HIV Exposure, Disease Acquisition and Progression Among Children: Role of Maternal Immunogenetics, Viral Genetic Diversity, HAART Exposure, Co-morbidities and Psycho-Social Status: (UZ-CHS Birth Cohort)

Over one million infants are born to HIV-1-infected women every year in Sub Saharan Africa. In Zimbabwe, annual births stand at 379,000 with approximately 48,000 infants being born every year to HIV-1-infected women on lifelong highly active antiretroviral therapy (HAART). Concerns have been expressed on the general health and developmental outcomes of HIV-1 exposed but uninfected (HEU) infants born to HIV-1-infected women. In spite of being HIV negative, HEU children have 3.9-and 2.0-fold higher mortality than HIV unexposed and uninfected (HUU) infants during the first and second year(s) of life, respectively. Compared to their HUU counterparts, HEU children may have adverse birth outcomes, impaired growth, development, and other health deficits. This is a significant public health concern as in adulthood, infants born with low birth weight (LBW) are more likely to die from non-communicable diseases (NCDs) such as hypertension, stroke and type 2 diabetes. In Zimbabwe, HEU infants have been well-studied during the pre-HAART era; however, contemporary evidence is lacking. In addition, previous studies have not characterized women in pregnancy and the outcome has not been controlled for other common antenatal infective pathogens including additional risk factors such as preterm birth, LBW, duration of breastfeeding, poverty and maternal psychosocial stressors. Therefore, an in-depth and comprehensive characterization of HEU infants is needed not only to avoid HIV-infection but also to improve short-and long-term health outcomes of the exposed.

Risks of HAART in pregnancy In Zimbabwe, the current standard of care for HIV infected women to prevent mother to child transmission (MTCT) of HIV consists of Tenofovir, Lamivudine and Efavirenz (TENOLAM-E). However, antiretroviral drugs can accumulate in the amniotic fluid, thus posing a risk during delicate embryonic and foetal developments. Timing of HAART might also be important, since a South African study showed that mothers who initiated zidovudine based HAART before conception had twice the odds of preterm delivery compared to mothers who started HAART after conception. Toxic mechanisms of anti-HIV drugs include mitochondrial toxicity and mitochondrial DNA mutations in mothers and possibly also in infants. Mitochondrial dysfunction will in turn increase the production of reactive oxygen species and activation of IL-1 production. Interference with lipid metabolism is another mechanism for HAART toxicity. Early exposure to Efavirenz-based HAART has been associated with neurodevelopmental and socio-emotional challenges which may lead to behavioural deficits. In addition, persistent infections, detrimental effects of socio-economic status and maternal dietary contaminants such as dioxins or chlorinated pesticides may also play a role.

The reasons for the observed adverse health outcomes of HEU infants could be related to an altered immune system state. However, immune profiles beyond one year of HEU children remain largely unexplored. In Zimbabwe, vaccination campaigns for active immunization of infants are promoted via the expanded program of immunization (EPI). Even though peak antibody titres following some EPI vaccines are normal in HEU infants, there have been no studies of the longevity of these immune responses. In utero HIV-exposure increases pro-inflammatory cytokine levels produced by placental cells. Co-infections seem to be important since Kenyan HEU neonates (with a high number of maternal co-infections) had higher levels of inflammatory plasma markers than HEU controls from studies in the USA. Further, HEU infants have higher CMV loads, which may be driven partly by maternal viremia and may contribute to immune activation. Thus, HEU infants continue to have baseline inflammation which can be linked to poor short- and long-term outcomes and anti-inflammatory interventions might improve infant health. Interventional studies with HAART treatment in pregnant women are ethically challenging; however, the impact of HAART on neuro/immune development could be assessed in studies like the UZ-CHS birth cohort, where more often, due to economic challenges mothers' book late for their antenatals, and some being HAART naïve in their third trimester. Evidence regarding the risk of HAART exposure in the option B+ era for the short and long-term outcomes of HEU infants remains limited. However, to the best of our knowledge, no study has correlated HAART levels in maternal amniotic fluid, urine, plasma and longitudinal breast milk and related to adverse pregnancy outcomes, infant growth, metabolism and (immune/neuro) development.

Methods The University of Zimbabwe College of Health Science (UZ-CHS) Birth Cohort study is a prospective observational cohort study comparing infants born to HIV infected and HIV uninfected women in a low-resource setting of high-density western suburbs of Harare primary health polyclinics. 1,200 pregnant women (600 HIV infected mothers and 600 HIV uninfected controls) in their third trimester were enrolled from January 2016 to June 2019. Participants are being followed as mother-baby pairs at birth, within 10 days of life 6, 10, 14, 24, 48, 72 and 96 weeks of age. At each visit clinical examinations are being used to assess health and the impact of environmental factors. In addition, questionnaires are administered and bio-samples for laboratory tests. The design of the study is non-interventional cohort but participants are being offered advice regarding health and hygiene.

Aim of the study This study aims to examine the impact of maternal HIV status, cumulative HAART exposure in utero and throughout breastfeeding, immune suppression and immune activation and environmental variables on short-and long-term outcomes of infants in a low resource environment. Our study is focusing on mortality and morbidity of HEU infants, testing established risk factors from previous cohorts. Data and bio-materials are being collected prospectively from mothers and infants from pregnancy to 2 years of age and compare HEU to HUU infants from the same community. For a comprehensive assessment, the role of maternal socio economic status, household factors, comorbidities including co-infections with persistent viruses such as cytomegalovirus (CMV), hepatitis b/c (HBV)/(HCV), bacterial diseases such as syphilis and tuberculosis (TB), intestinal helminths, emerging NCDs, such as gestational diabetes mellitus (GDM) and hypertensive disorders and maternal nutritional status on pregnancy outcomes, infant mortality and development, immunity and health will be tested. The UZ-CHS offers an opportunity to establish references ranges that are currently not available, for various subgroups of pregnant women with a favourable outcome of pregnancy for clinical use for future patients.