The Eswatini Study on Neurocognitive Performance in Adolescents Living With HIV

NCT ID: NCT07165639

Last Updated: 2025-09-15

Basic Information

• Recruitment Status: NOT_YET_RECRUITING
• Total Enrollment: 80 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2025-11-30
• Study Completion Date: 2026-05-31

Brief Summary

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.

Detailed 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.

Conditions

HIV (Human Immunodeficiency Virus)

Study Design

• Observational Model Type: CASE_CONTROL
• Study Time Perspective: CROSS_SECTIONAL

Study Groups

cases, HIV positive adolescent

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.

No interventions assigned to this group

Group: HIV-Negative Adolescents

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

No interventions assigned to this group

Eligibility Criteria

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

• 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.

• Minimum Eligible Age: 13 Years
• Maximum Eligible Age: 19 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Baylor Foundation Eswatini

UNKNOWN

Sponsor Role: collaborator

Eswatini Nazarene Health Institutions

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Phathizwe M Mantshana, BSc

Role: PRINCIPAL_INVESTIGATOR

Eswatini Nazarene Health Institution

Sarah H Perry, Ass professor

Role: STUDY_DIRECTOR

Baylor College of Medicine

Debrah Vambe, MD

Role: STUDY_DIRECTOR

Baylor College of Medicine

Mkunde S Chachage, PHD

Role: STUDY_DIRECTOR

University of Dar es Salaam-Mbeya

Clement Gascua AduGyamfi, G AduGyamfi,, PHD

Role: STUDY_DIRECTOR

Baylor College of Medicine

Alfred Balasa,, Associate Professor

Role: STUDY_DIRECTOR

Texas Children's Hospital Austin Baylor College of Medicine

ANDREW R DINARDO, associate professor

Role: STUDY_DIRECTOR

Baylor College of Medicine

Locations

Eswatini Nazarene Health Institution, Baylor College of Medicine Children's Foundation-Eswatini (Centers of Excellence in Mbabane and satellite clinic in Manzini in Raleigh Fitkin Memorial Hospital)

Manzini, , Eswatini

Countries

Eswatini

Central Contacts

Phathizwe M Mantshana, BSc

Role: CONTACT

stickenmud@gmail.com

+26878217451

Sarah H Perry, Associate Professor

Role: CONTACT

banner@bcm.edu

+268 2409 6000 ext. +268 2409 6000

Facility Contacts

Phathizwe M Eswatini Nazarene Health Institution, BSc

Role: primary

stickenmud@gmail.com

78217451 ext. +268 2409 6000

Sarah M Perry, BSc

Role: backup

banner@bcm.edu

References

Swanta N, Aryal S, Nejtek V, Shenoy S, Ghorpade A, Borgmann K. Blood-based inflammation biomarkers of neurocognitive impairment in people living with HIV. J Neurovirol. 2020 Jun;26(3):358-370. doi: 10.1007/s13365-020-00834-3. Epub 2020 Mar 19.

Reference Type: BACKGROUND

PMID: 32193795 (View on PubMed)

Moschopoulos CD, Stanitsa E, Protopapas K, Kavatha D, Papageorgiou SG, Antoniadou A, Papadopoulos A. Multimodal Approach to Neurocognitive Function in People Living with HIV in the cART Era: A Comprehensive Review. Life (Basel). 2024 Apr 15;14(4):508. doi: 10.3390/life14040508.

Reference Type: BACKGROUND

PMID: 38672778 (View on PubMed)

Mouchati C, El Kamari V, Sattar A, Yu J, McComsey GA. Comprehensive assessment of neurocognitive function, inflammation markers, and adiposity in treated HIV and control. Medicine (Baltimore). 2022 Oct 21;101(42):e31125. doi: 10.1097/MD.0000000000031125.

Reference Type: BACKGROUND

PMID: 36281153 (View on PubMed)

Kapetanovic S, Giganti MJ, Abzug MJ, Lindsey JC, Sirois PA, Montepiedra G, Canniff J, Agwu A, Boivin MJ, Weinberg A; International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) network. Plasma biomarker factors associated with neurodevelopmental outcomes in children with perinatal HIV infection and controlled viremia. AIDS. 2021 Jul 15;35(9):1375-1384. doi: 10.1097/QAD.0000000000002862.

Reference Type: BACKGROUND

PMID: 33710019 (View on PubMed)

Hoare J, Myer L, Heany S, Fouche JP, Phillips N, Zar HJ, Stein DJ. Cognition, Structural Brain Changes, and Systemic Inflammation in Adolescents Living With HIV on Antiretroviral Therapy. J Acquir Immune Defic Syndr. 2020 May 1;84(1):114-121. doi: 10.1097/QAI.0000000000002314.

Reference Type: BACKGROUND

PMID: 32032303 (View on PubMed)

Anderson AM, Jang JH, Easley KA, Fuchs D, Gisslen M, Zetterberg H, Blennow K, Ellis RJ, Franklin D, Heaton RK, Grant I, Letendre SL. Cognitive and Neuronal Link With Inflammation: A Longitudinal Study in People With and Without HIV Infection. J Acquir Immune Defic Syndr. 2020 Dec 15;85(5):617-625. doi: 10.1097/QAI.0000000000002484.

Reference Type: BACKGROUND

PMID: 32932412 (View on PubMed)

Related Links

https://doi.org/10.1007/s13365-020-00834-3

Peer-reviewed article in Journal of NeuroVirology (2020) identifying blood-based inflammatory biomarkers-such as CCL8, TIMP-1, and IL-23-associated with neurocognitive impairment in people living with HIV, using multivariate regression analysis

https://doi.org/10.1097/md.0000000000031125

Peer-reviewed article in Medicine (Baltimore) (2022) examining associations between inflammatory biomarkers and neurocognitive function in people living with HIV, highlighting links between systemic inflammation and cognitive impairment.

https://journals.lww.com/aidsonline/abstract/2021/07150/plasma_biomarker_factors_associated_with.5.aspx

This study investigates how plasma biomarkers-such as sCD14, IL-6, and TNF-α-correlate with neurodevelopmental outcomes in children with perinatal HIV who are virally suppressed. It's a key reference for understanding the biological mechanisms underlying

https://infospace.mrc.ac.za/bitstreams/4588c400-a2e8-4f56-9ca4-d9e4dc1dd68a/download

Peer-reviewed article from the \*Journal of NeuroVirology\* (2020) examining how earlier antiretroviral therapy initiation in youth with vertically transmitted HIV is associated with improved brain structure and working memory-related neural activation.

https://discovery.ucl.ac.uk/id/eprint/10110682/

ClinicalTrials.gov protocol entry for "The Eswatini Study on Neurocognitive Performance in Adolescents Living With HIV," detailing study identification, design, outcome measures, data sharing plans, and references for related publications and supporting

Other Identifiers

EHHRRB 049/2025

Identifier Type: -

Identifier Source: org_study_id