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Antiretroviral therapy during pregnancy and early neonatal life: consequences for HIV-exposed, uninfected children
El Beitune, Patrícia;Duarte, Geraldo;Quintana, Silvana Maria;Figueiró-Filho, Ernesto A.;Marcolin, Alessandra Cristina;Abduch, Renata;
Brazilian Journal of Infectious Diseases , 2004, DOI: 10.1590/S1413-86702004000200004
Abstract: women have emerged as the fastest growing human immunodeficiency virus (hiv) infected population worldwide, mainly because of the increasing occurrence of heterosexual transmission. most infected women are of reproductive age and one of the greatest concerns for both women and their physicians is that more than 1,600 infants become infected with hiv each day. almost all infections are a result of mother-to-child transmission of hiv. with the advent of combination antiretroviral therapies, transmission rates lower than 2% have been achieved in clinical studies. antiretroviral compounds differ from most other new pharmaceutical agents in that they have become widely prescribed in pregnancy in the absence of proof of safety. we reviewed antiretroviral agents used in pregnant women infected with human immunodeficiency virus, mother-to-child transmission, and their consequences for infants.
Neurodevelopmental status of HIV-exposed but uninfected children: A pilot study
P Springer, B Laughton, M Tomlinson, J Harvey, M Esser
South African Journal of Child Health , 2012,
Abstract: Introduction. HIV affects children both directly and indirectly, with evidence of increased infectious mortality and morbidity in the HIV-exposed but uninfected (HEU) infant. There is little published research on neurodevelopmental outcome of HEU infants in Africa. Following the introduction of successful prevention of mother-to-child transmission programmes, it has become important to determine whether differences exist between HEU infants and infants born to HIV-negative mothers in order to guide current management policies of this rapidly growing group of infants. Objectives. To compare the developmental outcome of infants exposed to HIV in utero who remained uninfected (HEU) with that of infants unexposed to HIV in utero (HUU). Methodology. This was a prospective, blinded, hospital-based study. Infants aged between 17 and 19 months were assessed on the Griffiths Mental Developmental Scales (GMDS). Birth history, previous hospitalisation, maternal and infant characteristics, antiretroviral exposure, anthropometric measurements and abnormal clinical findings were documented. Results. Of the original 55 infants enrolled at 2 weeks of age, 37 (17 HEU and 20 HUU) underwent neurological and developmental assessment. There were no significant differences between the groups with regard to the GMDS general quotient or other subscales, apart from the Personal/social subscale, where the HEU group performed significantly more poorly than the HUU participants (p=0.026). This difference is probably a result of cultural differences between the groups, as 76% of HEU and only 15% of HUU participants were of Xhosa origin. Discussion. There was no difference in neurodevelopmental outcome at 18 months between the HEU and HUU groups.
Antiretroviral agents and acid-base balance at delivery of the neonate
El-Beitune, P.;Duarte, G.;Morais, E.N. de;Campbell, O.;Spara-Gadelha, P.;Mauad-Filho, F.;Quintana, S.M.;Rodrigues, L.C.;
Brazilian Journal of Medical and Biological Research , 2007, DOI: 10.1590/S0100-879X2006005000126
Abstract: limited evidence is available regarding antiretroviral (arv) safety for uninfected infants exposed to these drugs in utero. our objective was to determine if arv administered to pregnant women is associated with decreasing umbilical arterial ph and base excess in uninfected infants. a prospective study was conducted on 57 neonates divided into three groups: zdv group, born to mothers taking zidovudine (n = 20), triple therapy (tt) group, born to mothers taking zidovudine + lamivudine + nelfinavir (n = 25), and control group (n = 12), born to uninfected mothers. umbilical cord blood was used to determine umbilical artery gases. a test was performed to calculate the sample by comparing means by the unpaired one-tailed t-test, with a = 0.05 and ? = 20%, indicating the need for a sample of 18 newborn infants for the study groups to detect differences higher than 20%. the control and arv groups were similar in gestational age, birth weight, and apgar scores. values of ph, pco2, bicarbonate, and base excess in cord arterial blood obtained at delivery from the newborns exposed to tt were 7.23, 43.2 mmhg, 19.5 meq/l, and -8.5 nmol/l, respectively, with no significant difference compared to the control and zdv groups. we conclude that intrauterine exposure to arv is not associated with a pathological decrease in umbilical arterial ph or base excess. while our data are reassuring, follow-up is still limited and needs to be continued into adulthood because of the possible potential for adverse effects of triple antiretroviral agents.
Safety of Pediatric HIV Elimination: The Growing Population of HIV- and Antiretroviral-Exposed but Uninfected Infants  [PDF]
Lynne M. Mofenson ,D. Heather Watts
PLOS Medicine , 2014, DOI: 10.1371/journal.pmed.1001636
Abstract:
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.
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).
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.
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
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.
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.
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