Assessment of the HIV CNS Reservoir, Neurological and Neuro-cognitive Effects, and Source of Rebound HIV in CNS

Acute HIV Infection Clinical Trial

Official title: Study SEARCH 026Assessment of the HIV CNS Reservoir, Neurological and Neuro-cognitive Effects, and Source of Rebound HIV in CNS in Subjects Participating in Study SEARCH 019

Status Completed

Clinical Trial Summary

This study aims to describe in depth the CNS, CNS HIV reservoir and CNS viral rebound in consenting SEARCH 019 subjects prior to, during and after the SEARCH 019 study intervention (VHM + ART or ART only), at 1) baseline, 2) end of study intervention and start of ART interruption, 3) viral rebound (if occurring) or mid-way during observed ART interruption, and 4) at the end of ART interruption. Study SEARCH 026 itself does not employ any therapeutic interventions. However, consenting subjects will participate in lumbar puncture, non-contrast MRI + MRS, and neuropsychological testing at at least three and at most four time points. Any of the 15 subjects to be enrolled in SEARCH 019 may consent to study SEARCH 026 participation and hence a maximum of 15 subjects may enroll. As this is a sub-study, data will be shared from study SEARCH 019 and no interventions (venipunctures) will be repeated unnecessarily.

Clinical Trial Description

1. Clinical 1.1 Neurological exam: SEARCH employs the AIDS Clinical Trials Group (ACTG)-derived HIV macroneurological examination, a physician rated symptoms assessment of cognitive features typical of HIV-associated neurocognitive disorder (HAND) and peripheral neuropathy.

1.2 Neuropsychological assessments: SEARCH employs the HIV neurocognitive battery originally developed by Maj et al. designed to minimize cultural bias and tested in Bangkok. All subjects will have the full SEARCH battery as previously published, avoiding evaluations following invasive procedures. All testing is completed by certified nurse-psychometrists. Data are compared to a normative set of 500 HIV-negative, healthy, community dwelling Thais and stratified by age and educational attainment to define standardized z-scores. A psychiatric inventory mirrors that used for RV254 and has broad Thai validity data, and research nurses perform a functional assessment based on the Clinical Dementia Scale.

1.3 Lumbar puncture: Lumbar punctures are completed per standard clinical procedures using a Sprotte® (pencil-point) needle to minimize complications. Standard assessments of CSF and serum, protein and cell count are completed and approximately 20cc are collected and ultra-centrifuged. Cell pellets of CSF will be cryopreserved for future potential studies, with subject consent. Supernatants are divided into 0.5cc aliquots, and frozen to -80oC on the same day. CSF VDRL/RPR will be assessed at baseline for those with positive serology in SEARCH 019 and in follow-up if a new positive serology is reported in SEARCH 019 or if subject was CSF positive at baseline. Participant hospitalization for any research-related adverse events requiring admission will be arranged, if needed.

1.4 Neuro-imaging: Imaging studies will be performed at the Chulalongkorn University Hospital which is 100 meters from the TRCARC in Bangkok. These studies will take up to one hour maximum MRI scanner time for each subject and may include brain MRI, MRS, DTI and resting state functional MRI (fMRI). MRI and MRS are non-invasive methods to detect brain pathology (MRI) and to determine the in-vivo concentration of brain metabolites (MRS). DTI is a sensitive non-invasive magnetic resonance technique to analyze the three-dimensional diffusion of water within brain tissue. The diffusion of water within the brain is highly dependent on the underlying micro-architecture of the surrounding tissue, which is affected by both normal physiological processes (such as aging) as well as local neuropathological disease processes, such as those seen with HIV infection. Resting state functional MRI (fMRI) reveals patterns of activation of brain networks and is a sensitive measure of brain function prior to structural and anatomical changes detected by other methods. Gadolinium will not be used for research purposes.

2. Laboratory (all pertaining to CSF)

2.1 Measurement of soluble markers: Commercial ELISA kits (Human Quantikine ELISA kits; R&D Systems, Inc.) and Millipore Luminex assays will be used following manufacturer's instructions at the Yale Immune Monitoring Core Laboratory. Soluble biomarkers associated with immune activation and neurocognitive impairment will be measured, including CSF neopterin, MCP-1, sCD14, IL-6, sCD163, and IP-10.

2.2 CSF virology Assays: HIV RNA standard quantitation will be completed using the Roche COBAS/Amplicor HIV-1 Viral Load v2.0 assay, with a lower limit of quantitation of 20cps/mL. Single Copy Assay (SCA) HIV RNA quantitation in the setting of ART will be performed using 5-10 ml of CSF. In addition, cell associated HIV-DNA (total, integrated and 2LTR circles in total CD4+ T cells will be assessed at CRC-CHUM.

2.3 TCR repertoire and avidity of HIV-specific CD8+ T cells in CSF: These may be measured in a subset of samples at VGTI Florida. For the repertoire assay, CSF cell pellets will be polyclonally expanded, and the TCR repertoire will be determined followed by TCR sequencing as previously described. For TCR avidity, T cell clones corresponding to the dominant clonotypes will be generated in vitro to measure their functional sensitivity. The HIV-specific CD8+ T cells clones generated by expansion in the presence of PHA, IL-2 and irradiated feeders will be sequenced for their TCR and will be tested for their TCR functional sensitivity.

2.4 Management of Subjects Resuming ART: If the decision is made to reinitiate ART as per SEARCH 019 ART resumption criteria, then the study visit before ART resumption will be considered this study's final visit and all procedures scheduled for end of study will be conducted at that visit. ;

Study Design

Observational Model: Cohort, Time Perspective: Prospective

Related Conditions & MeSH terms

• Acute HIV Infection
• HIV CNS Involvement

• NCT number: NCT02470351
• Study type: Observational
• Source: South East Asia Research Collaboration with Hawaii
• Status: Completed
• Phase: N/A
• Start date: January 2015
• Completion date: March 2016