HIV-unexposed Uninfected Infants Research Articles

Growth of HIV-Exposed Infants in Southwest China: A Comparative Study.

Objectives. Prevention of mother-to-child HIV transmission has been globally successful leading to a decline in HIV-infected infants. Thus, the number of HIV-exposed, but uninfected, infants is increasing. As growth is an important indicator of child health, this study aimed to evaluate growth parameters of HIV-exposed Chinese infants. Methods. A prospective study was conducted among HIV-exposed (HIV-infected and uninfected) infants born during 2007 to 2015 in Liuzhou, China. Their weight and length were assessed longitudinally from birth to 18 months of age and compared with HIV-unexposed, uninfected (HUU) infants from the same region. Results. There were 467 HIV-exposed infants. Four percent of infants were HIV-infected. The mean weight-for-age (WAZ) and length-for-age (LAZ) z scores of HIV-infected infants were significantly lower than those of HIV-exposed but uninfected (HEU) infants during 9 to 18 months and 12 to 18 months of age, respectively. Additionally, the mean WAZ and LAZ scores of HIV-infected infants were significantly lower than HUU infants during the first 12 months and 18 months of life, respectively. The mean WAZ and LAZ scores of HEU infants were significantly lower than HUU infants during the first 12 months and 6 months of life, respectively. HEU infants also had a lower mean weight-for-length z score than HUU infants during the first 6 months. Conclusion. We demonstrated poor growth among HIV-exposed Chinese infants, including HIV-uninfected, compared with HUU infants. The results emphasize the need for nutritional monitoring and interventions for HIV-exposed infants regardless of HIV infection status. Research is needed on long-term growth trajectories and factors affecting growth of HIV-exposed infants in China.

2571. Higher Rates of Hospitalization and Infection-Related Hospitalization Among HIV-Exposed Uninfected Infants Compared with HIV Unexposed Uninfected Infants in the United States

BackgroundStudies from multiple countries have suggested impaired immunity in perinatally HIV-exposed uninfected (HEU) children, with elevated rates of all-cause hospitalization and infections. We estimated the incidence of all-cause hospitalization and infection-related hospitalization in the first 2 years of life among HEU children and compared this with HIV-unexposed uninfected (HUU) children in the US Among HEU children, we evaluated associations of maternal HIV disease-related factors during pregnancy with risk of infant hospitalization.MethodsWe evaluated HEU children enrolled in the Surveillance Monitoring for ART Toxicities (SMARTT) Study dynamic cohort of the Pediatric HIV/AIDS Cohort Study (PHACS) network who were born 2006–2017 and followed from birth. Data on HUU children were obtained from the Medicaid Analytic Extract database, restricted to states participating in SMARTT. We compared rates of first hospitalization, total hospitalizations, first infection-related hospitalization, total infection-related hospitalizations, and mortality between HEU and HUU children using Poisson regression. Among HEU children, multivariable Poisson regression models were fit to evaluate associations of maternal HIV factors with risk of hospitalization.ResultsOur analysis included 2,404 HEU and 3,605,864 HUU children. HEU children had approximately 2 times greater rates of first hospitalization, total hospitalizations, first infection-related hospitalization, and total infection-related hospitalizations compared with HUU children (figure). There was no significant difference in mortality. Among HEU children, maternal HIV disease factors, including viral load, CD4 count, antiretroviral regimen, and mode of HIV acquisition, were not associated with hospitalization rates.ConclusionCompared with HUU, HEU children in the United States have nearly twice the rate of hospitalization and infection-related hospitalization in the first 2 years of life, consistent with studies in other countries. Closer monitoring of HEU infants for infection and further elucidation of immune mechanisms is needed.Figure:Rates of Hospitalization and Mortality in First 2 Years of Life (95% CI) among SMARTT HEU versus Medicaid HUU in the United States, 2007–2016Disclosures E. G. Chadwick, Abbott Labs: Shareholder, stock dividends. AbbVie: Shareholder, stock dividends. R. Van Dyke, Giliad Sciences: Grant Investigator, Research grant.

Breastfeeding mitigates the effects of maternal HIV on infant infectious morbidity in the Option B+ era.

The effects of in-utero HIV-exposure on infectious morbidity and mortality in settings with universal maternal treatment and high breastfeeding rates are unclear. Further, the benefits of exclusive feeding options have not been assessed in the Option B+ era. We investigated these in two African settings with high breastfeeding uptake and good HIV treatment infrastructure during the first year of life. Cox regression with time-changing variables in a birth cohort of 749 HIV-exposed uninfected and HIV-unexposed uninfected infants from Cape Town, South Africa and Jos, Nigeria. There was no difference in infectious morbidity incidence between HIV-exposed uninfected and HIV-unexposed uninfected infants (hazard ratio 1.01; 95% CI 0.78-1.32) after adjusting for confounding variables. Formula-fed infants had significantly higher infectious morbidity incidence when compared with exclusively breastfed infants (hazard ratio 1.64; 95% CI 1.03-2.63) and mixed-breastfed infants (hazard ratio 1.42; 95% CI 1.00-2.02) after adjusting for potential confounding variables. There was no significant difference in mortality among HIV-exposed infants and HIV-unexposed infants during the first year of life in this cohort (2.04 versus 0.94%, P = 0.38). Notably, exclusive breastfeeding for only 4 months had protective effects on morbidity up to 1 year. In settings with universal antiretroviral coverage and high breastfeeding rates, breastfeeding mitigates the effects of in-utero HIV exposure among infants during the first year of life. These findings support previous recommendations for exclusive breastfeeding among HIV-infected women and highlight the role that breastfeeding plays on the health of infants in settings where exclusive breastfeeding is not always feasible or where replacement feeding is recommended.

Lower mitochondrial DNA and altered mitochondrial fuel metabolism in HIV-exposed uninfected infants in Cameroon.

Evaluate blood mitochondrial DNA (mtDNA) content in HIV/antiretroviral-exposed uninfected (HEU) vs. HIV-unexposed uninfected (HUU) infants and investigate differences in mitochondrial-related metabolites by exposure group. We enrolled a prospective cohort of HIV-infected and HIV-uninfected pregnant woman/infant pairs in Cameroon. Dried blood spot mtDNA : nuclear DNA ratio was measured by monochrome multiplex quantitative polymerase chain reaction in HEU infants exposed to in-utero antiretrovirals and postnatal zidovudine (HEU-Z) or nevirapine (HEU-N), and in HUU infants at 6 weeks of life. Acylcarnitines and branch-chain amino acids (BCAAs) were measured via tandem mass spectrometry and consolidated into seven uncorrelated components using principal component analysis. Linear regression models were fit to assess the association between in-utero/postnatal HIV/antiretroviral exposure and infant mtDNA, adjusting for confounders and principal component analysis-derived acylcarnitine/BCAA component scores. Of 364 singleton infants, 38 were HEU-Z, 117 HEU-N, and 209 HUU. Mean mtDNA content was lowest in HEU-Z infants (140 vs. 160 in HEU-N vs. 174 in HUU, P = 0.004). After adjusting for confounders, HEU-Z infants remained at increased risk for lower mtDNA content compared with HUU infants (β: -4.46, P = 0.045), whereas HEU-N infants did not, compared with HUU infants (β: -1.68, P = 0.269. Furthermore, long-chain acylcarnitines were associated with lower (β: -2.35, P = 0.002) and short-chain and BCAA-related acylcarnitines were associated with higher (β: 2.96, P = 0.001) mtDNA content. Compared with HUU infants, HEU infants receiving postnatal zidovudine appear to be at increased risk for decreased blood mtDNA content which may be associated with altered mitochondrial fuel utilization in HEU-Z infants.

Birthweight, HIV exposure and infant feeding as predictors of malnutrition in Botswanan infants.

A better understanding of the nutritional status of infants who are HIV-Exposed-Uninfected (HEU) and HIV-Unexposed-Uninfected (HUU) during their first 1000 days is key to improving population health, particularly in sub-Saharan Africa. A cross-sectional study compared the nutritional status, feeding practices and determinants of nutritional status of HEU and HUU infants residing in representative selected districts in Botswana during their first 1000 days of life. Four hundred and thirteen infants (37.3% HIV-exposed), aged 6-24 months, attending routine child health clinics, were recruited. Anthropometric, 24-h dietary intake and socio-demographic data was collected. Anthropometric Z-scores were calculated using 2006 World Health Organization growth standards. Modelling of the determinants of malnutrition was undertaken using logistic regression. Overall, the prevalences of stunting, wasting and being underweight were 10.4%, 11.9% and 10.2%, respectively. HEU infants were more likely to be underweight (15.6% versus 6.9%), (P < 0.01) and stunted (15.6% versus 7.3%), (P < 0.05) but not wasted (P = 0.14) than HUU infants. HEU infants tended to be formula fed (82.5%), whereas HUU infants tended to breastfeed (94%) for the first 6 months (P < 0.001). Significant predictors of nutritional status were HIV exposure, birthweight, birth length, APGAR (appearance, pulse, grimace, activity and respiration) score and mother/caregiver's education with little influence of socio-economic status. HEU infants aged 6-24 months had worse nutritional status compared to HUU infants. Low birthweight was the main predictor of undernutrition in this population. Optimisation of infant nutritional status should focus on improving birthweight. In addition, specific interventions should target HEU infants aiming to eliminate growth disparity between HEU and HUU infants.

In Utero ART Exposure and Birth and Early Growth Outcomes Among HIV-Exposed Uninfected Infants Attending Immunization Services: Results From National PMTCT Surveillance, South Africa.

BackgroundDespite the recognized benefit of antiretroviral therapy (ART) for preventing and treating HIV, some studies have reported adverse birth outcomes with in utero ART exposure. We evaluated the effect of infant in utero HIV and ART exposure on preterm delivery (PTD), low birth weight (LBW), small for gestational age (SGA), and underweight for age (UFA) at 6 weeks.MethodsWe surveyed 6179 HIV-unexposed-uninfected (HUU) and 2599 HIV-exposed-uninfected (HEU) infants. HEU infants were stratified into 3 groups: ART, Zidovudine alone, and no antiretrovirals (None). The ART group was further stratified to explore pre- or postconception exposure. Multivariable logistic regression evaluated effects of HIV and ARV exposure on the outcomes.ResultsWe found higher odds of PTD, LBW, SGA, and UFA in HEU than HUU infants. HEU in the None group (adjusted odds ratio [AOR], 1.9; 95% confidence interval [CI], 1.2–3.0) or those whose mothers initiated ART preconception (AOR, 1.7; 95% CI, 1.1–2.5) had almost twice the odds of PTD than infants whose mothers started ART postconception, but no increased odds for other outcomes.ConclusionsThere was an association between preconception ART and PTD. As ART access increases, pregnancy registers or similar surveillance should be in place to monitor outcomes to inform future policy.

Cytomegalovirus viraemia is associated with poor growth and T-cell activation with an increased burden in HIV-exposed uninfected infants.

Objective:Factors associated with poor health in HIV-exposed-uninfected (HEU) infants are poorly defined. We describe the prevalence and correlates of cytomegalovirus (CMV) viraemia in HEU and HIV-unexposed-uninfected (HUU) infants, and quantify associations with anthropometric, haematological, and immunological outcomes.Design:Cross-sectional, including HEU and HUU infants from rural coastal Kenya.Methods:Infants aged 2–8 months were studied. The primary outcome was CMV viraemia and viral load, determined by quantitative PCR. Correlates were tested by logistic and linear regression; coefficients were used to describe associations between CMV viraemia and clinical/immunological parameters.Results:In total, 42 of 65 (64.6%) infants had CMV viraemia [median viral load, 3.0 (interquartile ranges: 2.7–3.5) log10 IU/ml]. Compared to community controls, HEU infants had six-fold increased odds of being viraemic (adjusted odds ratio 5.95 [95% confidence interval: 1.82–19.36], P = 0.003). Age, but not HEU/HUU status, was a strong correlate of CMV viral load (coefficient = −0.15, P = 0.009). CMV viral load associated negatively with weight-for-age (WAZ) Z-score (coefficient = −1.06, P = 0.008) and head circumference-for-age Z-score (coefficient = −1.47, P = 0.012) and positively with CD8+ T-cell coexpression of CD38/human leucocyte antigen DR (coefficient = 15.05, P = 0.003).Conclusion:The odds of having CMV viraemia was six-fold greater in HEU than HUU infants when adjusted for age. CMV viral load was associated with adverse growth and heightened CD8+ T-cell immune activation. Longitudinal assessments of the clinical effects of primary CMV infection and associated immunomodulation in early life in HEU and HUU populations are warranted.

Immunization with 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) according to different schedules in infants in South Africa: a phase III trial

ABSTRACT Background: Limited clinical data exists to assess differences between various infant pneumococcal conjugate vaccine schedules. In this trial, we evaluated immunogenicity of the 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) administered using 3 different immunization schedules in HIV unexposed-uninfected infants in South Africa. Methods: In this phase III, open, single‐center, controlled study (clinicaltrials.gov: NCT00829010), 300 infants were randomized (1:1:1) to 1 of 3 PHiD-CV schedules: 3-dose priming and booster (3 + 1); 3-dose priming without booster (3 + 0); or 2-dose priming and booster (2 + 1). The booster was administered at 9–10 months of age. immune responses were assessed up to 21 months after primary vaccination. Results: Post‐priming antibody levels tended to be lower in the 2 + 1 group. At 6 months post‐priming, antibody concentrations and opsonophagocytic activity titers were within similar ranges after 2‐ or 3‐dose priming. Robust increases were observed pre‐ to post‐booster in the 3 + 1 and 2 + 1 groups. Conclusions: PHiD-CV was immunogenic when administered in different schedules. Post‐booster responses suggest effective immunological priming with both 2‐ and 3‐dose primary series and support administration of the booster dose at 9–10 months of age.

Growth of HIV-exposed uninfected, compared with HIV-unexposed, Zambian children: a longitudinal analysis from infancy to school age

BackgroundEarly growth of HIV-exposed, uninfected (HEU) children is poorer than that of their HIV-unexposed, uninfected (HUU) counterparts but there is little longitudinal or longer term information about the growth effects of early HIV exposure.MethodsWe performed a longitudinal analysis to compare growth of HEU and HUU infants and children using data from two cohort studies in Lusaka, Zambia. Initially 207 HUU and 200 HEU infants from the Breastfeeding and Postpartum Health (BFPH) study and 580 HUU and 165 HEU from the Chilenje Infant Growth, Nutrition and Infection Study (CIGNIS) had anthropometric measurements taken during infancy and again when school-aged, at which time 66 BFPH children and 326 CIGNIS children were available. We analysed the data from the two cohorts separately using linear mixed models. Linear regression models were used as a secondary analysis at the later time points, adjusting for breastfeeding duration. We explored when the main group differences in growth emerged in order to estimate the largest ‘effect periods’.ResultsAfter adjusting for socioeconomic status and maternal education, HEU children had lower weight-for-age, length-for-age and BMI-for-age Z-scores during early growth and these differences still existed when children were school-aged. Exposure group differences changed most between 1 and 6 weeks and between 18 months and ~7.5 years.ConclusionsHEU children have poorer early growth than HUU children which persists into later growth. Interventions to improve growth of HEU children need to target pregnant women and infants.

Lymphocyte subsets in HIV-exposed uninfected infants and HIV-unexposed uninfected infants

Lymphocyte subsets in HIV-exposed uninfected infants and HIV-unexposed uninfected infants

Comparison of developmental milestone attainment in early treated HIV-infected infants versus HIV-unexposed infants: a prospective cohort study

BackgroundInfant HIV infection is associated with delayed milestone attainment. The extent to which effective antiretroviral therapy (ART) prevents these delays is not well defined.MethodsAges at attainment of milestones were compared between HIV-infected (initiated ART by age <5 months), and HIV-unexposed uninfected (HUU) infants. Kaplan Meier analyses were used to estimate and compare (log-rank tests) ages at milestones between groups. Adjusted analyses were performed using Cox proportional hazards models.ResultsSeventy-three HIV-infected on ART (median enrollment age 3.7 months) and 92 HUU infants (median enrollment age 1.6 months) were followed prospectively. HIV-infected infants on ART had delays in developmental milestone attainment compared to HUU: median age at attainment of sitting with support, sitting unsupported, walking with support, walking unsupported, monosyllabic speech and throwing toys were each delayed (all p-values <0.0005). Compared with HUU, the subset of HIV-infected infants with both virologic suppression and immune recovery at 6 months had delays for speech (delay: 2.0 months; P = 0.0002) and trend to later walking unsupported. Among HIV-infected infants with poor 6-month post-ART responses (lacking viral suppression and immune recovery) there were greater delays versus HUU for: walking unsupported (delay: 4.0 months; P = 0.0001) and speech (delay: 5.0 months; P < 0.0001).ConclusionsHIV infected infants with viral suppression on ART had better recovery of developmental milestones than those without suppression, however, deficits persisted compared to uninfected infants. Earlier ART may be required for optimized cognitive outcomes in perinatally HIV-infected infants.Trial registrationNCT00428116; January 22, 2007.

Malaria burden in a birth cohort of HIV-exposed uninfected Ugandan infants living in a high malaria transmission setting.

BackgroundHIV-exposed, uninfected (HEU) infants suffer high morbidity and mortality in the first year of life compared to HIV-unexposed, uninfected (HUU) infants, but accurate data on the contribution of malaria are limited.MethodsThe incidence of febrile illnesses and malaria were evaluated in a birth cohort of HEU infants. Infants were prescribed daily trimethoprim–sulfamethoxazole (TS) prophylaxis from 6 weeks of age until exclusion of HIV-infection after cessation of breastfeeding. Infants were followed for all illnesses using passive surveillance and routine blood smears were done monthly. Malaria was diagnosed as a positive blood smear plus fever. Placental malaria was determined by histopathology, placental blood smear and PCR. Risk factors for time to first episode of malaria were assessed using a Cox proportional hazards model. Malaria incidence among HEU infants aged 6–12 months was compared to that in other cohorts of HEU and HUU infants from the same region.ResultsAmong 361 HEU infants enrolled, 248 completed 12 months of follow-up resulting in 1562 episodes of febrile illness and 253 episodes of malaria after 305 person-years of follow-up. The incidence of febrile illness was 5.12 episodes per person-year (PPY), ranging from 4.13 episodes PPY in the first 4 months of life to 5.71 episodes PPY between 5 and 12 months of age. The overall malaria incidence was 0.83 episodes per person-year (PPY), increasing from 0.03 episodes PPY in the first 2 months of life to 2.00 episodes PPY between 11 and 12 months of age. There were no episodes of complicated malaria. The prevalence of asymptomatic parasitaemia was 1.2 % (19 of 1568 routine smears positive). Infants born to mothers with parasites detected from placental blood smears were at higher risk of malaria (hazard ratio = 4.51, P < 0.001). HEU infants in this study had a 2.4- to 3.5-fold lower incidence of malaria compared to HUU infants in other cohort studies from the same area.ConclusionThe burden of malaria in this birth cohort of HEU infants living in a high-transmission setting and taking daily TS prophylaxis was relatively low. Alternative etiologies of fever should be considered in HEU-infants taking daily TS prophylaxis who present with fever. Trial Registration NCT00993031, registered 8 October, 2009

Linking Susceptibility to Infectious Diseases to Immune System Abnormalities among HIV-Exposed Uninfected Infants.

HIV-exposed uninfected (HEU) infants experience increased overall mortality from infectious causes when compared to HIV-unexposed uninfected (HU) infants. This is the case in both the resource-rich and resource-limited settings. Here, we explore the concept that specific types of infectious diseases that are more common among HEU infants could provide clues as to the potential underlying immunological abnormalities. The most commonly reported infections in HEU vs. HU infants are caused by encapsulated bacteria, suggesting the existence of a less effective humoral (antibody, complement) immune response. Decreased transplacental transfer of protective maternal antibodies has consistently been observed among HEU newborns, suggesting that this may indeed be one of the key drivers of their susceptibility to infections with encapsulated bacteria. Reassuringly, HEU humoral response to vaccination appears to be well conserved. While there appears to be an increase in overall incidence of acute viral infections, no specific pattern of acute viral infections has emerged; and although there is evidence of increased chronic viral infection from perinatal transmission of hepatitis C and cytomegalovirus, no data exist to suggest an increase in adverse outcomes. Thus, no firm conclusions about antiviral effector mechanisms can be drawn. However, the most unusual of reported infections among the HEU have been opportunistic infections, suggesting the possibility of underlying defects in CD4 helper T cells and overall immune regulatory function. This may relate to the observation that the immunological profile of HEUs indicates a more activated T cell profile as well as a more inflammatory innate immune response. However, both of these observations appear transient, marked in early infancy, but no longer evident later in life. The causes of these early-life changes in immune profiles are likely multifactorial and may be related to in utero exposure to HIV, but also to increased environmental exposure to pathogens from sicker household contacts, in utero and postnatal antiretroviral drug exposure, and, in certain circumstances, differences in mode of feeding. The relative importance of each of these factors will be important to delineate in an attempt to identify those HEU at highest risk of adverse outcomes for targeted interventions.

HIV-Exposed Uninfected Infants Show Robust Memory B-Cell Responses in Spite of a Delayed Accumulation of Memory B Cells: an Observational Study in the First 2 Years of Life.

Improved HIV care has led to an increase in the number of HIV-exposed uninfected (HEU) infants born to HIV-infected women. Although they are uninfected, these infants experience increased morbidity and mortality. One explanation may be that their developing immune system is altered by HIV exposure, predisposing them to increased postnatal infections. We explored the impact of HIV exposure on the B-cell compartment by determining the B-cell subset distribution, the frequency of common vaccine antigen-specific memory B cells (MBCs), and the levels of antibodies to the respective antigens in HEU and HIV-unexposed uninfected (HUU) infants born to uninfected mothers, using flow cytometry, a B-cell enzyme-linked immunosorbent spot assay, and an enzyme-linked immunosorbent assay, respectively, during the first 2 years of life. For the majority of the B-cell subsets, there were no differences between HEU and HUU infants. However, HIV exposure was associated with a lower proportion of B cells in general and MBCs in particular, largely due to a lower proportion of unswitched memory B cells. This reduction was maintained even after correcting for age. These phenotypic differences in the MBC compartment did not affect the ability of HEU infants to generate recall responses to previously encountered antigens or reduce the antigen-specific antibody levels at 18 months of life. Although HIV exposure was associated with a transient reduction in the proportion of MBCs, we found that the ability of HEU infants to mount robust MBC and serological responses was unaffected.

Epidemiology of Acute Lower Respiratory Tract Infection in HIV-Exposed Uninfected Infants.

Increased morbidity and mortality from lower respiratory tract infection (LRTI) has been suggested in HIV-exposed uninfected (HEU) children; however, the contribution of respiratory viruses is unclear. We studied the epidemiology of LRTI hospitalization in HIV-unexposed uninfected (HUU) and HEU infants aged <6 months in South Africa. We prospectively enrolled hospitalized infants with LRTI from 4 provinces from 2010 to 2013. Using polymerase chain reaction, nasopharyngeal aspirates were tested for 10 viruses and blood for pneumococcal DNA. Incidence for 2010-2011 was estimated at 1 site with population denominators. We enrolled 3537 children aged <6 months. HIV infection and exposure status were determined for 2507 (71%), of whom 211 (8%) were HIV infected, 850 (34%) were HEU, and 1446 (58%) were HUU. The annual incidence of LRTI was elevated in HEU (incidence rate ratio [IRR] 1.4; 95% confidence interval [CI] 1.3-1.5) and HIV infected (IRR 3.8; 95% CI 3.3-4.5), compared with HUU infants. Relative incidence estimates were greater in HEU than HUU, for respiratory syncytial virus (RSV; IRR 1.4; 95% CI 1.3-1.6) and human metapneumovirus-associated (IRR 1.4; 95% CI 1.1-2.0) LRTI, with a similar trend observed for influenza (IRR 1.2; 95% CI 0.8-1.8). HEU infants overall, and those with RSV-associated LRTI had greater odds (odds ratio 2.1, 95% CI 1.1-3.8, and 12.2, 95% CI 1.7-infinity, respectively) of death than HUU. HEU infants were more likely to be hospitalized and to die in-hospital than HUU, including specifically due to RSV. This group should be considered a high-risk group for LRTI.

Low Birth Weight in Perinatally HIV-Exposed Uninfected Infants: Observations in Urban Settings in Cameroon

BackgroundThe 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.MethodsThe 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.ResultsAmong 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.ConclusionMaternal 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.

Antibody Responses to Vaccination among South African HIV-Exposed and Unexposed Uninfected Infants during the First 2 Years of Life

HIV-exposed but uninfected (HEU) infants born to HIV-infected mothers from areas in the world with a high burden of infectious disease suffer higher infectious morbidity and mortality than their HIV unexposed uninfected (HUU) peers. Vaccination provides protection from infection. The possibility exists that altered response to vaccination contributes to the higher rate of infection in HEU than in HUU infants. While short-term, cross-sectional studies support this notion, it is unclear whether or not HEU infants develop long-term protective immune responses following the WHO extended program on immunization (EPI). Vaccine-specific antibody responses were compared between HEU and HUU infants from 2 weeks until 2 years of age in a longitudinal South African cohort. Total IgG and antibodies specific for Bordetella pertussis, Haemophilus influenzae type b (Hib), tetanus toxoid, hepatitis B virus (HepB), and measles virus were measured at multiple time points throughout the first 2 years of life. Prevaccine antibodies (maternal antibodies passively acquired) specific for tetanus were lower in HEU than in HUU infants, while prevaccine antibodies to HepB were higher in HEU than in HUU infants. Both groups responded similarly to tetanus, Hib, and HepB vaccination. HEU demonstrated stronger pertussis vaccine responses, developing protective titers 1 year earlier than HUU patients, and maintained higher anti-tetanus titers at 24 months of age. Vaccine-induced antibodies to measles virus were similar in both groups at all time points. Our results suggest that the current EPI vaccination program as practiced in South Africa leads to the development of vaccine-specific antibody responses that are equivalent in HEU and HUU infants. However, our data also suggest that a large fraction of both HEU and HUU South African infants have antibody titers for several infectious threats that remain below the level of protection for much of their first 2 years of life.

HIV-Exposed Uninfected Infants are at Increased Risk for Severe Infections in the First Year of Life

HIV-exposed uninfected (HEU) infants have higher infectious morbidity than HIV-unexposed uninfected (HUU) infants. We present the clinical outcomes from a pilot cohort study of 27 HEU and 28 HUU infants. In the absence of infant malnutrition or advanced maternal HIV, HEU infants experienced a 2.74 (0.85-8.78) times greater risk of hospitalization in the first year.