Neuroinflammation and Neurodegeneration in HIV-positive Subjects Switched and Initially Treated With INSTI

NCT ID: NCT04887675

Last Updated: 2021-12-01

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: NA
• Total Enrollment: 120 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-05-01
• Study Completion Date: 2022-10-01

Brief Summary

Since the HIV changed its course to the chronic disease, high incidence of metabolic syndrome both in HIV positive and negative subjects has become an issue. Given the successful peripheral suppression of HIV after introduction of combined antiretroviral therapy (cART), comorbidities associated with aging and cognitive functioning, play the main role in the overall quality of life and adherence to the therapy. Continuous low-level neuroinflammation results in continuous and diffuse neuronal death or dysfunction leading to a certain level of neurodegeneration. Additionally, metabolic syndrome contributes to neurodegeneration causing damage to the brain vasculature and provoking the ischemic incidents.

The aim of this study would be to explore the influence of switching to the INSTI based cART using neuroimaging biomarkers of inflammation and neurodegeneration. The second aim would be to monitor these neuroimaging biomarkers in patients receiving INSTI-based cART in a one-year follow-up period. Additionally, we would compare the markers of metabolic syndrome and cognitive functioning (executive functions) in HIV-positive patients after switching to INSTI-based cART and in HIV-positive patients receiving INSTI-based cART from the start.

This study represents a single-center, prospective, interventional, two-armed single study. Arm I will include 60 patients on PI/EFV based ART, stable on treatment, who are switched to INSTI based regimen at the beginning of the study due to side effects or long-term toxicities like hyperlipidemia, diarrhea, (PI), insomnia, headache (EFV), high Framingham score (PI/EFV). Arm II will include 60 patients initially on INSTI-based ART, stable on treatment. The same data sets will be collected for both groups of patients. The variables collected will be related to metabolic syndrome (levels of LDL and HDL cholesterol, triglycerides, fasting insulin, glucose, blood pressure, waist circumference, waist to hip and waist to height ratio), performance on neurocognitive tests and MR spectroscopy neuroinflammation and neurodegeneration markers at the beginning of the study, as well as in 12 months follow up. Presence of steatosis and visceral fat thickness will be assessed using ultrasonography of abdomen.

The primary imaging will be performed at the time of enrollment of patients, along with the neurocognitive testing and blood sampling. The secondary imaging (follow up) will be performed 12 months after the initial, also followed by neurocognitive assessment and blood sampling.

Anthropometric measurements will be acquired at the time of blood sampling. Statistical analysis will be performed after collecting the data. Our work could significantly contribute to the better life quality in the aging of HIV positive subjects in the domain of cognitive functioning, tightly associated with adherence and overall life quality.

Detailed Description

Serbia is low income country with epidemiology of HIV infection resembling those in developed countries, with average age of patients around 50 years and majority of them being the MSM population. Another important issue is the high incidence of metabolic syndrome both in HIV positive and negative subjects. With the successful peripheral suppression of HIV after introduction of combination antiretroviral therapy (cART), HIV disease has changed its course and now represents a chronic disease with majority of patients reaching senium. In these patients, comorbidities associated with aging, especially in the means of cognitive functioning, play the main role in the overall quality of life and adherence to the therapy. Considering the fact that viral particles of HIV remain latent in microglial cells and macrophages, virus only triggers the inflammatory response in the brain, which is afterwards maintained in the form of low-level neuroinflammation by the microglia and macrophages, resulting in continuous and diffuse neuronal death or dysfunction and leading to a certain level of neurodegeneration. With aging of HIV-positive subject, this form of neurodegeneration is combined with the physiological aging of the brain, most probably in the synergistic manner. Recent studies showed that this peripheral inflammation alters the blood-brain barrier and allows the penetration of HIV and particles, starting the "circulus vitiosus" all over again. Additionally, metabolic syndrome contributes to neurodegeneration causing damage to the brain vasculature and provoking the ischemic incidents.

The switch from the old fashion to the modern INSTI based cART and its influence on the process of neurodegeneration, as well as the role of neuroprotection of INSTI are still not well examined and documented. The aim of this study would be to explore the influence of switching to the INSTI based cART on neuroimaging biomarkers of inflammation and neurodegeneration obtained by MRS. The second aim would be to monitor these neuroimaging biomarkers in patients receiving INSTI based cART from the start in a one-year follow up period. Additionally, we would compare the markers of metabolic syndrome and cognitive functioning (executive functions) in HIV-positive patients after switching to INSTI based cART and in HIV-positive patients receiving INSTI based cART from the start.

This study represents a single-center, prospective, interventional, two-armed single study. Arm I will include 60 patients on PI/EFV based ART, stable on treatment, who will be switched to INSTI based regimen at the beginning of the study due to side effects or long-term toxicities like hyperlipidemia, diarrhea, (PI), insomnia, headache (EFV), high Framingham score (PI/EFV). Arm II will include 60 patients initially started on INSTI based ART, stable on treatment. The same data set will be collected in both groups of patients. The variables collected will be related to metabolic syndrome (levels of LDL and HDL cholesterol, triglycerides, fasting insulin, glucose, blood pressure, waist circumference, waist to hip and waist to height ratio), performance on neurocognitive tests and MRS neuroinflammation and neurodegeneration markers at the beginning of the study, as well as the 12 months after the beginning.

Besides the biochemical and anthropometric parameters of metabolic syndrome, presence of steatosis and visceral fat thickness will be assessed using ultrasonography of abdomen.

The primary imaging will be performed at the time of enrollment of patients. At the same time point, immediately before of after the imaging, patients will fulfill the neurocognitive testing. Blood samples will be taken within one week prior to imaging. The secondary imaging (follow up) will be performed 12 months after the initial, also followed by neurocognitive assessment in the same time relationship. Blood samples will be taken within one week prior to imaging.

Anthropometric measurements will be acquired at the time of blood sampling. Adequate statistical analysis will be performed after collecting the data. Our work could significantly contribute to the better life quality in the aging of HIV positive subjects in the domain of cognitive functioning, tightly associated with adherence and overall life quality.

Conditions

HIV I Infection; HIV Associated Lipodystrophy; Metabolic Syndrome; Aging

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: DOUBLE

Study Groups

Patients switched from PI/EFV based ART to INSTI based ART

60 patients on PI/EFV based ART, stable on treatment (undetectable viral load for at least 6 months). At the beginning of the study they are switched to INSTI based regimen. The reasons for the switch will be side effects or long-term toxicities like hyperlipidemia, diarrhea, (PI), insomnia, headache (EFV), high Framingham score (PI/EFV)

Group Type: ACTIVE_COMPARATOR

MRI

Intervention Type: DIAGNOSTIC_TEST

Both groups with undergo neuroimaging on 3T magnetic resonance unit (Trio Tim, Siemens, Erlangen, Germany) in the Center for Diagnostic Imaging, Oncology Institute of Vojvodina, Serbia. Multivoxel MRS will be performed in the supratentorial cerebral parenchyma, covering white matter of frontal and parietal lobes, as well as cortical grey matter in frontal and parietal lobes and the whole cingulate gyrus.

Patients initially treated with INSTI based regimens

60 patients initially started on INSTI based ART (raltegravir and dolutegravir), stable on treatment (undetectable viral load for at least 6 months).

Group Type: ACTIVE_COMPARATOR

MRI

Intervention Type: DIAGNOSTIC_TEST

Both groups with undergo neuroimaging on 3T magnetic resonance unit (Trio Tim, Siemens, Erlangen, Germany) in the Center for Diagnostic Imaging, Oncology Institute of Vojvodina, Serbia. Multivoxel MRS will be performed in the supratentorial cerebral parenchyma, covering white matter of frontal and parietal lobes, as well as cortical grey matter in frontal and parietal lobes and the whole cingulate gyrus.

Interventions

MRI

Both groups with undergo neuroimaging on 3T magnetic resonance unit (Trio Tim, Siemens, Erlangen, Germany) in the Center for Diagnostic Imaging, Oncology Institute of Vojvodina, Serbia. Multivoxel MRS will be performed in the supratentorial cerebral parenchyma, covering white matter of frontal and parietal lobes, as well as cortical grey matter in frontal and parietal lobes and the whole cingulate gyrus.

Intervention Type: DIAGNOSTIC_TEST

Eligibility Criteria

Inclusion Criteria

• Male (in order to eliminate the hormonal influences on the levels of brain metabolites),
• older than 18 years,
• HIV seropositivity confirmed on PCR testing,
• undetectable viral load for over one year,
• conventional magnetic resonance imaging (MRI) normal.
• In group I, the additional criterion would be stable cART not containing INSTI for over one year.

Exclusion Criteria

• active infiltrative or infective/opportunistic neurological illness,
• chronic neurological diseases (multiple sclerosis, vascular and non-vascular dementia, other neurodegenerative conditions),
• active abuse of narcotic drugs,
• hepatitis B or C coinfection,
• deep white matter lesions (focal or diffuse, such as lacunar stroke, leukoaraiosis, infiltrative or infective foci, metastases etc.),
• International HIV Dementia Scale (IHDS) score <10 (only neuro-asymptomatic subjects would be included in the study), and
• contraindications for MRI examination

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 45 Years
• Eligible Sex: MALE
• Accepts Healthy Volunteers: No

Sponsors

Merck Sharp & Dohme LLC

INDUSTRY

Sponsor Role: collaborator

University of Novi Sad

OTHER

Sponsor Role: lead

Responsible Party

Snezana Brkic

Full Professor, Dean of Faculty of Medicine

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Snezana Brkic

Role: PRINCIPAL_INVESTIGATOR

University of Novi Sad

Locations

Faculty of Medicine, University of Novi Sad

Novi Sad, , Serbia

Site Status: RECRUITING

Countries

Serbia

Central Contacts

Snezana Brkic

Role: CONTACT

Phone: +38163570350

Email: brkicsnezana@yahoo.com

Facility Contacts

Snezana Brkic

Role: primary

Other Identifiers

UNoviSad

Identifier Type: -

Identifier Source: org_study_id