Altered methionine-sulfone levels are associated with impaired growth in HIV-exposed-uninfected children.

OBJECTIVE: To determine immune-metabolic dysregulation in children born to women living with HIV. METHODS: Longitudinal immune-metabolomic analyses of plasma of 32 pregnant women with HIV (WHIV) and 12 uninfected women and their children up to 1.5 years of age were performed. RESULTS: Using liquid chromatography-mass spectrometry and a multiplex bead assay, 280 metabolites (57 amino acids, 116 positive lipids, 107 signalling lipids) and 24 immune mediators (e.g. cytokines) were quantified. combinational antiretroviral therapy (cART) exposure was categorized as cART initiation preconception (long), cART initiation postconception up to 4 weeks before birth (medium) and cART initiation within 3 weeks of birth (short). Plasma metabolite profiles differed between HIV-exposed-uninfected (HEU)-children with long cART exposure compared to HIV-unexposed-children (HUU). Specifically, higher levels of methionine-sulfone, which is associated with oxidative stress, were detected in HEU-children with long cART exposure compared to HUU-children. High infant methionine-sulfone levels were reflected by high prenatal plasma levels in the mother. Increased methionine-sulfone levels in the children were associated with decreased growth, including both weight and length. CONCLUSION: These findings based on longitudinal data demonstrate that dysregulation of metabolite networks associated with oxidative stress in children born to WHIV is associated with restricted infant growth.

The University of Zimbabwe College of Health Sciences (UZ-CHS) BIRTH COHORT study: rationale, design and methods.

BACKGROUND: Commencing lifelong antiretroviral therapy (ART) immediately following HIV diagnosis (Option B+), has greatly improved maternal-infant health. Thus, large and increasing numbers of HIV-infected women are on ART during pregnancy, a situation concurrently increasing numbers of HIV-exposed-uninfected (HEU) infants. Compared to their HIV-unexposed-uninfected (HUU) counterparts, HEU infants show higher rates of adverse birth outcomes, mortality, infectious/non-communicable diseases including impaired growth and neurocognitive development. There is an urgent need to understand the impact of HIV and early life ART exposures, immune-metabolic dysregulation, comorbidities and environmental confounders on adverse paediatric outcomes. METHODS: Six hundred (600) HIV-infected and 600 HIV-uninfected pregnant women ≥20 weeks of gestation will be enrolled from four primary health centres in high density residential areas of Harare. Participants will be followed up as mother-infant-pairs at delivery, week(s) 1, 6, 10, 14, 24, 36, 48, 72 and 96 after birth. Clinical, socio-economic, nutritional and environmental data will be assessed for adverse birth outcomes, impaired growth, immune/neurodevelopment, vertical transmission of HIV, hepatitis-B/C viruses, cytomegalovirus and syphilis. Maternal urine, stool, plasma, cord blood, amniotic fluid, placenta and milk including infant plasma, dried blood spot and stool will be collected at enrolment and follow-up visits. The composite primary endpoint is stillbirth and infant mortality within the first two years of life in HEU versus HUU infants. Maternal mortality in HIV-infected versus -uninfected women is another primary outcome. Secondary endpoints include a range of maternal and infant outcomes. Sub-studies will address maternal stress and malnutrition, maternal-infant latent tuberculosis, Helicobacter pylori infections, immune-metabolomic dysregulation including gut, breast milk and amniotic fluid dysbiosis. DISCUSSION: The University of Zimbabwe-College of Health-Sciences-Birth-Cohort study will provide a comprehensive assessment of risk factors and biomarkers for HEU infants' adverse outcomes. This will ultimately help developing strategies to mitigate effects of maternal HIV, early-life ART exposures and comorbidities on infants' mortality and morbidity. TRIAL REGISTRATION: ClinicalTrial.gov Identifier: NCT04087239 . Registered 12 September 2019.

Predictors of attrition among children born in a PMTCT programme in Zimbabwe followed up over 5 years.

Eliminating of paediatric HIV within prevention of mother to child transmission (PMTCT) interventions rests on complete follow-up of all children. We report on predictors of child attrition in the PMTCT cascade over 5 years where 1050 pregnant women were enrolled at 36 gestational weeks. Mother and child pairs were followed up at birth, 6 weeks, 4 months, 9 months, and every 6 months thereafter for 60 months. Higher attrition was observed for children of economically advantaged, socially stable mothers regardless of HIV status, whereas compliance was observed for children whose mothers tested positive for HIV-1, HSV-2 and Syphilis. Low birthweight was associated with attrition regardless of maternal HIV status. Five years predictors of attrition did not differ by maternal HIV status, as HIV-exposed children succumbed to mortality and those not exposed were loss to follow-up (LFU). Child follow-up is influenced more by maternal lifestyle and health risks leading to retention of high-risk children in PMTCT programmes.

Neurodevelopmental impairment among infants born to mothers infected with human immunodeficiency virus and uninfected mothers from three peri-urban primary care clinics in Harare, Zimbabwe.

AIM: The aim of this article is to document the risk of neurodevelopmental impairment (NDI) among infants enrolled in a programme for the prevention of mother-to-child transmission of HIV (human immunodeficiency virus) in Zimbabwe using the Bayley Infant Neurodevelopmental Screener (BINS). METHOD: We prospectively followed up infants at three primary care clinics in Harare, Zimbabwe. Neurodevelopmental assessments using the BINS were conducted during the first 12 months of life. NDI risk category and associated risk factors were examined. RESULTS: Of the 598 infants assessed, 305 (51%) were female and 293 (49%) were male. Sixty-five infants (11%) were infected with HIV, 188 (31%) were exposed but uninfected, 287 (48%) were unexposed, and 58 (10%) were of unknown status. The prevalence of a high risk of NDI was 9.4% (95% confidence interval [CI] 7.1-11.1%): 9.2% in males and 9.6% in females. Of the 598 infants, 549 (92%) had ever been breastfed, 49% of whom had mothers infected with HIV. The risk of NDI was higher among infants infected early with HIV, i.e. by 3 months of age (p value <0.001). The NDI high-risk category included twice as many infants infected with HIV as uninfected infants (odds ratio [OR] 2.1; 95% CI 1.0-4.3). After adjusting for other factors, head circumference and family financial subsistence remained risk factors for NDI with an OR of 2.22 (1.04-4.82) and 2.55 (1.02-6.36) respectively. INTERPRETATION: The background prevalence of high-risk NDI category of 9.4% across groups seems high but is similar to that reported previously in developing countries. Integration of an early infant neurodevelopmental screening programme into child HIV management protocols will assist in the early referral of children exposed to HIV.

Human Immunodeficiency Virus (HIV) types Western blot (WB) band profiles as potential surrogate markers of HIV disease progression and predictors of vertical transmission in a cohort of infected but antiretroviral therapy naïve pregnant women in Harare, Zimbabwe.

BACKGROUND: Expensive CD4 count and viral load tests have failed the intended objective of enabling access to HIV therapy in poor resource settings. It is imperative to develop simple, affordable and non-subjective disease monitoring tools to complement clinical staging efforts of inexperienced health personnel currently manning most healthcare centres because of brain drain. Besides accurately predicting HIV infection, sequential appearance of specific bands of WB test offers a window of opportunity to develop a less subjective tool for monitoring disease progression. METHODS: HIV type characterization was done in a cohort of infected pregnant women at 36 gestational weeks using WB test. Student-t test was used to determine maternal differences in mean full blood counts and viral load of mothers with and those without HIV gag antigen bands. Pearson Chi-square test was used to assess differences in lack of bands appearance with vertical transmission and lymphadenopathy. RESULTS: Among the 64 HIV infected pregnant women, 98.4% had pure HIV-1 infection and one woman (1.7%) had dual HIV-1/HIV-2 infections. Absence of HIV pol antigen bands was associated with acute infection, p = 0.002. All women with chronic HIV-1 infection had antibody reactivity to both the HIV-1 envelope and polymerase antigens. However, antibody reactivity to gag antigens varied among the women, being 100%, 90%, 70% and 63% for p24, p17, p39 and p55, respectively. Lack of antibody reactivity to gag p39 antigen was associated with disease progression as confirmed by the presence of lymphadenopathy, anemia, higher viral load, p = 0.010, 0.025 and 0.016, respectively. Although not statistically significant, women with p39 band missing were 1.4 times more likely to transmit HIV-1 to their infants. CONCLUSION: Absence of antibody reactivity to pol and gag p39 antigens was associated with acute infection and disease progression, respectively. Apart from its use in HIV disease diagnosis, WB test could also be used in conjunction with simpler tests like full blood counts and patient clinical assessment as a relatively cheaper disease monitoring tool required prior to accessing antiretroviral therapy for poor resource settings. However, there is also need to factor in the role of host-parasite genetics and interactions in disease progression.

Antenatal HIV-1 RNA load and timing of mother to child transmission; a nested case-control study in a resource poor setting.

OBJECTIVE: To determine HIV-1 RNA load during the third trimester of pregnancy and evaluate its effect on in utero and intra-partum/postpartum transmissions in a breastfeeding population. DESIGN: A nested case-control study within a PMTCT cohort of antiretroviral therapy naive pregnant women and their infants. METHODS: A case was a mother who transmitted HIV-1 to her infant (transmitter) who was matched to one HIV-1 positive but non-transmitting mother (control). RESULTS: From a cohort of 691 pregnant women, 177 (25.6%) were HIV-1 positive at enrollment and from these 29 (23%) transmitted HIV-1 to their infants, 10 and 19 during in utero and intra-partum/postpartum respectively. Twenty-four mothers sero-converted after delivery and three transmitted HIV-1 to their infants. Each unit increase in log10 viral load was associated with a 178 cells/mm(3) and 0.2 g/dL decrease in TLC and hemoglobin levels, p = 0.048 and 0.021 respectively, and a 29% increase in the risk of transmission, p = 0.023. Intra-partum/postpartum transmitters had significantly higher mean viral load relative to their matched controls, p = 0.034. CONCLUSION: Antenatal serum HIV-1 RNA load, TLC and hemoglobin levels were significantly associated with vertical transmission but this association was independent of transmission time. This finding supports the rationale for preventive strategies designed to reduce vertical transmission by lowering maternal viral load.