional regulators estrogen receptor, FOS, and STAT3 was predicted in fetuses of obese women, suggesting a pro-estrogenic, pro-inflammatory milieu. Conclusion Maternal obesity affects fetal neurodevelopmental and metabolic gene expression as early as the second trimester. These findings may have implications for postnatal neurodevelopmental and metabolic abnormalities described in the offspring of obese women.
Association of Serum Albumin with Markers of Nutritional Status among HIV-Infected and Uninfected Rwandan Women  [PDF]
Jean-Claude Dusingize, Donald R. Hoover, Qiuhu Shi, Eugene Mutimura, Elizabeth Kiefer, Mardge Cohen, Kathryn Anastos
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0035079
Abstract: Introduction The objectives of this study are to address if and how albumin can be used as an indication of malnutrition in HIV infected and uninfected Africans. Methods In 2005, 710 HIV-infected and 226 HIV-uninfected women enrolled in a cohort study. Clinical/demographic parameters, CD4 count, albumin, liver transaminases; anthropometric measurements and Bioelectrical Impedance Analysis (BIA) were performed. Malnutrition outcomes were defined as body mass index (BMI), Fat-free mass index (FFMI) and Fat mass index (FMI). Separate linear predictive models including albumin were fit to these outcomes in HIV negative and HIV positive women by CD4 strata (CD4>350,200–350 and <200 cells/μl). Results In unadjusted models for each outcome in HIV-negative and HIV positive women with CD4>350 cells/μl, serum albumin was not significantly associated with BMI, FFMI or FMI. Albumin was significantly associated with all three outcomes (p<0.05) in HIV+ women with CD4 200–350 cells/μl, and highly significant in HIV+ women with CD4<200 cells/μl (P<0.001). In multivariable linear regression, albumin remained associated with FFMI in women with CD4 count<200 cells/μl (p<0.01) but not in HIV+ women with CD4>200. Discussion While serum albumin is widely used to indicate nutritional status it did not consistently predict malnutrition outcomes in HIV- women or HIV+ women with higher CD4. This result suggests that albumin may measure end stage disease as well as malnutrition and should not be used as a proxy for nutritional status without further study of its association with validated measures.
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