HIV-uninfected Mothers Research Articles

HIV-Infected and HIV-Uninfected Western Kenyan Women Produce Equivalent Amounts of Breast Milk at 6 Wk and 6 Mo Postpartum: A Prospective Cohort Study Using Deuterium Oxide Dose-to-Mother Technique

BackgroundRegardless of their HIV serostatus, mothers are advised to exclusively breastfeed infants ≤6 mo postpartum. How this guidance impacts breast milk intake among HIV-exposed infants in varied contexts needs to be better understood. ObjectivesThe objective of this study was to compare breast milk intake of HIV-exposed and HIV-unexposed infants at 6 wk and 6 mo of age, as well as the associated factors. MethodsIn a prospective cohort design, which we followed from a western Kenya postnatal clinic, 68 full-term HIV-uninfected infants born to HIV-1–infected mothers (HIV-exposed) and 65 full-term HIV-uninfected infants born to HIV-uninfected mothers were assessed at 6 wk and 6 mo of age. Breast milk intake of infants (51.9% female) weighing 3.0–6.7 kg (at 6 wk of age) was determined using the deuterium oxide dose-to-mother technique. Student t test for independent samples compared the variations in breast milk intake between the 2 groups. Correlation analysis detected the associations between breast milk intake and maternal and infant factors. ResultsDaily breast milk intakes by HIV-exposed and HIV-unexposed infants were not significantly different at either 6 wk (721 ± 111 g/d and 719 ± 121 g/d, respectively) or 6 mo (960 ± 121 g/d and 963 ± 107 g/d, respectively) of age. Maternal factors that significantly correlated with infant breast milk intake were FFM at both 6 wk (r = 0.23; P < 0.05) and 6 mo (r = 0.36; P < 0.01) of age and weight at 6 mo postpartum (r = 0.28; P < 0.01). Infant factors that significantly correlated at 6 wk were birth weight (r = 0.27; P < 0.01), present weight (r = 0.47; P < 0.01), length-for-age z-score (r = 0.33; P < 0.01), and weight-for-age (r = 0.42; P > 0.01). At 6 mo, they were infant length-for-age (r = 0.38; P < 0.01), weight-for-length (r = 0.41; P > 0.01), and weight-for-age (r = 0.60; P > 0.01). ConclusionsFull-term breastfeeding infants born to HIV-1–infected and HIV-1–uninfected women attending standard Kenyan postnatal care clinics ≤6 mo of age in this resource-poor setting consume comparable amounts of breast milk. This trial was registered at clinicaltrials.gov as PACTR201807163544658.

Efficiency of transplacental transfer of respiratory syncytial virus (RSV) specific antibodies among pregnant women in Kenya.

Background: Maternal immunisation to boost respiratory syncytial virus (RSV) antibodies in pregnant women, is a strategy being considered to enhance infant protection from severe RSV associated disease. However, little is known about the efficiency of transplacental transfer of RSV-specific antibodies in a setting with a high burden of malaria and HIV, to guide the implementation of such a vaccination program. Methods: Using a plaque reduction neutralization assay, we screened 400 pairs of cord and maternal serum specimens from pregnant women for RSV-specific antibodies. Participants were pregnant women of two surveillance cohorts: 200 participants from a hospital cohort in Kilifi, Coastal Kenya and 200 participants from a surveillance cohort in Siaya, Western Kenya. Transplacental transfer efficiency was determined by the cord to maternal titre ratio (CMTR). Logistic regression was used to determine independent predictors of impaired transplacental transfer of RSV-specific antibodies. Results: A total of 800 samples were screened from the 400 participants. At enrollment the median age was 25 years (Interquartile range (IQR): 21-31). Overall, transplacental transfer was efficient and did not differ between Kilifi and Siaya cohort (1.02 vs. 1.02; p=0.946) but was significantly reduced among HIV-infected mothers compared to HIV-uninfected mothers (mean CMTR: 0.98 vs 1.03; p=0.015). Prematurity <33 weeks gestation (Odds ratio [OR]: 0.23, 95% confidence interval [CI] 0.06-0.85; p=0.028), low birth weight <2.5 kgs (OR: 0.25, 95% CI: 0.07-0.94; p=0.041) and HIV infection (OR: 0.47, 95% CI:0.23-0.98; p=0.045) reduced efficiency of transplacental transfer among these women. Conclusions: Transplacental transfer of RSV-specific antibodies among pregnant women in Kenya is efficient. A consideration to integrate other preventive interventions with maternal RSV vaccination targeting infants born premature (<33 weeks gestation), with low birth weight <2.5 kgs, or HIV-infected mothers is likely to improve vaccine outcomes in this setting.

Efficiency of transplacental transfer of respiratory syncytial virus (RSV) specific antibodies among pregnant women in Kenya

Background: Maternal immunisation to boost respiratory syncytial virus (RSV) antibodies in pregnant women, is a strategy being considered to enhance infant protection from severe RSV associated disease. However, little is known about the efficiency of transplacental transfer of RSV-specific antibodies in a setting with a high burden of malaria and HIV, to guide the implementation of such a vaccination program. Methods: Using a plaque reduction neutralization assay, we screened 400 pairs of cord and maternal serum specimens from pregnant women for RSV-specific antibodies. Participants were pregnant women of two surveillance cohorts: 200 participants from a hospital cohort in Kilifi, Coastal Kenya and 200 participants from a surveillance cohort in Siaya, Western Kenya. Transplacental transfer efficiency was determined by the cord to maternal titre ratio (CMTR). Logistic regression was used to determine independent predictors of impaired transplacental transfer of RSV-specific antibodies. Results: A total of 800 samples were screened from the 400 participants. At enrollment the median age was 25 years (Interquartile range (IQR): 21-31). Overall, transplacental transfer was efficient and did not differ between Kilifi and Siaya cohort (1.02 vs. 1.02; p=0.946) but was significantly reduced among HIV-infected mothers compared to HIV-uninfected mothers (mean CMTR: 0.98 vs 1.03; p=0.015). Prematurity <33 weeks gestation (Odds ratio [OR]: 0.23, 95% confidence interval [CI] 0.06–0.85; p=0.028), low birth weight <2.5 kgs (OR: 0.25, 95% CI: 0.07–0.94; p=0.041) and HIV infection (OR: 0.47, 95% CI:0.23-0.98; p=0.045) reduced efficiency of transplacental transfer among these women. Conclusions: Transplacental transfer of RSV-specific antibodies among pregnant women in Kenya is efficient. A consideration to integrate other preventive interventions with maternal RSV vaccination targeting infants born premature (<33 weeks gestation), with low birth weight <2.5 kgs, or HIV-infected mothers is likely to improve vaccine outcomes in this setting.

Efficiency of transplacental transfer of respiratory syncytial virus (RSV) specific antibodies among pregnant women in Kenya

Background: Maternal immunisation to boost respiratory syncytial virus (RSV) antibodies in pregnant women, is a strategy being considered to enhance infant protection from severe RSV associated disease. However, little is known about the efficiency of transplacental transfer of RSV-specific antibodies in a setting with a high burden of malaria and HIV, to guide the implementation of such a vaccination program. Methods: Using a plaque reduction neutralization assay, we screened 400 pairs of cord and maternal serum specimens from pregnant women for RSV-specific antibodies. Participants were pregnant women of two surveillance cohorts: 200 participants from a hospital cohort in Kilifi, Coastal Kenya and 200 participants from a surveillance cohort in Siaya, Western Kenya. Transplacental transfer efficiency was determined by the cord to maternal transfer ratio (CMTR). Logistic regression was used to determine independent predictors of impaired transplacental transfer of RSV-specific antibodies. Results: A total of 800 samples were screened from the 400 participants. At enrollment the median age was 25 years (Interquartile range (IQR): 21-31). Overall, transplacental transfer was efficient and did not differ between Kilifi and Siaya cohort (1.02 vs. 1.02; p=0.946) but was significantly reduced among HIV-infected mothers compared to HIV-uninfected mothers (mean CMTR: 0.98 vs 1.03; p=0.015). Prematurity &lt;33 weeks gestation (Odds ratio [OR]: 0.23, 95% confidence interval [CI] 0.06–0.85; p=0.028), low birth weight &lt;2.5 kgs (OR: 0.25, 95% CI: 0.07–0.94; p=0.041) and HIV infection (OR: 0.47, 95% CI:0.23-0.98; p=0.045) reduced efficiency of transplacental transfer among these women. Conclusions: Transplacental transfer of RSV-specific antibodies among pregnant women in Kenya is efficient. A consideration to integrate other preventive interventions with maternal RSV vaccination targeting infants born premature (&lt;33 weeks gestation), with low birth weight &lt;2.5 kgs, or HIV-infected mothers is likely to improve vaccine outcomes in this setting.

Polyunsaturated Fatty Acid Composition in Breast Milk Plasma of HIV-infected and Uninfected Mothers in Relation to Infant Clinical Outcomes.

Background:The increased coverage of prevention of mother to child transmission (PMTCT) services has significantly reduced paediatric HIV infection incidence. The aim of the study was to compare breast milk omega-6 and omega-3 polyunsaturated fatty acid profiles of HIV infected and uninfected mothers and determine the association between fatty acid profiles and postnatal transmission of HIV, morbidity/mortality of HIV exposed and unexposed infants.Methods:A prospective cohort study of 57 HIV infected and 57 HIV uninfected lactating mothers was conducted in Gweru, Zimbabwe from July 2019 to March 2020. The women’s 114 babies (term and preterm) were also enrolled and stratified by HIV exposure and infection status. The mother-infant pairs were followed up at 6 weeks, 16 weeks and 6 months postpartum to determine, HIV transmission rate, breast milk polyunsaturated fatty acid profiles as well as infant clinical outcomes.Results:The mean breast milk docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) levels in HIV uninfected mothers (0.82 ± 0.92; 0.47 ± 0.75 μg/ml respectively) at 6 weeks postpartum were significantly higher compared to those of HIV infected mothers (0.33 ± 0.32; 0.08 ± 0.14 μg/ml) respectively. The same pattern was observed at 16 weeks postpartum in terms of DHA and EPA mean concentration. However, the arachidonic acid (AA) levels and AA/DHA ratio measured at 6 weeks postpartum were significantly higher in HIV infected mothers (2.31 ± 2.01; 17.18 ± 52.47 respectively) compared to HIV uninfected mothers (0.82 ± 0.54; 9.71 ± 21.80; P < .001). A higher morbidity rate was observed amongst HIV exposed infants than HIV unexposed infants (3.26 ± 0.13; 2.49 ± 0.09; P < .001) respectively. A significant positive correlation was observed between AA and infant morbidity (r = .388; P < .001).Conclusion:Deficiencies in breast milk omega-3 fatty acids were observed in HIV infected women. Maintaining a healthy balance between omega-6 and omega-3 fatty acid diets is critical for breast feeding mothers regardless of their HIV status. The adverse clinical outcomes observed amongst HIV exposed infants emphasise their vulnerability under conditions of maternal universal antiretroviral therapy.

Levels of Total Antioxidant Capacity, sCD14, and TGF-β2 in Breast Milk Plasma of HIV-Infected and HIV-Uninfected Lactating Women.

Introduction: Breast milk provides nourishment for infants and nonnutritive bioactive factors, which possess key protective and developmental benefits essential in shaping the infant immune system. However, the impact of human immunodeficiency virus (HIV) and universal antiretroviral therapy (ART) on breast milk nutritional composition and immunity status is not well documented. Objective: The study aimed to compare breast milk immune factors; total antioxidant capacity (TAC), soluble cluster of differentiation 14 (sCD14), and transcription growth factor-beta 2 (TGF-β2) levels between HIV-infected and HIV-uninfected lactating mothers and determine the association between breast milk parameters with HIV disease progression and duration of ART. Methods: Breast milk sCD14, TAC, and TGF-β2 were quantified using enzyme-linked immunosorbent assays and spectrophotometric techniques in 57 HIV-infected breast feeding mothers on option B+ therapy for prevention of vertical transmission of HIV and 57 HIV-uninfected mothers at 6 weeks postpartum. The plasma HIV viral load was measured on enrollment and demographic data were recorded. Results: Mean breast milk plasma TAC levels were significantly lower in HIV-infected mothers (1,250.5 ± 280.4 μmolTE/L) compared to the HIV-uninfected participants (1,915.4 ± 326 μmolTE/L; p < 0.001). Soluble CD14 levels in HIV-infected mothers were significantly higher (7,059.3 ± 1,604.7 ng/mL) compared to the HIV-uninfected group (5,670.7 ± 1,268.3 pg/mL; p < 0.001). Similarly, TGF-β2 concentration was also significantly elevated in the HIV-infected mothers (1,426.1 ± 695.4 pg/mL) compared to the HIV-uninfected counterparts (709.2 ± 196.8 pg/mL; p < 0.001). A positive correlation was observed between breast milk plasma sCD14 concentration and the plasma viral load (r = 0.576, p < 0.001), while a significant negative correlation was observed with the duration of ART (r = -0.285, p = 0.032). TAC and TGF-β2 concentrations were inversely correlated with plasma viral load levels. Conclusion: HIV-infected mothers are at risk of oxidative stress. Nutritional intervention with antioxidant rich foods is recommended for this vulnerable group during breastfeeding.

Role of antenatal plasma cytomegalovirus DNA levels on pregnancy outcome and HIV-1 vertical transmission among mothers in the University of Zimbabwe birth cohort study (UZBCS)

IntroductionDespite being a leading infectious cause of childhood disability globally, testing for cytomegalovirus (CMV) infections in pregnancy is generally not done in Sub-Sahara Africa (SSA), where breastfeeding practice is almost universal. Whilst CMV and human immunodeficiency virus (HIV) are both endemic in SSA, the relationship between antenatal plasma CMV-DNA, HIV-1-RNA levels and HIV-1-mother to child transmission (MTCT) including pregnancy outcomes remains poorly described.MethodsPregnant women at least 20 weeks’ gestational age at enrolment were recruited from relatively poor high-density suburbs in Harare, Zimbabwe. Mother-infant dyads were followed up until 6 months postpartum. In a case–control study design, we tested antenatal plasma CMV-DNA levels in all 11 HIV-1 transmitting mothers, as well as randomly selected HIV-infected but non-transmitting mothers and HIV-uninfected controls.CMV-DNA was detected and quantified using polymerase chain reaction (PCR) technique. Antenatal plasma HIV-1-RNA load was quantified by reverse transcriptase PCR. Infants’ HIV-1 infection was detected using qualitative proviral DNA-PCR. Predictive value of antenatal plasma CMV-DNAemia (CMV-DNA of > 50 copies/mL) for HIV-1-MTCT was analyzed in univariate and multivariate regression analyses. Associations of CMV-DNAemia with HIV-1-RNA levels and pregnancy outcomes were also explored.ResultsCMV-DNAemia data were available for 11 HIV-1 transmitting mothers, 120 HIV-infected but non-transmitting controls and 46 HIV-uninfected mothers. In a multivariate logistic regression model, we found a significant association between CMV-DNAemia of > 50 copies/mL and HIV-1 vertical transmission (p = 0.035). There was no difference in frequencies of detectable CMV-DNAemia between HIV-infected and -uninfected pregnant women (p = 0.841). However, CMV-DNA levels were higher in immunosuppressed HIV-infected pregnant women, CD4 < 200 cells/µL (p = 0.018). Non-significant associations of more preterm births (< 37 weeks, p = 0.063), and generally lower birth weights (< 2500 g, p = 0.450) were observed in infants born of HIV-infected mothers with CMV-DNAemia. Furthermore, in a multivariate analysis of HIV-infected but non-transmitting mothers, CMV-DNAemia of > 50 copies/mL correlated significantly with antenatal plasma HIV-1-RNA load (p = 0.002).ConclusionAntenatal plasma CMV-DNA of > 50 copies/mL may be an independent risk factor for HIV-1-MTCT and higher plasma HIV-1-RNA load, raising the possibility that controlling antenatal CMV-DNAemia might improve infant health outcomes. Further studies with larger sample sizes are warranted to confirm our findings.

Infant sex modifies associations between placental malaria and risk of malaria in infancy

BackgroundPlacental malaria (PM) has been associated with a higher risk of malaria during infancy. However, it is unclear whether this association is causal, and is modified by infant sex, and whether intermittent preventive treatment in pregnancy (IPTp) can reduce infant malaria by preventing PM.MethodsData from a birth cohort of 656 infants born to HIV-uninfected mothers randomised to IPTp with dihydroartemisinin–piperaquine (DP) or Sulfadoxine–pyrimethamine (SP) was analysed. PM was categorized as no PM, active PM (presence of parasites), mild-moderate past PM (> 0–20% high powered fields [HPFs] with pigment), or severe past PM (> 20% HPFs with pigment). The association between PM and incidence of malaria in infants stratified by infant sex was examined. Causal mediation analysis was used to test whether IPTp can impact infant malaria incidence via preventing PM.ResultsThere were 1088 malaria episodes diagnosed among infants during 596.6 person years of follow-up. Compared to infants born to mothers with no PM, the incidence of malaria was higher among infants born to mothers with active PM (adjusted incidence rate ratio [aIRR] 1.30, 95% CI 1.00–1.71, p = 0.05) and those born to mothers with severe past PM (aIRR 1.28, 95% CI 0.89–1.83, p = 0.18), but the differences were not statistically significant. However, when stratifying by infant sex, compared to no PM, severe past PM was associated a higher malaria incidence in male (aIRR 2.17, 95% CI 1.45–3.25, p < 0.001), but not female infants (aIRR 0.74, 95% CI 0.46–1.20, p = 0.22). There were no significant associations between active PM or mild-moderate past PM and malaria incidence in male or female infants. Male infants born to mothers given IPTp with DP had significantly less malaria in infancy than males born to mothers given SP, and 89.7% of this effect was mediated through prevention of PM.ConclusionPM may have more severe consequences for male infants, and interventions which reduce PM could mitigate these sex-specific adverse outcomes. More research is needed to better understand this sex-bias between PM and infant malaria risk.Trial registration ClinicalTrials.gov, NCT02793622. Registered 8 June 2016, https://clinicaltrials.gov/ct2/show/NCT02793622

Growth and Neurodevelopment Outcomes in HIV-, Tenofovir-, and Efavirenz-Exposed Breastfed Infants in the PMTCT Option B+ Program in Malawi.

Pregnant and breastfeeding women in Option B+ in Malawi received antiretroviral drugs (ARVs) containing efavirenz (EFV) and tenofovir disoproxil fumarate (TDF). However, effects on growth, renal, bone metabolism, and neurodevelopment of long-term exposure to low doses of these drugs through breast milk in HIV-exposed infants are unclear. Prospective cohorts of TDF-and-EFV-exposed and TDF-and-EFV-unexposed breastfed infants of HIV-infected and HIV-uninfected mothers in Option B+ were recruited in 2:1 ratio, respectively, followed from birth to 18 months. Infants with low birth weight, premature birth, and congenital abnormalities were excluded. Anthropometrics were assessed at birth, 6 weeks, 3, 6, 12, and 18 months. Neurodevelopment assessments used the Bayley Scales of Infant and Toddler Development III from 6 weeks. Creatinine, alkaline phosphatase, and phosphorus were assessed at 3, 6, and 12 months. Of 260 HIV-and-ARV-exposed and 125 HIV-and-ARV-unexposed infants enrolled at birth, 87% and 57%, 78% and 59%, 77% and 54%, 73% and 51%, and 65% and 43% completed 6-weeks, 3, 6, 12, and 18 months visits, respectively. There were no significant differences in the mean Z-scores for length-for-age, weight-for-age, weight-for-length, mid-upper arm circumference-for-age, and head circumference-for-age between groups except at 6-weeks for length-for-age. No bone fractures occurred. Neurodevelopment outcomes were similar between groups. Of creatinine, alkaline phosphatase, and serum phosphate measurements, 1.7%, 2.6%, and 3.3% reached any toxicity levels grades 1-4, respectively, with no differences between groups. Long-term exposure to EFV and TDF through breastfeeding in infants of HIV-infected mothers does not seem to result in significant growth, neurodevelopment, renal, or bone adverse outcomes. Data support safety of breastfeeding through 18 months within the Option B+ program.

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.

The Impact of Maternal Human Immunodeficiency Virus Infection on the Burden of Respiratory Syncytial Virus Among Pregnant Women and Their Infants, Western Kenya.

BackgroundRespiratory syncytial virus (RSV) is an important cause of respiratory illness worldwide; however, burden data on mother–infant pairs remain sparse in sub-Saharan Africa, where human immunodeficiency virus (HIV) is prevalent. We evaluated the impact of maternal HIV infection on the burden of RSV among mothers and their infants in western Kenya.MethodsWe enrolled pregnant women (≤20 weeks’ gestation) and followed them and their newborns weekly for up to 3–6 months postpartum, to document cases of acute respiratory illness (ARI). Nasal/oropharyngeal swabs were collected and tested for RSV using polymerase chain reaction. Analyses were stratified by maternal HIV status and incidence was computed per 1000 person-months.ResultsCompared to RSV-negative ARI cases, RSV-positive cases were associated with cough, apnea, and hospitalization among infants. RSV incidence per 1000 person-months among mothers was 4.0 (95% confidence interval [CI], 3.2–4.4), and was twice that among the HIV-infected mothers (8.4 [95% CI, 5.7–12.0]) compared to the HIV-uninfected mothers (3.1 [95% CI, 2.3–4.0]). Among infants, incidence per 1000 person-months was 15.4 (95% CI, 12.5–18.8); incidence did not differ by HIV exposure or prematurity.ConclusionsHIV infection may increase the risk of RSV illness among pregnant women. Future maternal RSV vaccines may have added benefit in areas with high HIV prevalence.

Horizontal HIV transmission to children of HIV-uninfected mothers: A case series and review of the global literature

BackgroundVertical transmission is the predominant route for acquisition of HIV infection in children, either in utero, intrapartum or postnatally through breast feeding. Less frequently, children may acquire HIV by horizontal transmission. Horizontal transmission may be healthcare-associated (infusion of HIV-contaminated blood products, use of contaminated needles, syringes and medical equipment, or through ingestion of HIV in expressed breastmilk). Community-acquired HIV transmission to children may occur following surrogate breastfeeding, pre-mastication of food, and sexual abuse. MethodsChildren with suspected horizontally acquired HIV infection were identified by retrospective folder review of existing patients (2004–2014) and by prospective interview and examination of new patients (from 2009 onwards), at a hospital-based paediatric antiretroviral clinic in Cape Town, South Africa. The global literature on horizontal HIV transmission to children (1 January 1986–1 November 2019) was reviewed, to contextualize the local findings. ResultsAmong the 32 children with horizontal HIV transmission (15 identified retrospectively and 17 prospectively), the median age at first diagnosis was 79 months (interquartile range 28.5–91.5); most children (90.6%) had advanced HIV disease at presentation. HIV transmission was considered healthcare-associated in 15 (46.9%), community-associated in ten (31.3%), possibly healthcare or community-associated in five (15.6 %); and unknown in two children (6.3%). ConclusionHorizontal HIV transmission to children is an important public health issue, with prevention efforts requiring intervention at healthcare facility- and community-level. Greater effort should be made to promptly identify and comprehensively investigate each horizontally HIV-infected child to establish possible routes of transmission and inform future prevention strategies.

Assessing the effects of maternal HIV infection on pregnancy outcomes using cross-sectional data in Malawi

BackgroundSeveral studies have shown that maternal HIV infection is associated with adverse pregnancy outcomes such as low birth weight and perinatal mortality. However, the association is conflicted with the effect of antiretroviral therapy (ART) on the pregnancy outcomes and it remains unexamined. If the association is confirmed then it would guide policy makers towards more effective prevention of mother to child HIV transmission interventions. Using methods for matching possible confounders, the objectives of the study were to assess the effect of maternal HIV infection on birth weight and perinatal mortality and to investigate the effect of ART on these two pregnancy outcomes in HIV-infected women.MethodsData on 4111 and 4759 children, born within five years of the 2010 and 2015-16 Malawi Demographic and Health Surveys (MDHS) respectively, whose mothers had an HIV test result, were analysed. A best balancing method was chosen from a set of covariate balance methods namely, the 1:1 nearest neighbour (NN) matching, matching on the propensity score (PS) and inverse weighting on the PS. HIV and ART data were only available in the MDHS 2010, permitting an assessment of the moderating effect of ART on the association between maternal HIV infection and birth weight and perinatal mortality.ResultsThe overall average birth weight was 3227.9g (95% CI: 3206.4, 3249.5) in 2010 and 3226.4g (95%: 3205.6, 3247.2) in 2015-16 and perinatal mortality was 3.8% (95%: 3.2, 4.3) in 2010 and 3.5% (95%: 2.8, 3.8) in 2015-16. The prevalence of HIV among the mothers was 11.1% (95%: 10.1, 12.0) and 9.2% (95% CI: 8.4, 10.1) in 2010 and 2015-16, respectively. In 2010, maternal HIV infection was negatively associated with birth weight (mean= -25.3g, 95% CI:(-95.5, -7.4)) and in 2015-16 it was positively associated with birth weight (mean= 116.3g, 95% CI:(27.8, 204.7)). Perinatal mortality was higher in infants of HIV-infected mothers compared to infants of HIV-uninfected mothers (OR = 1.5, 95% CI:(1.1 - 3.1)) in 2010, while there was no difference in the rate in 2015-16 (OR = 1.0, 95% CI:(0.4, 1.6)). ART was not associated with birth weight, however, it was associated with perinatal mortality (OR=3.9, 95% CI:(1.1, 14.8)).ConclusionThe study has found that maternal HIV infection had an adverse effect on birth weight and perinatal mortality in 2010. Birth weight was not dependent on ART uptake but perinatal mortality was higher among infants of HIV-infected mothers who were not on ART. The higher birth weight among HIV-infected mothers and similarity in perinatal mortality with HIV-uninfected mothers in 2015-16 may be indicative of successes of interventions within the PMTCT program in Malawi.

Neural-Tube Defects and Antiretroviral Treatment Regimens in Botswana

BackgroundA preliminary safety signal for neural-tube defects was previously reported in association with dolutegravir exposure from the time of conception, which has affected choices of antiretroviral treatment (ART) for human immunodeficiency virus (HIV)–infected women of reproductive potential. The signal can now be evaluated with data from follow-up of additional pregnancies.MethodsWe conducted birth-outcomes surveillance at hospitals throughout Botswana, expanding from 8 to 18 sites in 2018. Trained midwives performed surface examinations of all live-born and stillborn infants. Research assistants photographed abnormalities after maternal consent was obtained. The prevalence of neural-tube defects and major external structural defects according to maternal HIV infection and ART exposure status was determined. In the primary analyses, we used the Newcombe method to evaluate differences in prevalence with 95% confidence intervals.ResultsFrom August 2014 through March 2019, surveillance captured 119,477 deliveries; 119,033 (99.6%) had an infant surface examination that could be evaluated, and 98 neural-tube defects were identified (0.08% of deliveries). Among 1683 deliveries in which the mother was taking dolutegravir at conception, 5 neural-tube defects were found (0.30% of deliveries); the defects included two instances of myelomeningocele, one of anencephaly, one of encephalocele, and one of iniencephaly. In comparison, 15 neural-tube defects were found among 14,792 deliveries (0.10%) in which the mother was taking any non-dolutegravir ART at conception, 3 among 7959 (0.04%) in which the mother was taking efavirenz at conception, 1 among 3840 (0.03%) in which the mother started dolutegravir treatment during pregnancy, and 70 among 89,372 (0.08%) in HIV-uninfected mothers. The prevalence of neural-tube defects was higher in association with dolutegravir treatment at conception than with non-dolutegravir ART at conception (difference, 0.20 percentage points; 95% confidence interval [CI], 0.01 to 0.59) or with other types of ART exposure. Major external structural defects were found in 0.95% of deliveries among women exposed to dolutegravir at conception and 0.68% of those among women exposed to non-dolutegravir ART at conception (difference, 0.27 percentage points; 95% CI, −0.13 to 0.87).ConclusionsThe prevalence of neural-tube defects was slightly higher in association with dolutegravir exposure at conception than with other types of ART exposure at conception (3 per 1000 deliveries vs. 1 per 1000 deliveries). (Funded by the National Institutes of Health.)

Primary HIV prevention in pregnant and lactating Ugandan women: A randomized trial.

BackgroundThe ‘Primary HIV Prevention among Pregnant and Lactating Ugandan Women’ (PRIMAL) study aimed to assess the effectiveness of an enhanced HIV counseling intervention for preventing HIV acquisition among HIV-uninfected mothers during pregnancy and throughout the breastfeeding period.MethodsWe conducted an unblinded randomized control trial between 22 February 2013 and 22 April 2016 to assess the effectiveness of an extended repeat HIV testing and enhanced counseling (ERHTEC) intervention aimed at preventing primary HIV infection among HIV-uninfected pregnant and lactating women in Uganda. HIV-uninfected pregnant women aged 15–49 were enrolled 1:1 individually or in couples together with their partner. Enrolled women and couples were randomized 1:1 to an intervention (ERHTEC) or control (extended repeat HIV testing and standard counseling) group and followed up to 24 months postpartum or six weeks past complete cessation of breastfeeding, whichever came first. Both groups were tested for sexually transmitted infections (STIs) and HIV at enrollment, delivery, 3 and 6 months postpartum and every 6 months thereafter until the end of follow-up. The intervention group received enhanced HIV prevention counseling every 3 months throughout follow-up. The control group received standard counseling at the time of HIV retesting. Both intervention and control couples were offered couple HIV testing and counseling at all study visits.Main outcome measuresFrequency of condom use and incidence of HIV, syphilis, gonorrhea, chlamydia and trichomoniasis over follow-up.ResultsBetween February 2013 and April 2014, we enrolled 820 HIV-uninfected pregnant women presenting for antenatal care individually (n = 410) or in couples (n = 410 women and 410 partners) in one urban and one rural public Ugandan hospital. Women’s median age was 24 years (IQR 20–28 years). At baseline, participants did not differ in any socio-demographic, reproductive health, HIV testing history, sexual behavior, medical history or STI status characteristics; 96% (386/402) of couples were tested and counseled for HIV together with their partners at enrolment, 2.1% (7/329) of whom were found to be HIV-infected. Six hundred twenty-five (76%) women completed follow-up as per protocol (S1 Protocol). Women were followed for an average of 1.76 years and cumulated 1,439 women-years of follow-up or 81% of the maximum 1,779 women-years of follow-up assuming no dropouts. Men were followed for an average of 1.72 years.The frequency of consistent condom use and the proportion of women who used condoms over the last 3 months or at last vaginal sex increased substantially over follow-up in both arms, but there were no statistically significant differences in increases between the intervention and control arms.During follow-up, on average 42% (range 36%-46%) of couple partners were counseled together. Between 3.8% and 7.6% of women tested positive at any follow-up visit for any STI including syphilis, gonorrhea, C. trachomatis or T. vaginalis. Four women (two in each arm) and no enrolled men became infected with HIV, representing an overall HIV incidence rate of 0.186 per 100 person-years. Three of the women seroconverters had enrolled individually, one as a couple. At or before seroconversion, all four women reported their partners had extramarital relationships and/or had not disclosed their suspected HIV-infected status. There were no statistically significant differences between study arms for STI or HIV incidences.ConclusionsA sustained enhanced HIV prevention counseling intervention for up to 2 years postpartum among pregnant and breastfeeding women did not have a statistically significant effect on condom use or HIV incidence among these women. However, in both study arms, condom use increased over follow-up while STI and HIV incidence remained very low when compared to similar cohorts in and outside Uganda, suggesting that repeat HIV testing during breastfeeding, whether with enhanced or standard counseling, may have had an unintended HIV preventive effect among pregnant and lactating women in this setting. Further research is needed to verify this hypothesis.Trial registrationClinicalTrials.gov NCT01882998

Immune response to asymptomatic infections by Entamoeba histolytica and other enteric pathogens in pregnant women and their infants in a high HIV burdened setting in Zimbabwe.

Asymptomatic Entamoeba histolytica infections in pregnant women puts infants at risk of infection through vertical transmission or transmission during breastfeeding in high HIV prevalence areas. The study aimed at investigating the immune response to asymptomatic E.histolytica infection in pregnant women and their infants in a high HIV burdened setting in Harare, Zimbabwe. Serum samples from 39 predominantly breastfeeding mother-infant pairs were analyzed for inflammatory cytokine and immunoglobulin profiles using BIOPLEX. The infants' ages ranged from 10 days to 14 weeks. IL-1r, IL-4, IL-9, IL-12p70, IL-17a, G-CSF and PDGF-BB were significantly raised in E. histolytica infected compared to non-infected lactating mothers (p<0.05). Carriage of any form of enteric infection such as Non-lactose fermenters (NLFs) including E. histolytica significantly increased concentration levels of IL-1r, IL-4, IL-9, IL-10, IL-12p70, IL17a, G-CSF, GM-CSF, IFN-γ, PDGF-BB and TNF-α cytokines (p<0.05) but no significant differences in immunoglobulin levels among the mothers. Anti-inflammatory cytokines (IL-1r, IL-2, IL-4, IL-5, IL-6), pro-inflammatory cytokines (IL-9, IL-12-p70, IL-15, IL-17a, TNF-α) and growth factors (FGF-β, G-CSF, GM-CSF, PDGF-bb) were significantly raised in HIV-uninfected mothers and not HIV-infected mothers during E. histolytica infection (p<0.05). In infants, E. histolytica carriage and HIV exposure had no significant impact on the cytokine and immunoglobulin concentrations. Pro-inflammatory cytokines and chemokines are highly raised in lactating mothers with asymptomatic enteric pathogens hence there is need to check cytokine profiles in pregnant women and their infants to assist in decision making linked to treatment and prevention in times of pandemics.

2572. Decreased T-Cell Response, but Appropriate Antibody Production to Tetanus Vaccine Among HIV-Exposed Uninfected Infants in Botswana

BackgroundIn Botswana, more than 10% of HIV-exposed, uninfected infants (HEU) are hospitalized or die in the first 6 months of life, largely due to infectious causes. Vaccine responses can act as a marker of the immune response to infectious antigens. Previous studies of vaccine responses in HEU have had conflicting results. We compared T-cell responses to tetanus and purified protein derivative (PPD), and antibody titers to tetanus, between HEU and HIV-unexposed infants (HUU).MethodsA total of 443 HIV-infected and 451 HIV-uninfected mothers and their 453 HEU/457 HUU live-born infants were followed from pregnancy/delivery through 24 months postpartum in a prospective observational study in Botswana (“Tshipidi”). T-cell expression of interferon (IFN)-γ and interleukin (IL)-2 were measured at 6 months using FluoroSpot after stimulation with tetanus toxoid or PPD. Quantitative tetanus toxoid IgG was measured in plasma at 18 months using ELISA. Mean spot-forming units (sfu) per 105 cells and geometric mean antibody titers were compared between HEU and HUU infants who had received 3 doses of tetanus and 1 dose of Bacille Calmette–Guérin (BCG) vaccines by 6 months, and 3 or 4 doses of tetanus vaccine by 18 months. Results. Peripheral blood mononuclear cells were available at 6 months for 63 HEU and 18 HUU. Plasma was available at 18 months for 39 HEU and 42 HUU. HEU infants had significantly lower IL-2 expression after tetanus stimulation than HUU infants (4.4 vs. 16.1 sfu/105 cells, P = 0.004; figure), but no difference in IFNγ expression. There were no differences in T-cell responses to PPD between HEU and HUU. There were no differences in tetanus geometric mean antibody titers between HEU and HUU. Conclusion. In this cohort of infants from Botswana, we found decreased T-cell responses, but not antibody responses, to tetanus toxoid and no differences in T-cell responses to PPD. Cell-mediated immune defects may play a greater role than humoral immune defects in the increased susceptibility to infection among HEU. BCG vaccine produces robust T-helper 1 responses, which may overcome cell-mediated immune defects in HEU. Disclosures All authors: No reported disclosures.

HIV Exposure and Formula Feeding Predict Under-2 Mortality in HIV-Uninfected Children, Botswana

To prospectively assess rates and detailed predictors of morbidity and mortality among HIV-exposed uninfected children and HIV-unexposed children in Botswana in a more recent era. We enrolled HIV-infected and HIV-uninfected mothers and their children in the prospective observational Tshipidi study at 2 sites (1 city and 1 village) in Botswana from May 2010-July 2012. Live-born children and their mothers were followed for 24 months postpartum. Detailed sociodemographic data, health, and psychosocial characteristics were collected at baseline and prospectively, and health outcomes ascertained. Mothers chose infant feeding method with counselling. A total of 893 live-born HIV-uninfected children (436 HIV-exposed uninfected, 457 HIV-unexposed) were followed. HIV-infected mothers had a median CD4 count of 410 cells/mm3, 32% took 3-drug antiretroviral treatment during pregnancy, 67% took only zidovudine, and 1% took <2 weeks of any antiretrovirals antepartum. Twenty four-month vital status was available for 888 (99.4%) children. HIV-exposed uninfected children had a significantly higher risk of death compared with children of HIV-uninfected mothers (5.0% vs 1.8%) (adjusted hazard ratio 3.27, 95% CI 1.44-7.40). High collinearity between maternal HIV status and child feeding method precluded analysis of these factors as independent predictors of mortality. Preterm birth, low birth weight, and congenital anomaly were also associated with mortality (in separate analyses), but maternal socioeconomic factors, depression, substance use, and social support were not significant predictors. The strongest predictors of 24-month mortality among children in Botswana were HIV exposure and formula feeding, although the relative contribution of these factors to child health could not be separated.

Early Breastfeeding Cessation Among HIV-Infected and HIV-Uninfected Women in Western Cape Province, South Africa.

As part of the Mother-Infant Health Study, we describe infant feeding practices among HIV-infected and HIV-uninfected mothers over a 12-month period when the Western Cape Province prevention of mother-to-child transmission (PMTCT) program was transitioning from a policy of exclusive formula feeding to one of exclusive breastfeeding. Two hundred pairs of mother and HIV-uninfected infant were included in the analysis, among whom 81 women were HIV uninfected and breastfeeding. Of the 119 HIV-infected mothers, 50 (42%) were breastfeeding and 69 (58%) were formula feeding. HIV-infected mothers predominantly breastfed for 8.14 (7.71-15.86) weeks; HIV-uninfected mothers predominantly breastfed for 8.29 (8.0-16.0) weeks; and HIV-infected mothers predominantly formula fed for 50.29 (36.43-51.43) weeks. A woman's HIV status had no influence on the time to stopping predominant breastfeeding (P = 0.20). Our findings suggest suboptimal duration of breastfeeding among both HIV-infected and HIV-uninfected mothers. Providing support for all mothers postdelivery, regardless of their HIV status, may improve breastfeeding practices.

Prevalence and correlates of non-disclosure of maternal HIV status to male partners: a national survey in Kenya

BackgroundPrevention of mother-to-child HIV transmission (PMTCT) programs usually test pregnant women for HIV without involving their partners. Non-disclosure of maternal HIV status to male partners may deter utilization of PMTCT interventions since partners play a pivotal role in decision-making within the home including access to and utilization of health services.MethodsMothers attending routine 6-week and 9-month infant immunizations were enrolled at 141 maternal and child health (MCH) clinics across Kenya from June–December 2013. The current analysis was restricted to mothers with known HIV status who had a current partner. Multivariate logistic regression models adjusted for marital status, relationship length and partner attendance at antenatal care (ANC) were used to determine correlates of HIV non-disclosure among HIV-uninfected and HIV-infected mothers, separately, and to evaluate the relationship of non-disclosure with uptake of PMTCT interventions. All analyses accounted for facility-level clustering,ResultsOverall, 2522 mothers (86% of total study population) met inclusion criteria, 420 (17%) were HIV-infected. Non-disclosure of HIV results to partners was higher among HIV-infected than HIV-uninfected women (13% versus 3% respectively, p < 0.001). HIV-uninfected mothers were more likely to not disclose their HIV status to male partners if they were unmarried (adjusted odds ratio [aOR] = 3.79, 95% CI: 1.56–9.19, p = 0.004), had low (≤KSH 5000) income (aOR = 1.85, 95% CI: 1.00–3.14, p = 0.050), experienced intimate partner violence (aOR = 3.65, 95% CI: 1.84–7.21, p < 0.001) and if their partner did not attend ANC (aOR = 4.12, 95% CI: 1.89–8.95, p < 0.001). Among HIV-infected women, non-disclosure to male partners was less likely if women had salaried employment (aOR = 0.42, 95%CI: 0.18–0.96, p = 0.039) and each increasing year of relationship length was associated with decreased likelihood of non-disclosure (aOR = 0.90, 95% CI: 0.82–0.98, p = 0.015 for each year increase). HIV-infected women who did not disclose their HIV status to partners were less likely to uptake CD4 testing (aOR = 0.32, 95% CI: 0.15–0.69, p = 0.004), to use antiretrovirals (ARVs) during labor (OR = 0.38, 95% CI 0.15–0.97, p = 0.042), or give their infants ARVs (OR = 0.08, 95% CI 0.02–0.31, p < 0.001).ConclusionHIV-infected women were less likely to disclose their status to partners than HIV-uninfected women. Non-disclosure was associated with lower use of PMTCT services. Facilitating maternal disclosure to male partners may enhance PMTCT uptake.