HIV-exposed Children Research Articles

Birth Prevalence of Congenital Cytomegalovirus Infection in HIV-Exposed Uninfected Children in the Era of Combination Antiretroviral Therapy

MU Purswani, JS Russell, M Dietrick. J Pediatr . 2020;216:82–87.e2 To identify the birth prevalence of congenital CMV (cCMV) and related neurodevelopmental (ND) and hearing outcomes in HIV-exposed uninfected children in mothers treated with combination antiretroviral therapy (cART). The study population was composed of participants from the Surveillance Monitoring for ART Toxicities (SMARTT) cohort, which is an ongoing observational cohort study established in 22 sites in the US and Puerto Rico. The SMARTT cohort has been enrolling HIV-exposed uninfected infants since 2007, and as of February 1, 2017, 2579 infants and children were monitored with medical history, physical examinations, and …

Exploring the meanings of male partner involvement in the prevention of MTCT of HIV in Zimbabwe

Male partner involvement (MPI) in the prevention of mother-to-child transmission (PMTCT) of human immunodeficiency virus (HIV) is considered as one of the priority interventions in reducing paediatric HIV. However, there is neither a standard definition nor measurement for MPI in PMTCT. The study explored meanings of MPI in PMTCT programmes in Zimbabwe. Eight focus group discussions (FGDs) were conducted with men and women aged 18 years and above. Seven key informants (KII) from health institutions and organisations providing PMTCT services were interviewed. Eight in-depth interviews (IDIs) were conducted with pregnant women at two public health facilities. Thematic analysis was used for data analysis. Five major themes were identified which facilitated our understanding of MPI. Male partner involvement was referred to as participation of male partners in HIV couple counselling and testing. Acceptance of condom use during pregnancy and breastfeeding was deemed vital as this prevents HIV transmission. Male partners were expected to have knowledge of administering antiretroviral drugs to an HIV-exposed child. Provision of financial support was another form of male involvement commonly expected during antenatal and postnatal periods. Faithfulness in marriage was a major theme that was highlighted, especially by respondents in marital relationships. Male partner presence in PMTCT community educational sessions was also considered. However, the provision of male-oriented educational programmes was identified as poor. The study suggested a definition for MPI in PMTCT in Zimbabwe. The merit of this definition was that it took a holistic approach to include activities beyond antenatal activities and HIV testing. Future research should explore how public health institutions could create male-oriented health services within PMTCT programmes, as this has the potential of increasing men’s involvement in PMTCT of HIV.Contribution: This article contributed to the knowledge on how world views, which is shaped by culture and religion, influenced the formation of meanings on MPI PMTCT programmes.

Mother-child separation among women living with HIV and their children in the first four years postpartum in South Africa.

Mother-child pairs may separate during early life, yet the health impacts thereof are unclear. We explored the patterns and impact of separation among women living with HIV (WLHIV) and their children in South Africa. WLHIV who had initiated antiretroviral therapy (ART) during pregnancy received HIV viral load (VL) testing and completed a timeline questionnaire of mother-child separation since delivery at 3-5years post-partum. Health care usage was abstracted from routine medical records. We examined associations between separation and (a) maternal health outcomes (engagement in HIV care and HIV viral suppression, [VS]) and (b) child health outcomes (post-breastfeeding HIV testing and immunisation completion), using logistic regression. Of 346 mother-child pairs (median maternal age at antenatal ART initiation, 28years), 24% were ever separated (median time to first separation 20months, interquartile range [IQR] 9, 31). Most separated children were living with their grandmothers (65/83, 78%). Mothers who ever separated were younger, and more likely to be employed, and to reside in informal housing than those who never separated. Any separation reduced the odds of VS≤50 copies/mL at four years post-partum (odds ratio 0.57; 95% CI 0.34-0.93); associations were similar for VL≤1000 copies/mL and maternal engagement in care. No association was found between separation and child confirmatory HIV testing or immunisation completion. In this setting, mother-child separation is common in the first four years of life and appears associated with suboptimal maternal outcomes. Further research is required to understand the drivers and implications of mother-child separation.

Neurodevelopment of HIV-exposed uninfected children in Cape Town, South Africa.

BackgroundEvidence shows that antiretroviral (ART) exposure is associated with neurodevelopmental delays in human immunodeficiency virus (HIV)-exposed uninfected (HEU) children. However, there are few insights into modifiable maternal and child factors that may play a role in improving neurodevelopment in HEU children. We used a parent-centric neurodevelopment tool, Ages & Stages Questionnaire (ASQ) to examined neurodevelopment in HEU children at 12–24 months of age, and associations with maternal and child factors.Methods505 HIV-infected women (initiated ART pre- or during pregnancy) with live singleton births attending primary health care were enrolled; 355 of their HEU children were assessed for neurodevelopment (gross motor, fine motor, communication, problem solving and personal-social domains) at 12–24 months using age-specific ASQ administered by a trained fieldworker. Associations with maternal and child factors were examined using logistic regression models.ResultsAmong mothers (median age 30 years, IQR, 26–34), 52% initiated ART during pregnancy; the median CD4 count was 436 cells/μl (IQR, 305–604). Most delayed neurodevelopment in HEU children was in gross (9%) and fine motor (5%) functions. In adjusted models, maternal socio-economic status (aOR 0.42, 95% CI 0.24–0.76) was associated with reduced odds of delayed gross-fine motor neurodevelopment. Maternal age ≥35 years (aOR 0.22, 95% CI 0.05–0.89) and maternal body mass index (BMI) <18.5 (aOR 6.76, 95% CI 1.06–43.13) were associated with delayed communication-problem-solving-personal-social neurodevelopment. There were no differences in odds for either domain by maternal ART initiation timing.ConclusionsDelayed neurodevelopment was detected in both gross and fine motor functions in this cohort of HEU children, with strong maternal predictors that may be explored as potentially modifiable factors associated with neurodevelopment at one to two years of age.

Implementation planning for community-based point-of-care HIV testing for infants: Recommendations from community leaders in Kenya.

BackgroundEarly infant diagnosis (EID) establishes the presence of HIV infection in HIV-exposed infants and children younger than 18 months of age. EID services are hospital-based, and thus fail to capture HIV-exposed infants who are not brought to the hospital for care. Point-of-care (POC) diagnostic systems deployed in the community could increase the proportion tested and linked to treatment, but little feasibility and acceptability data is available.MethodsSemi-structured interviews (n = 74) were conducted by a Kenyan team with community members (Community Health Workers/Volunteers [CHW/CHV], Traditional Birth Attendants [TBAs], community leaders) and parents of HIV-exposed infants at four study sites in Kenya to elicit feedback on the acceptability and feasibility of community-based POC HIV testing.ResultsParticipants described existing community health resources that could be leveraged to support integration of community-based POC HIV testing; however, the added demand placed on CHW/CHV could pose a challenge. Participants indicated that other potential barriers (concerns about confidentiality, disclosure, and HIV stigma) could be overcome with strong engagement from trusted community leaders and health providers, community sensitization, and strategic location and timing of testing. These steps were seen to improve acceptability and maximize the recognized benefits (rapid results, improved reach) of community-based testing.ConclusionCommunity members felt that with strategic planning and engagement, community-based POC HIV testing could be a feasible and acceptable strategy to overcome the existing barriers of hospital-based EID.

Minimum Acceptable Diet and Associated Factors Among HIV-Exposed Children Aged 6-24 Months in Debre Tabor Town, Ethiopia.

IntroductionMinimum acceptable diet is a composite indicator of minimum dietary diversity and minimum meal frequency. World Health Organization’s newborn child feeding and HIV guidelines suggestbeginning complementary nourishments at six months, and breastfeeding for HIV-exposed children. HIV infected mothers may be more sensitive on feeding practices to protect their children from contracting the disease. On the other hand, HIV infection is associated with higher risk food insecurity which may affect feeding practices of children. But in Ethiopia, there is lack of evidence on extent of minimum acceptable diet of HIV-exposed children. Therefore, the objective of this study was to assess minimum acceptable diet and associated factors among HIV-exposed 6–24 months aged children.MethodsAn institution-based cross-sectional study was conducted in health institutions of Debre Tabor town. The study was conducted on 287 mother-child pairs attending antiretroviral therapy (ART) and prevention of mother-to-child transmission (PMTCT) at public health facilities. Descriptive statistics like frequency, proportions, mean and standard deviation were computed. Multi-variable logistic regression was run to identify independent predictors of the outcome variable (minimum acceptable diet). A p-value <0.05 was used to declare statistical significance.ResultsAbout 76% (95% CI: 70.8–80.8) and 58.2% (95% CI: 53.0–68.3) children were fed with appropriate meal frequency and recommended dietary diversity, respectively. One hundred (34.8%) (95% CI: 29.3–40.4) of children were fed a minimum acceptable diet and 59.9% (95% CI: 54.0–65.9) of children consumed iron rich or fortified food. Out of the total, 203 (71.0%) (95% CI: 66.1–76.2) of the mothers had good knowledge on minimum dietary diversity and meal frequency feeding practices. In multi-variable logistic regression poor knowledge with AOR = 0.32, 95% CI: 0.17–0.58, maternal workload with AOR = 0.38, 95% CI: 0.19–0.75 and inadequate information about child feeding from health care providers with AOR = 0.46, 95% CI: 0.26–0.81 were statistically significant predictors of minimum acceptable diet.ConclusionThe study revealed that the proportion of children who received minimal acceptable diet was lower than that of WHO recommendation for good practice. Knowledge, maternal workload and information related to complementary feeding were associated with low minimum acceptable diet.

18-24-month HIV-free survival as measurement of the effectiveness of prevention of mother-to-child transmission in the context of lifelong antiretroviral therapy: Results of a community-based survey.

IntroductionPopulation-based HIV-free survival at 18–24 months of age among HIV-exposed infants in high prevalence settings in the era of treatment for all is largely unknown. We conducted a community-based survey to determine outcomes of HIV-exposed infants at 18–24 months in Lesotho.MethodsBetween November 2015 and December 2016, we conducted a survey among households with a child born 18–24 months prior to data collection. Catchment areas from 25 health facilities in Butha-Buthe, Maseru, Mohale’s Hoek and Thaba-Tseka districts were randomly selected using probability proportional to size sampling. Consecutive households were visited and eligible consenting caregivers and children were enrolled.Rapid HIV antibody testing was performed on mothers of unknown HIV status (never tested or tested HIV-negative >3 months prior) and their children, and to children born to known HIV-positive mothers. Information on demographics, health-seeking behavior, HIV, and mortality were captured for mothers and children, including those who died.The difference in survival between subgroups was determined using the log-rank test.ResultsOf the 1,852 mothers/caregivers enrolled, 570 mothers were HIV-positive. The mother-to-child HIV transmission rate was 5.7% [95% CI: 4.0–8.0]. The mortality rate was 2.6% [95% CI: 1.6–4.2] among HIV-exposed children compared to 1.4% (95% CI: 0.9–2.3) among HIV-unexposed children. HIV-free survival was 91.8% [95% CI: 89.2–93.8] among HIV-exposed infants. Disclosure of mother’s HIV status (aOR = 4.9, 95% CI: 1.3–18.2) and initiation of cotrimoxazole prophylaxis in the child (aOR = 3.9, 95% CI: 1.2–12.6) were independently associated with increased HIV-free survival while child growth problems (aOR = 0.2, 95% CI: 0.09–0.5) were independently associated with reduced HIV-free survival.ConclusionEven in the context of lifelong antiretroviral therapy among pregnant and breastfeeding women, HIV has a significant effect on survival among HIV-exposed children compared to unexposed children. Lesotho has not reached elimination of HIV transmission from mother to child.

Association of maternal and infant inflammation with neurodevelopment in HIV-exposed uninfected children in a South African birth cohort

HIV-exposed uninfected (HEU) children may have altered immune regulation and poorer neurodevelopment outcomes compared to their HIV-unexposed (HU) counterparts. However, studies investigating the association of maternal and infant inflammation with neurodevelopment in HEU children are limited and longitudinal data are lacking. This study investigated serum inflammatory markers in women living with HIV vs. HIV-uninfected women during pregnancy and in their children, as well as associations with neurodevelopmental outcomes at two years of age in an African birth cohort study. A sub-group of mother–child dyads from the Drakenstein Child Health Study had serum inflammatory markers measured at ≈26 week’s gestation (n = 77 HIV-infected mothers; n = 190 HIV-uninfected mothers), at 6–10 weeks (n = 63 HEU infants and n = 159 HU infants) and at 24–28 months (n = 77 HEU children and n = 190 HU children). Serum inflammatory markers [granulocyte–macrophage colony-stimulating factor (GM-CSF), interferon-γ (IFN-γ), interleukin IL-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12p70, IL-13, tumor necrosis factor-α (TNF-α), neutrophil gelatinase-associated lipocalin (NGAL) and metalloproteinase-9 (MMP-9)] were analyzed with a multiplex bead array and ELISA assays. The Bayley Scales of Infant and Toddler Development, third edition, was used to assess neurodevelopment at 24–28 months. After correcting for multiple comparisons, HIV infection during pregnancy was associated with lower serum levels of inflammatory markers in mothers at 26 weeks gestation (GM-CSF and MMP-9, p < 0.05) and HEU children at 6–10 weeks (IFN-γ and IL-1β, p < 0.01), and at 24–28 months (IFN-γ, IL-1β, IL-2 and IL-4, p < 0.05) compared to HIV-uninfected mothers and HU children. In HEU infants at 6–10 weeks, inflammatory markers (GM-CSF, IFN-γ, IL-10, IL-12p70, IL-1β, IL-2, IL-4, IL-6 and NGAL, all p < 0.05) were associated with poorer motor function at two years of age. This is the first study to evaluate the associations of follow-up immune markers in HEU children with neurodevelopment. These findings suggest that maternal HIV infection is associated with immune dysregulation in mothers and their children through two years of age. An altered immune system in HEU infants is associated with poorer follow-up motor neurodevelopment. These data highlight the important role of the immune system in early neurodevelopment and provide a foundation for future research.

Vitamin D status, nutrition and growth in HIV-infected mothers and HIV-exposed infants and children in Botswana.

Poor vitamin D status is a global health problem and common in patients with human immunodeficiency virus (HIV) in high-income countries. There is less evidence on prevalence of vitamin D deficiency and nutrition and growth in HIV-infected and -exposed children in low- and middle-income countries. To determine the vitamin D status in Batswana HIV-infected mothers and their children, differences among HIV-infected mothers and between HIV-exposed and -infected infants and children, and associations between vitamin D and disease-related outcomes, nutrition, and growth. This was a cross-sectional study of HIV+ mothers and HIV-exposed infants and unrelated children (1-7.9 years). Serum 25-hydroxyvitamin D (25(OH)D) was measured, among other nutritional indicators, for mothers, infants and children. Vitamin D status for HIV-infected mothers and children, and an immune panel was assessed. History of HIV anti-retroviral medications and breastfeeding were obtained. Data were collected prior to universal combination antiretroviral therapy in pregnancy. Mothers (n = 36) had a mean serum 25(OH)D of 37.2±12.4ng/mL; 11% had insufficient (<20ng/mL), 17% moderately low (20.0-29.9ng/mL) and 72% sufficient (≥30ng/mL) concentrations. No infants (n = 36) or children (n = 48) were vitamin D insufficient; 22% of HIV- and no HIV+ infants had moderately low concentrations and 78% of HIV- and 100% of HIV+ infants had sufficient status, 8% of HIV- and no HIV+ children had moderately low concentrations and 92% of HIV- and 100% HIV+ children had sufficient concentrations. HIV+ children had significantly lower length/height Z scores compared to HIV- children. Length/height Z score was positively correlated with serum 25(OH)D in all children (r = 0.33, p = 0.023), with a stronger correlation in the HIV+ children (r = 0.47 p = 0.021). In mothers, serum 25(OH)D was positively associated with CD4% (r = 0.40, p = 0.016). Results showed a low prevalence of vitamin D insufficiency in Botswana. Growth was positively correlated with vitamin D status in HIV-exposed children, and HIV+ children had poorer linear growth than HIV- children.

Cerebrovascular Disease in Children Perinatally Infected With Human Immunodeficiency Virus in Zambia

BackgroundHigh rates of cerebrovascular disease (CVD) have previously been described in pediatric human immunodeficiency virus (HIV). However, little is known about pediatric CVD in the era of antiretroviral therapy or about the contribution of CVD to HIV-associated neurocognitive disorders. MethodsWe completed a neuroimaging substudy of the HIV-Associated Neurocognitive Disorders in Zambia study, a prospective cohort study of neurocognitive complications of pediatric HIV. Brain magnetic resonance imaging (1.5 T) was acquired for 34 HIV+ children on antiretroviral therapy and 17 HIV-exposed uninfected children (aged eight to 17 years). Demographics, medical history, neurological examination, and neuropsychologic testing results were collected. Two neuroradiologists, unaware of HIV status and clinical course, read the scans. ResultsCVD was identified in seven of 34 children with HIV (HIV+ CVD+) and no HIV-exposed uninfected children (21% vs 0%, P = 0.05). Three participants had white matter changes suggestive of small vessel disease, four had infarcts, and two had evidence of intracranial artery stenosis. Age of antiretroviral therapy initiation and exposure to protease inhibitors or efavirenz was not significantly different between children with and without CVD. HIV+ CVD+ children had significantly worse scores on a summary measure of cognition than the HIV+ CVD− group (NPZ8 score −0.57 vs 0.33, P = 0.04). ConclusionsThis study demonstrates high rates of CVD in children with HIV despite antiretroviral therapy, and worse cognitive performance in children with CVD. Longitudinal studies are necessary to determine the mechanisms and incidence of new-onset CVD in children with HIV.

HIV epidemic and cascade of care in 12 east African rural fishing communities: results from a population-based survey in Uganda

BackgroundIn East Africa, fishing communities are considered most-at-risk populations for the acquisition of HIV. We estimated HIV prevalence and assessed progress towards the UNAIDS 90–90-90 targets along the HIV treatment cascade in 12 fishing communities surrounding Lakes Edward and George, Uganda.MethodsWe conducted a cross-sectional household-based survey between September and November 2016. All adults between 15 and 69 years old were eligible to participate. Children below 15 years old were eligible for HIV testing if either parent was HIV-positive. Viral load testing was done for all HIV-infected individuals. Logistic regression models adjusted for sociodemographic-behavioral variables were used to assess the association between occupation and HIV positivity.ResultsOverall, 1738 adults (959 women, 779 men) and 148 children were included. Adult inclusion rate was 96.0%. Of the men, 58% reported to be fishermen. The HIV-prevalence among adults was 17.5% (95%CI: 15.8–19.4) and 6.1% (95%CI: 3.1–11.4) among HIV-exposed children. HIV prevalence was higher among women than among men (20.9% vs. 13.5%, p < 0.001). Among men, fishermen had a higher HIV prevalence (18.7%; 95%CI: 15.1–22.3) and a higher risk of being HIV-positive (aOR: 4.2; 95%CI: 2.0–9.1) than men of other occupations (p < 0.001). Progress towards the UNAIDS 90–90-90 targets was as follows: 86.5% (95%CI: 82.3–90.1%) of the HIV-positive participants were diagnosed, 98.7% (95%CI: 96.1–99.6%) of those aware were on antiretroviral therapy (ART), and 87.3% (95%CI: 82.3–91.0%) of those on ART were virally suppressed. Overall, 73% of all HIV-positive individuals were virally suppressed. Viral suppression was lower among individuals 15–24 years (45.5%) than among those 25–44 years (74.0%) and 45–69 years (85.0%), p < 0.001. Fishermen did not to have significant differences in the HIV cascade of care compared to men with other occupations.ConclusionsHIV prevalence was high in these fishing communities, particularly among women and fishermen. Important progress has been made along the HIV treatment cascade, and the UNAIDS goal for viral suppression in population was achieved. However, gaps remain and HIV care strategies focusing on young people are urgently needed. HIV preventive interventions should target particularly women, young people and fishermen though HIV preventive and care services should remain available to the whole fishing communities.

Risk factors for mortality among Tanzanian infants and children

BackgroundDuring the era of the Millennium Development Goals, under 5 mortality rates decreased significantly worldwide; however, reductions were not equally distributed. Children in sub-Saharan Africa still account for more than 50% of the world’s annual childhood deaths among children under 5 years of age. Understanding upstream risk factors for mortality among children may reduce the large burden of childhood mortality in sub-Saharan Africa. Our objective was to identify risk factors for mortality among infants and children in Tanzania.MethodsWe conducted a secondary analysis of data pooled from two randomized-controlled micronutrient supplementation trials. A total of 4787 infants were enrolled in the two trials (n = 2387 HIV-exposed and n = 2400 HIV-unexposed). Predictors of mortality were assessed using unadjusted and adjusted hazard ratios (aHRs).ResultsThere were 307 total deaths, 262 (11%) among children who were HIV-exposed and 45 (2%) among children who were HIV-unexposed (P < 0.001). The most common cause of death was respiratory diseases (n = 109, 35.5%). Causes of death did not significantly differ between HIV-exposed and HIV-unexposed children. In adjusted regression analyses, children with birth weight <2500 g (aHR 1.75, 95% CI 1.21–2.54), Apgar score of ≤7 at 5 min (aHR 2.16, 95% CI 1.29–3.62), or who were HIV-exposed but not infected (aHR 3.35, 95% CI 2.12–5.28) or HIV-infected (aHR 27.56, 95% CI 17.43–43.58) had greater risk of mortality.ConclusionsInfection with HIV, low birthweight, or low Apgar scores were associated with higher mortality risk. Early identification and modification of determinants of mortality among infants and children may be the first step to reducing such deaths.

Active pediatric HIV case finding in Kenya and Uganda: A look at missed opportunities along the prevention of mother-to-child transmission of HIV (PMTCT) cascade.

BackgroundChildren living with HIV remain undiagnosed due to missed opportunities along the prevention of mother-to-child HIV transmission cascade. This study addresses programmatic gaps in the cascade by describing pregnancy and HIV-related services received by mothers of children newly identified as HIV-positive through active case finding.MethodsThis was a prospective observational cohort (2017–2018) of HIV-positive children <15 years of age newly diagnosed at study facilities and/or surrounding communities in Kenya and Uganda. At enrollment, caregivers were interviewed about maternal and child health and HIV history. Child medical and laboratory information was abstracted at two months post-diagnosis. Descriptive summary statistics were calculated; associations between selected factors and child age at HIV diagnosis were evaluated using generalized estimating equations.Results174 HIV-positive children (median age 2.4 years) were enrolled. Among maternal caregivers, 110/132 (83.3%) attended antenatal care and 60 (45.5%) reported testing HIV-negative in antenatal care. Of 41 and 56 women known to be HIV-positive during pregnancy and breastfeeding respectively, 17 (41.5%) and 15 (26.8%) did not receive antiretroviral drugs. Despite known maternal HIV-positive status during pregnancy, 39% of these children were not diagnosed until after two years of age; children were diagnosed at younger ages in Uganda (p = 0.0074) and if mother was the caregiver (p<0.0001). The most common HIV testing points identifying children were outpatient (44.3%) and maternal/child health departments (29.9%). Nearly all children initiated antiretroviral therapy within two weeks of diagnosis.ConclusionsMultiple missed opportunities for HIV prevention and delays in HIV testing of HIV-exposed children were identified in newly diagnosed children. Findings support critical prevention messaging and retesting of HIV-negative women during pregnancy and breastfeeding, strengthening HIV treatment initiation and follow-up systems and interventions to ensure HIV-positive women receive lifelong antiretroviral therapy throughout the cascade, and broader implementation of community case finding so children not engaged in care receive testing services.

Influence of tenofovir exposure in utero on primary dentition.

Tenofovir disoxoproxil fumarate (TDF) is recommended for antiretroviral treatment for pregnant women living with HIV. As a comparative method to study bone density, we investigated the influence of in utero tenofovir exposure on the prevalence and distribution of developmental defects of enamel (DDE) in the primary dentition, as the mineralization process in teeth is higher and more complex and thus more vulnerable. HIV-exposed children with in utero exposition to tenofovir were included in this prospective observational single-center study. Dental status and enamel defects were assessed by an experienced dentist following a standardized protocol. Further information was collected using a standardized questionnaire, available in German and English. The prevalence of developmental defects in children with intrauterine tenofovir exposure was compared with literature data from a recent study of 377 healthy children in Germany and literature data from a study of 1221 healthy African children. Thirty-one children (mean age 2.1 ± 0.3years; 41.9% female) were included. Median tenofovir exposure in utero was 28weeks (mean ± 10.52 SD). Prevalence of developmental defects in the primary dentition in tenofovir-exposed children was similar compared to data of unexposed children (16.1% vs. 5.3%, p = 0.051 (compared to German cohort); 16.1% vs. 33.3%, p = 0.068 (compared to African cohort)).Conclusion: HIV-uninfected infants with in utero exposure to TDF showed no significant differences in the prevalence of DDE in comparison to cross-sectional data of HIV- and TDF-unexposed children; thus, the in utero exposure to TDF did not negatively influence the prevalence or distribution of DDE. What is Known: • There are no data available on the prevalence of developmental defects of enamel (DDE) in the primary dentition in intrauterine HIV- and tenofovir-exposed children. • Conclusions can be drawn from intrauterine milk tooth development to bone development and mineralization. What is New: • Prevalence of developmental defects in the primary dentition in tenofovir-exposed children was similar compared to data of unexposed children. • Preterm birth and hospitalization did not show a significant association on the prevalence of developmental defects in the primary dentition.

Immune checkpoint dysregulation and immune activation in HIV-exposed uninfected children

Abstract Children who are HIV-exposed uninfected (CHEU) are a growing population worldwide. CHEU suffer greater morbidity and mortality from infectious diseases, likely due to their impaired cell-mediated immunity (CMI) and hyper-inflammatory responses. As CMI and inflammatory responses are regulated by immune checkpoints (ICPs) that play a key role in maintaining immune homeostasis, we determined whether CHEU had altered expression of the ICP axes. We used multiplex immunoassays to quantify plasma levels of 16 soluble ICPs (sBTLA, sCD27, sCD28, sCD40, sCD80, sCTLA-4, sGITR, sGITRL, sHVEM, sICOS, sLAG-3, sLIGHT, sPD-1, sPD-L1, sTIM-3, and sTLR-2) from 46 CHEU and 37 children who are HIV-unexposed uninfected (CHUU) from AMPATH in western Kenya. We demonstrated that all ICPS except GITR were detected in all samples. Compared to CHUU, CHEU had significantly higher levels of 2 sICPs: soluble CD40 (sCD40) and soluble TIM-3 (sTIM-3). As CD40 plays an essential role in antigen-presenting cell functions, while TIM-3 is a key member of immunosuppressive ICPs that inactivate T cell activity, the dysregulated sCD40 and sTIM-3 could play a role in the impaired CMI in CHEU and can be explored as biomarkers for adverse health outcomes in CHEU. A previous study showed that the percentage of activated CD8 T cells (CD8+CD38high) was increased in Canadian CHEU. Therefore, we also studied the activation of T cells in PBMCs from Kenya and found that CHEU had higher percentages of activated CD4 (CD4+CD38+HLA-DR+) and CD8 (CD8+CD38+HLA-DR+) T cells in the peripheral blood compared to CHUU. Our study demonstrated that the ICP axes were dysregulated in CHEU, and we provided additional support to the notion that the immune system in CHEU is altered.

Early child development in children who are HIV-exposed uninfected compared to children who are HIV-unexposed: observational sub-study of a cluster-randomized trial in rural Zimbabwe.

IntroductionExposure to maternal HIV may affect early child development (ECD), although previous studies have reported heterogeneous findings. We evaluated ECD among children who were HIV‐exposed uninfected (CHEU) and children who were HIV‐unexposed (CHU) recruited to the SHINE trial in rural Zimbabwe.MethodsSHINE was a community‐based cluster‐randomized trial of improved infant feeding and/or improved water, sanitation and hygiene. Pregnant women were enrolled between 2012 and 2015. We assessed ECD in a sub‐study at 24 months of age, between 2016 and 2017, using the Malawi Developmental Assessment Tool (MDAT; assessing motor, cognitive, language and social development); MacArthur‐Bates Communicative Development Inventory (CDI) (assessing vocabulary and grammar); A‐not‐B test (assessing object permanence); and a self‐control task. Mothers and infants were tested longitudinally for HIV. We used generalized estimating equations to compare ECD scores between CHEU and CHU, accounting for the cluster‐randomized design. Primary results were adjusted for trial‐related factors that could affect measurement reliability of ECD: study nurse, age of child, calendar month of birth, sex and randomized arm.ResultsA total of 205 CHEU and 1175 CHU were evaluated. Mean total MDAT score was 90.6 (SD 8.7) in CHEU compared to 92.4 (9.1) in CHU (adjusted mean difference −1.3, 95% CI: −2.3, −0.3), driven mostly by differences in gross motor (−0.5, 95% CI: −0.9, −0.2) and language scores (−0.6, 95% CI: −1.1, −0.1). There was evidence that fine motor scores were lower in CHEU (adjusted mean difference −0.4, 95% CI: −0.8, 0.0) but no evidence of a difference in social scores (0.1, 95% CI: −0.2, 0.4). Mean MacArthur‐Bates CDI vocabulary score was 57.9 (SD 19.2) in CHEU compared to 61.3 (18.8) in CHU (adjusted mean difference −2.9 words, 95% CI: −5.7, −0.1). Object permanence and self‐control scores were similar between groups.ConclusionsCHEU in rural Zimbabwe had total child development and vocabulary scores that were approximately 0.15 standard deviations lower than CHU at two years of age. More detailed and specific studies are now needed to unravel the reasons for developmental delay in CHEU and the likelihood that these delays persist in the longer term.

High proportion of unknown HIV exposure status among children aged less than 2 years: An analytical study using the 2015 National AIDS Indicator Survey in Mozambique.

BackgroundDetermination of the human immunodeficiency virus (HIV) exposure status in infants and young children is required to guarantee timely diagnosis and access to appropriate care. HIV prevalence among Mozambican women aged 15–49 years is 15%, and vertical transmission rate is still high. The study investigated HIV exposure in children aged less than 2 years in Mozambique and the factors associated with unknown HIV exposure and with HIV exposure status in this population.MethodsThis was a cross-sectional analytical study using data from the 2015 Survey of Indicators on Immunization, Malaria and HIV/AIDS in Mozambique. A total of 2141 mothers (15–49 years) with children aged less than 2 years were interviewed. The dependent variables were “known HIV exposure status in a child” and “HIV-exposed child,” and the explanatory variables were mother’s social, demographic, economic, and reproductive health characteristics. We used binary and logistic regression, adjusted for complex sampling, to determine the association between variables.ResultsHIV exposure status was unknown in 27% of children (95% CI, 25.1–28.9). Mothers residing in the North (AOR, 4.41; 95% CI, 2.18–8.91), in rural area (AOR, 2.44; 95% CI, 1.33–4.35), with no education (AOR, 2.72; 95% CI, 1.38–5.36), and not having utilized any health services in the last pregnancy (AOR, 1.9; 95% CI, 1.42–2.55) were more likely to have a child with unknown HIV exposure status. Six percent of children were HIV-exposed (95% CI, 5–7). Children were less likely to be HIV-exposed if the head of the household was a male (AOR, 0.26; 95% CI, 0.08–0.86), if the mother was residing in the North (AOR, 0.41; 95% CI, 0.26–0.66) and did not utilize any health services in her last pregnancy (AOR, 0.52; 95% CI, 0.32–0.83).ConclusionThe high proportion of children with unknown HIV exposure status and the associated socioeconomic factors suggests that HIV retesting of eligible women throughout breastfeeding should be intensified and identifies the urgent need to reach women without prior access to health care using a multisectoral approach.

Response to Zhao and Zhou: Diagnosis of HIV infection in breastfed infants of mothers on antiretroviral therapy.

We thank Zhao and Zhou [1] for their thoughtful comments on our report of two infants born to women with HIV who had unusual trajectories of diagnostic tests. The two HIV-exposed infants were initially positive on nucleic acid amplification tests in the first month of life but had multiple negative tests during breastfeeding and presented with definitive evidence of HIV infection around the time of breastfeeding cessation. We hypothesize that constituents of breast milk, or processes induced by breastfeeding, most likely in combination with antiviral effects of maternal antiretroviral therapy, led to the undetectable test results that we observed in already infected infants until breastfeeding ended. We considered the alternative explanation of postnatal transmission proposed by Zhao and Zhou [1], but this explanation requires dismissing the initial positive test results on the early samples as transient infections or false-positive results. A rigorous investigation of 42 cases of suspected transient infection, failed to confirm a single one, despite the plausibility of this concept [2]. In one of the infants in our report, virus was detected in peripheral blood mononuclear cells (PBMCs) from three separate blood samples collected over the first month of life making laboratory errors an unlikely explanation. In this same case, CD4+ T cells from one of these early age time points were found to be positive for 2-LTR episomal HIV-1 DNA. Detection of 2-LTR episomal DNA in CD4+ T cells, although at low levels, provides evidence of viral replication as these episomal circles are a by-product thereof [3]. We acknowledge that early samples were not available for the second case making the alternative explanation of an initial false-positive result followed by postnatal infection a possible explanation of this second case. It should be noted that current birth testing and early treatment guidelines in South Africa would provide indefinite treatment to transient infections should they occur [4]. We would like to clarify the implications of our observations in the context of current guidance around antiretroviral use for women and their children to prevent vertical transmission of HIV. Maintenance of maternal therapeutic antiretroviral drug regimens over the full duration of breastfeeding and beyond is now considered standard of care for prevention of HIV transmission to children. This recommendation is consistent with clinical trials demonstrating exceptionally low rates of postnatal transmission if effective maternal antiretroviral drug treatment is in place [5]. Longer term infant prophylaxis is recommended only for infants whose mothers initiated treatment late and/or who are nonadherent with treatment. In both cases, maternal viral loads through the breastfeeding period were less than 1000 RNA copies/ml and in-country treatment guidelines were followed in terms of prophylactic regimens [6]. Because of concerns that infant prophylaxis may mask underlying HIV infections, some have encouraged repeat testing after prophylaxis has ended [7]. What distinguishes our cases is that the pattern of negative results was observed after discontinuation of antiretrovirals given to the infants but during continuation of maternal antiretroviral treatment and breastfeeding. Although the profile of the results that we observed is rare, we support repeat testing of HIV-exposed breastfed infants after complete cessation of all breastfeeding. The profile of HIV antibodies is of great interest, but it is unlikely that changes in standard anti-HIV IgG antibody titres over time in these infants will be helpful to resolve the timing of transmission. Infant antiretroviral prophylaxis. and on-going antiretroviral exposure via breast milk, like early treatment, may lead to undetectable antibodies [8]. The ability to detect HIV antibody would probably be at the time when these factors are no longer in place and viral levels rise and drive antibody production. Thus, a rise in antibodies, only once breastfeeding has stopped, might not necessarily mean the children were infected later. More sensitive assays differentiating antibody isotypes and antigen specificity may be more informative but will need comparison with the usual profile of antibodies in HIV-exposed uninfected children. The utility of HIV antibodies as markers of viral processes is well appreciated and this is likely to be a productive, albeit complex, line of research. Acknowledgements Conflicts of interest There are no conflicts of interest.

Health concerns for HIV-exposed but non-infected children.

Health concerns for HIV-exposed but non-infected children.

Left ventricular diastolic dysfunction in HIV-uninfected infants exposed in utero to antiretroviral therapy.

To longitudinally measure LV diastolic function in HIV-exposed but uninfected (HEU) children perinatally exposed to ART. HEU children who were perinatally exposed to antiretroviral therapy (ART) may be at risk for adverse cardiac effects. We have previously reported that those children have decreased left ventricular (LV) mass, dimension, and septal thickness with increased contractility. Serial echocardiograms were obtained at specific times from birth to 48 months from two groups of HIV-uninfected children: 148 HIV-negative children who were perinatally exposed to ART and 130 non-ART-exposed HIV-unexposed healthy controls. The following LV diastolic indices were obtained: mitral valve early and late diastolic velocity (E and A), tissue Doppler-derived LV-free wall and septal early diastolic velocity (LV e' and sep e'). All echocardiographic indices were significantly different in ART-exposed children compared with ART-unexposed healthy controls. Both E and A were overall lower at all ages by 8.28 cm/s (P = 0.0002) and 13.46 cm/s (P < 0.0001) respectively. E/A ratio was higher by 0.27, 0.46, and 0.28 units at birth, 1 year and 2 years of age, respectively (all P ≤ 0.01). Moreover, LV e' and sep e' were overall lower at all ages by 0.84 cm/s (P = 0.01) and 0.47 cm/s (P = 0.02), respectively. Children who were exposed to ART in utero have subclinical yet significant differences in specific LV diastolic indices. Follow-up with serial echocardiograms are recommended in this population to further assess the potential cardiac toxicity of perinatal exposure to ART.