Cohort profile: longitudinal and population comparison of children who are HIV-exposed uninfected and children who are HIV unexposed in Kenya (HOPE study)

Introduction

Every year, an estimated over 1.2 million children exposed to HIV (HIV-exposed uninfected, HEU) are born; a majority in sub-Saharan Africa (SSA).1 With the expansion of prevention of vertical transmission through HIV programmes—81% of pregnant mothers were receiving antiretroviral therapy (ART) in 20212—most HEU infants are exposed to ART in utero and during breastfeeding. There are an estimated 14.8 million HEU in SSA,1 with continued growth in the population of HEU expected given the high prevalence of HIV among women of reproductive age in SSA.

Evidence from systematic reviews and meta-analysis demonstrate approximately 50% higher mortality among HEU in the era of maternal ART3 and an over 50% higher risk of morbidity from pneumonia and diarrhoeal diseases compared with HIV-unexposed uninfected children (HUU).4 Excess morbidity and mortality could be attributed to lack of or poor breastfeeding practices and poor maternal health,5 challenges that could potentially partly be addressed by newer and more effective ART and breastfeeding guidelines. Additionally, there is evidence of linear growth disparities between HEU and HUU, with consistent evidence of stunting among HEU.6 7 Even in the ART era, there is evidence of a higher stunting prevalence in HEU than HUU, both in areas with high and low general prevalence of stunting.7–9 HEU also have a higher prevalence of underweight and some studies have reported lower mean head circumference scores among HEU associated with specific ART regimens.7 10 Neurodevelopment among HEU may also be impaired, with HEU showing evidence of cognitive impairment, motor and language delays compared with HUU.11–14 However, this evidence is mixed, with some studies showing no differences except for language delays.13 15 16 Some studies have identified hearing differences comparing HEU to HUU; with HEU more likely to have abnormalities or be referred for additional assessments.17 18 Many of these studies have been conducted in infancy or early childhood, and few have studied older HEU. Similar to studies on younger children, the evidence for HEU/HUU differences among older HEU is mixed with some studies showing no differences in cognitive, motor, attention or executive functioning19 and others showing lower math grade scores.20 A systematic review comparing cognitive, neurodevelopmental or behavioural differences among older HEU and HUU identified that HEU had significantly lower performance scores in at least one measure in 7 of 11 studies,21 suggesting concern for future functioning as HEU ages to adulthood.

Prenatal development of mental illness has been studied for illnesses such as schizophrenia, autism spectrum disorders (ASD), attention deficit hyperactivity disorder (ADHD), depression and suicide.22–26 The pathogenesis is thought to be related to maternal infections, maternal stress, placental pathology, fetal brain pathology, genetic predisposition and epigenetic changes due to placental inflammation.22 27 In addition to the risk of opportunistic infections, pregnant women living with HIV in SSA have a high prevalence of mental health challenges and stress and lack support for care.28 Since 2019, guidelines for ART use have switched from first-line efavirenz (EFZ)-based ART to dolutegravir (DTG)-based regimes.29 DTG regimens are associated with fewer adverse drug reactions, better virological profile and are associated with improved maternal health.30 31 However, both DTG and efavirenz are associated with mental health symptoms among mothers living with HIV, but at low prevalence.32–34 Among HEU, there is suggestive evidence that fetal EFZ and DTG exposure is associated with increased neurologic conditions.35 Animal models suggest direct exposure to DTG on the embryo brain during a critical period of development, and therefore, potential for neurotoxicity.36

Many of the existing studies comparing HEU/HUU have examined short-term outcomes among HEU, yet the impact of exposure to drugs or infections in utero could manifest as neurodevelopmental or psychiatric disorders later in childhood, adolescence or in adulthood. Longitudinal studies that track maternal and infant mental and neurodevelopment are lacking; and this gap is compounded by weak health system tracking and reporting for adverse drug reactions for pregnancy exposures.

As HEU populations grow, it is critical to develop robust health services and monitoring systems that can track the health and well-being of this growing population. It is, therefore, imperative to develop screening procedures to support longer-term assessments for neurodevelopment and mental health and enhance referrals for advanced brain and mental healthcare. While differences may be subtle in the era of optimised ART, they could potentially impact future academic and career success. Many countries in SSA lack health systems to track HEU beyond the first 2 years or life or after breast feeding once HIV status is confirmed. Building these systems will require incorporation of simple screening tools useful for long-term surveillance, screening and referral.

The HEU outcomes: population-evaluation and screening strategies (HOPE) study aims to (1) longitudinally compare growth, hearing, neurodevelopment and telomere length among HEU and HUU enrolled at 4–10 weeks of life and followed 6 monthly to 3 years of age, (2) in a cross-sectional study design, pilot and test a mobile screening strategy to detect neurodevelopmental and mental health outcomes in older HEU (ages 3–18 years) and (3) to support future programmatic scale up and integration of HEU screening, estimate the costs of a population screening strategy for older HEU and convene a stakeholder workshop on programmatic integration of HEU screening. Parallel study designs were selected to provide evidence on early outcomes among HEU with universal maternal ART (longitudinal cohort) and provide an estimate of the prevalence of neurodevelopmental and mental health outcomes among older HEU (cross-sectional cohort). The cross-sectional study was preceded by a pilot phase to test recruitment strategies and identify tools for the larger population-based study. Figure 1 summarises the study design and cohorts.

Figure 1
Figure 1

HOPE study design and cohorts. HEU, HIV-exposed uninfected; HOPE, HEU outcomes: population-evaluation and screening strategies; HUU, HIV-unexposed uninfected.

Acknowledgments

We acknowledge the participating clinics and their leadership for their support. We also thank the University of Washington Global Center for the Integrated Health of Women, Adolescents and Children, (Global WACh) for input provided during study design and manuscript development. We thank the HOPE study staff for their dedication and hard work to achieve the study outcomes. We thank various groups that have supported HOPE study training including the INCLEN TRUST, KEMRI anthropometry monitors, University of Nairobi department of psychiatry, George Mathenge for providing vision training and AMPATH for supporting NIH toolbox training. Most of all, we thank the clinics, health care workers, caregivers and children/youth who will participate in the study.

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