The Eswatini Study on Neurocognitive Performance in Adolescents Living With HIV

Eswatini Nazarene Health Institutions

Status: Not yet enrolling

Conditions: HIV (Human Immunodeficiency Virus)

Study type: Observational

Funder types: Other

Identifiers

NCT07165639

EHHRRB 049/2025

Details and patient eligibility

About

This study explores the link between inflammatory biomarkers and neurocognitive performance in adolescents living with HIV (ALHIV) in Eswatini. Persistent HIV infection during adolescence has been associated with ongoing systemic inflammation and subsequent neurocognitive dysfunction. However, the exact nature of this relationship is not well-defined, especially in resource-limited settings where epidemiological and mechanistic data are scarce.

objectives

• To determine the prevalence of cognitive impairment among a sample of adolescents living with HIV, compared to HIV-negative adolescents in Eswatini
• To assess the relationship between neurocognitive performance and current viral load status in adolescent living with HIV (ALHIV).
• To examine the association between inflammation biomarkers and viral load suppression status in ALHIV.
• To investigate whether adolescents with HIV experiencing neurocognitive decline exhibit a high inflammatory status.

A case-control design will be employed, involving 80 adolescents aged 13-19 years: 50 who are HIV-positive and 30 HIV-negative controls. Participants will be recruited from Baylor Manzini and Mbabane, as well as Raleigh Fitkin Memorial Hospital. Neurocognitive function will be evaluated using the Symbol Digit Modalities Test, focusing on areas such as processing speed, motor coordination, attention, and visual scanning.

Blood samples will be collected to measure key inflammatory biomarkers, including C-reactive protein (CRP), soluble CD14 (sCD14), lipopolysaccharide (LPS), soluble CD163 (sCD163), and monocyte chemoattractant protein-1 (MCP-1). Sociodemographic and clinical data will be gathered through questionnaires and medical record reviews.

Primary outcomes will include neurocognitive performance scores, while secondary outcomes will involve biomarker levels and their correlation with cognitive function. Multivariate regression models will assess associations, adjusting for confounders such as age, sex, education, and HIV disease severity. Structural equation modeling will be used to explore potential mediators in the inflammation-cognition pathway.

Full description

Adolescents living with HIV (ALHIV) in sub-Saharan Africa face a complex health burden that goes beyond virological control. In Eswatini, where HIV prevalence ranks among the highest globally, the combination of chronic infection, immune dysregulation, and neurodevelopmental vulnerability poses a significant public health challenge. Although antiretroviral therapy (ART) has greatly improved survival rates, emerging evidence indicates that ongoing immune activation may lead to subtle yet clinically significant neurocognitive deficits in youth. These impairments can impact academic performance, psychosocial functioning, and long-term quality of life.

This study aims to explore the biological correlates of neurocognitive performance in ALHIV, with a particular focus on inflammatory biomarkers. It seeks to determine the extent to which systemic inflammation measured through specific immunological markers relates to cognitive functioning in adolescents and whether these associations differ between HIV-positive and HIV-negative individuals.

Utilizing a case-control design, the study will generate comparative data to enhance understanding of the neuroimmune interface in this population. Study Population and Recruitment The study will enroll 80 adolescents aged 13 to 19 years, consisting of: 50 HIV-positive participants, recruited from HIV care centers at Baylor College of Medicine Children's Foundation-Eswatini (Manzini & Mbabane), and Raleigh Fitkin Memorial Hospital. 30 HIV-negative controls, matched by age and sex, recruited from the same geographic catchment areas to ensure contextual comparability. Eligibility criteria include confirmed HIV status (positive or negative), age within the specified range, and capacity to participate in neurocognitive testing. Exclusion criteria include acute illness, neurological disorders unrelated to HIV, or inability to provide informed consent/assent.

Neurocognitive Assessment Protocol Cognitive functioning will be assessed using the Symbol Digit Modalities Test (SDMT), a standardized neuropsychological instrument sensitive to changes in processing speed and attention. The SDMT is particularly suitable for use in low-resource settings due to its minimal language dependence and brief administration time. It evaluates: Visual scanning Psychomotor speed Sustained attention Working memory Testing will be conducted in a quiet, controlled environment by trained research personnel fluent in local languages and familiar with adolescent developmental norms.

Biomarker Collection and Analysis Venous blood samples will be collected from all participants under sterile conditions. Samples will be processed and stored according to biosafety protocols and analyzed using enzyme-linked immunosorbent assay (ELISA) techniques. The following biomarkers will be quantified: C-reactive protein (CRP): A general marker of systemic inflammation. Soluble CD14 (sCD14): Reflects monocyte activation and microbial translocation. Lipopolysaccharide (LPS): Indicates gut barrier dysfunction and endotoxemia. Soluble CD163 (sCD163): Associated with macrophage activation and neurodegeneration. Monocyte chemoattractant protein-1 (MCP-1): A chemokine involved in leukocyte recruitment and neuroinflammatory signaling. These biomarkers were selected based on their relevance to HIV-associated immune activation and their potential role in neurocognitive outcomes.

Sociodemographic and Clinical Data Collection

Participants will engage in structured interviews and complete questionnaires to gather sociodemographic information, including:

• Age
• Gender
• Educational attainment
• Household composition
• Socioeconomic status

Clinical data will be sourced from medical records, encompassing:

• Duration of HIV infection
• ART regimen and adherence history
• CD4+ T-cell count and viral load
• History of opportunistic infections
• Neurological symptoms or diagnoses This comprehensive dataset will facilitate robust adjustment for confounding variables in statistical analyses.

Outcome Measures

Primary Outcome:

Neurocognitive performance scores derived from SDMT results.

Secondary Outcomes:

• Quantitative levels of inflammatory biomarkers.
• Correlation coefficients between biomarker levels and cognitive scores.
• Group differences in biomarker profiles and cognitive outcomes. Statistical Analysis Plan

Data will be analyzed using multivariate regression models to evaluate the relationship between inflammatory biomarkers and neurocognitive performance. These models will adjust for potential confounders, including:

• Age
• Sex
• Educational level
• HIV disease severity (e.g., CD4 count, viral load)
• ART adherence Interaction terms will be explored to determine if the strength of associations varies by HIV status. Additionally, structural equation modeling (SEM) will be employed to investigate potential mediating pathways, such as the role of monocyte activation in linking HIV infection to cognitive impairment. SEM allows for the simultaneous estimation of direct and indirect effects, providing a nuanced understanding of the biological mechanisms involved.

Ethical Considerations The study protocol has been reviewed and approved by the Eswatini Health and Human Research Review Board (EHHRRB). Informed consent will be obtained from all participants aged 18 and above, and assent will be obtained from minors alongside parental or guardian consent. All data will be anonymized and securely stored, with access restricted to authorized personnel. Participants will be informed of their right to withdraw at any time without consequence.

Data Management and Quality Assurance Data will be entered into a secure electronic database with built-in validation checks. Double data entry and periodic audits will be conducted to ensure accuracy. Laboratory assays will be performed in duplicate, and inter-assay variability will be monitored. All research staff will undergo training in Good Clinical Practice (GCP) and ethical conduct of research involving human subjects.

Potential Risks and Benefits Risks to participants are minimal and primarily related to blood draw procedures (e.g., discomfort, bruising). Psychological distress from cognitive testing is considered low. Participants may benefit from increased awareness of their cognitive health and receive referrals for further evaluation if significant impairments are detected.

Significance and Innovation

This study addresses a critical gap in understanding HIV-associated neurocognitive impairment in adolescents, particularly in high-prevalence, resource-limited settings. By integrating immunological and neuropsychological data, it offers a novel approach to characterizing the neuroimmune interface in ALHIV. The findings may:

• Identify biomarkers predictive of cognitive decline.
• Inform early screening and intervention strategies.
• Support the development of targeted therapies to mitigate neuroinflammation.
• Enhance clinical guidelines for adolescent HIV care. Moreover, the study contributes to global efforts to improve the long-term outcomes of adolescents living with HIV, aligning with UNAIDS goals for health equity and sustainable development.

Enrollment: 80 estimated patients

Sex: All

Ages: 13 to 19 years old

Volunteers: Accepts Healthy Volunteers

Inclusion criteria

• Cases

  • Adolescents aged 13-19 years
  • HIV-positive
  • Undergoing antiretroviral therapy at Baylor Clinic
  • Providing consent or assent to participate

Controls

• Adolescents aged 13-19 years
• HIV-negative
• Providing consent or assent to participate

Exclusion criteria

• Exclusion Criteria

  • Recent (within 2 months) acute conditions: influenza, COVID-19, TB, acute gastroenteritis (as these conditions elevate CRP levels)
  • Chronic conditions: diabetes, hypertension, asthma
  • Neurological disorders: epilepsy, cerebrovascular accident, neurodegenerative diseases
  • History of significant cranial trauma or perinatal complications
  • All the aforementioned conditions will be identified through self-reported data and medical records.

Trial design

80 participants in 2 patient groups

cases, HIV positive adolescent

Description:

This group comprises adolescents aged 13-19 years living with HIV in Eswatini, recruited from Baylor College of Medicine Children's Foundation-Eswatini Centers of Excellence and affiliated clinical sites. Participants are virally suppressed or on antiretroviral therapy (ART) and will undergo standardized neurocognitive assessments, psychosocial evaluations, and clinical data collection, including CD4+ T-cell count, plasma viral load, ART regimen history, and inflammatory biomarker profiling. No therapeutic or behavioral intervention will be administered as part of the study; all procedures are observational and non-invasive. The objective is to characterize neurocognitive performance and identify biological correlates of cognitive outcomes in adolescents with perinatally acquired HIV.

Group: HIV-Negative Adolescents

Description:

This group consists of adolescents aged 13-19 years who are HIV-negative, recruited from Raleigh Fitkin Memorial (RFM) Hospital in Eswatini. Participants will undergo the same standardized neurocognitive assessments and psychosocial evaluations as their HIV-positive counterparts. No therapeutic or behavioral intervention will be administered; all procedures are observational and non-invasive. This group serves as a control population to facilitate comparative analyses of neurocognitive performance and inflammatory biomarker profiles, thereby helping to isolate the effects of HIV infection on neurodevelopmental outcomes