IMPAACT 2015 - Evaluation of the HIV-1 Reservoir in the Central Nervous System of Perinatally-Infected Youth and Young Adults With Cognitive Impairment

• ClinicalTrials.gov Identifier: NCT03416790
• Recruitment Status: Completed
• First Posted: January 31, 2018
• Last Update Posted: July 8, 2020
• Sponsor: International Maternal Pediatric Adolescent AIDS Clinical Trials Group
• Collaborators: National Institute of Allergy and Infectious Diseases (NIAID); Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); National Institute of Mental Health (NIMH)
• Information provided by (Responsible Party): International Maternal Pediatric Adolescent AIDS Clinical Trials Group

Study Description

Brief Summary:

IMPAACT 2015 is a cross-sectional, exploratory study that will investigate the central nervous system (CNS) reservoir in perinatally HIV-infected adolescents and young adults on effective antiretroviral therapy with neurocognitive impairment. The study will assess the frequency with which HIV is detected in the cerebral spinal fluid (CSF) in this population and assess whether detectable HIV in the CSF correlates with markers of inflammation and neuronal injury. Findings from this study will advance understanding of the role of the CNS in HIV-1 persistence and its implications for future HIV-1 remission research.

Condition or disease
HIV-1-infection

Detailed Description:

IMPAACT 2015 is a cross-sectional, exploratory study aiming to investigate the central nervous system (CNS) reservoir in perinatally HIV-infected adolescents and young adults on effective antiretroviral therapy with neurocognitive impairment. The study will assess the frequency with which HIV is detected in the cerebral spinal fluid (CSF) in this population and assess whether detectable HIV in the CSF correlates with markers of inflammation and neuronal injury. CSF will be examined for persistence of HIV-1 RNA or DNA despite antiretroviral therapy (ART) and for evidence of intrathecal inflammation. Perinatally-infected youth and young adults are of particular interest because there are very limited CSF data available in this population and reasons to be concerned about the CNS reservoir. In addition, measures of HIV-1 RNA in the CSF and associated biomarkers have not previously been explored in this population. A better understanding of viral persistence in the CSF, as well as CSF biomarker profiles, will provide preliminary data to move the field forward in understanding the role of the CNS in HIV-1 persistence and will have implications for future HIV-1 remission research.

Study Design

• Study Type: Observational
• Actual Enrollment: 24 participants
• Observational Model: Case-Only
• Time Perspective: Cross-Sectional
• Official Title: IMPAACT 2015 - Evaluation of the HIV-1 Reservoir in the Central Nervous System of Perinatally-Infected Youth and Young Adults With Cognitive Impairment
• Actual Study Start Date: February 6, 2019
• Actual Primary Completion Date: March 26, 2020
• Actual Study Completion Date: March 26, 2020

Groups and Cohorts

Outcome Measures

Primary Outcome Measures :

1. Prevalence of quantifiable cell-free HIV-1 RNA CSF [ Time Frame: Within 30 Days of Screening Initiation ]
   Quantifiable cell-free HIV-1 RNA CSF defined as an HIV-1 RNA assay result of ≥20 copies/mL
2. Prevalence of detectable HIV-1 DNA in CSF cell pellets [ Time Frame: Within 30 Days of Screening Initiation ]
   Detectable HIV-1 DNA in CSF cell pellets defined as an HIV-1 DNA assay result of ≥1 copy in the cell pellet obtained from ≥10 ml of CSF

Secondary Outcome Measures :

1. Concentrations of inflammatory and neuronal injury biomarkers in CSF [ Time Frame: Within 30 Days of Screening Initiation ]
   Biomarkers to be evaluated include neopterin, neurofilament light chain (NFL), tyrosine (Y), lysine (K) and leucine (L) - 40kDa (YKL-40), interleukin (IL-6), C-reactive protein (CRP), interferon gamma-induced protein 10 (IP-10/CXCL10), monocyte chemoattractant protein 1 (MCP-1/CCL2), tumor necrosis factor (TNF-α), sCD14, soluble CD163 (sCD163), soluble intercellular adhesion molecule type 5 (sICAM-5) (immunoassays). Concentrations of each of these biomarkers in CSF will be summarized descriptively.
2. Concentrations of inflammatory and neuronal injury biomarkers in plasma [ Time Frame: Within 30 Days of Screening Initiation ]
   Biomarkers to be evaluated include neopterin, neurofilament light chain (NFL), tyrosine (Y), lysine (K) and leucine (L) - 40kDa (YKL-40), interleukin (IL-6), C-reactive protein (CRP), interferon gamma-induced protein 10 (IP-10/CXCL10), monocyte chemoattractant protein 1 (MCP-1/CCL2), tumor necrosis factor (TNF-α), sCD14, soluble CD163 (sCD163), soluble intercellular adhesion molecule type 5 (sICAM-5) (immunoassays). Concentrations of each of these biomarkers in plasma will be summarized descriptively.
3. Associations of the above-listed secondary outcomes with the primary outcomes [ Time Frame: Within 30 Days of Screening Initiation ]
   Associations will be assessed with Spearman correlations (and corresponding confidence intervals).

Biospecimen Retention:   Samples With DNA

CSF, PBMC, plasma

Eligibility Criteria

• Ages Eligible for Study: 13 Years to 24 Years (Child, Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No
• Sampling Method: Non-Probability Sample

Study Population

Perinatally HIV-1-infected youth and young adults (13-24 years of age) with cognitive impairment, on suppressive antiretroviral therapy, from study sites in the United States

Criteria

Inclusion Criteria:

• 13-24 years of age (inclusive) at enrollment (i.e., on the day the participant is enrolled in the study)
• Spoken fluency in English or Spanish
• If not of legal age to provide independent informed consent: Parent or legal guardian, or other legally authorized representative is willing and able to provide written informed consent for study participation and potential participant is willing and able to provide written assent for study participation
• If of legal age but not able to provide independent informed consent due to cognitive impairment as determined by site standard operating procedures (SOPs) and consistent with site institutional review board/ethics committee (IRB/EC) policies and procedures: Parent, legal guardian, or other legally authorized representative is willing and able to provide written informed consent for study participation and potential participant is willing and able to provide written assent for study participation
• If of legal age and able to provide independent informed consent as determined by site SOPs and consistent with site IRB/EC policies and procedures: Willing and able to provide written informed consent for study participation
• Has confirmed perinatal HIV-1 infection - with no documented evidence to suggest another route of transmission - based on review of available medical records
• Has been taking combination ART comprised of at least three agents from at least two classes of antiretroviral therapy for at least 12 consecutive months prior to enrollment as determined by the site investigator or designee based on participant or parent/guardian report and available medical records; regimen changes within the 12 months prior to enrollment are permitted, provided the virologic requirements in criterion below are met
• Has at least two consecutive documented plasma HIV-1 RNA values less than 40 copies/mL, at least three months apart, in the 12 months prior to enrollment; one of these values must be based on testing of a specimen collected within the 60 days prior to enrollment
• Has a Fluid Cognition Composite Score at least one-and-a-half standard deviations below the published normative mean (i.e., less than 78) based on administration of the NIH Toolbox Cognition Battery

Exclusion Criteria:

• Any ART interruption for more than seven consecutive days in the 12 months prior to enrollment
• Any HIV-1 RNA value greater than 200 copies/mL in the 12 months prior to enrollment
• Completed any of the NIH Toolbox subtests specified within 90 days prior to screening
• Any documented full scale intelligence quotient (IQ) score more than three standard deviations below the published normative mean (i.e., less than 55) or a Fluid Cognition Composite Score more than three standard deviations below the published normative mean (i.e., less than 55) based on administration of the NIH Toolbox Cognition Battery at screening
• Any documented diagnosis of autism spectrum disorder, schizophrenia, or other psychotic disorder
• Any known prior infection of the CNS that may be persistent or recurrent (e.g., cryptococcal meningitis, neurosyphilis)
• Any known non-HIV-related cause or significant contributing factor for cognitive impairment (e.g., birth injury, head injury, stroke, major or mild neurocognitive disorder due to a condition other than HIV) per Diagnostic and Statistical Manual of Mental Disorders 4th Edition (DSM-V) criteria
• Any known or suspected current contraindication to lumbar puncture
• Any current sensory or motor impairment severe enough to preclude participation in study evaluations (e.g., blindness, lack of upper limb control)
• If female and of reproductive potential (defined as having experienced menarche and having no documented history of a sterilization procedure), known or suspected pregnancy
• Any serious or otherwise clinically significant infection of the CNS or bloodstream (other than HIV-1 infection) within 30 days prior to enrollment
• Any live vaccine received within 30 days prior to enrollment
• Any other (non-live) vaccine received within 7 days prior to enrollment
• Received prolonged (more than 14 days) or high dose immunosuppressants within 30 days prior to enrollment (high dose would include >1 mg/kg prednisone (or equivalent) or any biologic immunosuppressant such as monoclonal antibody based therapy)
• Ever received any medication or other approved or investigational agent that may impact HIV-1 reservoirs, including but not limited to: HIV-1 vaccines, HIV-1 gene therapies, Anti-HIV-1 broadly neutralizing antibodies (e.g., VRC01), Anti-PD-1 or anti-PD-L1 antibody, Histone deacetylase inhibitors (e.g., vorinostat, romidepsin, panobinostat), Toll-like receptor agonists, Cytotoxic chemotherapies, Roxolitinib, and Sirolimus

Contacts and Locations

Locations

United States, California

University of Southern California (CRS 5048)

Los Angeles, California, United States, 90089

David Geffen School of Medicine at University of California, Los Angeles (CRS 5112)

Los Angeles, California, United States, 90095

University of California, San Diego Mother-Child-Adolescent HIV Program (CRS 4601)

San Diego, California, United States, 92103

United States, Colorado

University of Colorado, Denver (CRS 5052)

Aurora, Colorado, United States, 80045

United States, Georgia

Emory University School of Medicine (CRS 5030)

Atlanta, Georgia, United States, 30322

United States, Maryland

Johns Hopkins University (CRS 5092)

Baltimore, Maryland, United States, 21287

United States, Massachusetts

Boston Medical Center Pediatric HIV Program (CRS 5011)

Boston, Massachusetts, United States, 02118

United States, New York

Bronx-Lebanon Hospital Center (CRS 5114)

Bronx, New York, United States, 10457

Jacobi Medical Center (CRS 5013)

Bronx, New York, United States, 10461

United States, Tennessee

St. Jude Children's Research Hospital (CRS 6501)

Memphis, Tennessee, United States, 38105

United States, Washington

Seattle Children's Hospital (CRS 5017)

Seattle, Washington, United States, 98105

Puerto Rico

University of Puerto Rico Pediatric HIV/AIDS Research Program (CRS 6601)

San Juan, Puerto Rico, 00936

Sponsors and Collaborators

International Maternal Pediatric Adolescent AIDS Clinical Trials Group

National Institute of Allergy and Infectious Diseases (NIAID)

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

National Institute of Mental Health (NIMH)

Investigators

• Study Chair: Ann Chahroudi, MD, PhD; Emory University
• Study Chair: Thor Wagner, MD; University of Washington

More Information

• Responsible Party: International Maternal Pediatric Adolescent AIDS Clinical Trials Group
• ClinicalTrials.gov Identifier: NCT03416790
• Other Study ID Numbers: IMPAACT 2015; DAIDS ID 35123 ( Other Identifier: DAIDS CRMS )
• First Posted: January 31, 2018
• Last Update Posted: July 8, 2020
• Last Verified: July 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by International Maternal Pediatric Adolescent AIDS Clinical Trials Group:

Central Nervous System; HIV Persistence; HIV Reservoirs

Additional relevant MeSH terms:

Cognitive Dysfunction; Cognition Disorders; Neurocognitive Disorders; Mental Disorders