Advanced Neuroimaging Evaluation of the Central Nervous System Biological Changes Associated With Efavirenz Therapy and Switch to an Elvitegravir-based Regimen

This study is not yet open for participant recruitment. (see Contacts and Locations)
Verified August 2013 by Massachusetts General Hospital
Sponsor:
Collaborators:
Brigham and Women's Hospital
Gilead Sciences
Information provided by (Responsible Party):
Nina Lin, MD, Massachusetts General Hospital
ClinicalTrials.gov Identifier:
NCT01929759
First received: August 23, 2013
Last updated: August 27, 2013
Last verified: August 2013
  Purpose

In this study we will use a multi-modal imaging approach of MRS and fMRI to comprehensively assess the biological changes in the brain associated with EFV-based regimen (EFV/FTC/TDF), specifically alterations in the brain circuitry, function and local neurochemistry, and their correlation with neuropsychological function. In a cohort of HIV-infected patients who are clinically stable on the commonly use regimen of EFV/emtricitabine (FTC)/truvada (TDF) or Atripla, we propose to replace the EFV component with a new integrase inhibitor, elvitegravir (EVG) boosted with cobicistat (COBI), given as the EVG/COBI/FTC/TDF Single Tablet Regimen (STR) to evaluate the EFV-related neural alterations. This is a multidisciplinary study which involves a team of infectious disease experts in the field of HIV, neuroradiologists with expertise in fMRI and MRS techniques to study various central nervous system and psychiatric disorders and a psychiatrist with experience and expertise in research on abnormalities of affective and motivational processing in the context of neuropsychiatric disorders. We will utilize the established clinical research platform in the Infectious Disease outpatient clinical practice at the Brigham and Women's Hospital, where there is currently have many ongoing HIV-related studies and a large panel of HIV-infected patients motivated to be involved in clinically relevant research. We propose to use advanced neuroimaging to measure biologically changes in the brain associated with long-term EFV use with the following specific aims:

  1. Determine changes in neurometabolites measured by MRS in the brain associated with long-term EFV use
  2. Assess for alterations in neural activity correlated with affective symptoms associated with EFV vs STR use using fMRI, and their associations with changes in neurometabolites assessed by MRS, and with changes in cognition assessed by Trail Making and Digit Substitution Tests.
  3. Determine changes in emotion, cognition and sleep quality after switching from EFV to STR, and how they correlate with subject treatment preference.

This clinical study will extend our current understanding of EFV neurotoxicity by further defining the nature of these biological changes. Further elucidation of the neurobiological underpinnings of EFV-induced CNS toxicity will have clinical relevance in improving the quality of life and drug adherence of HIV-infected patients on ART, especially among older patients or those with baseline neuropsychiatric disorders, whom at baseline are more vulnerable to neurocognitive decline from long-term HIV infection.


Condition Intervention
HIV Disease
Drug: Stribild (elvitegravir, cobicistat, emtricitabine and tenofovir)

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Basic Science
Official Title: Advanced Neuroimaging Evaluation of the Central Nervous System Biological Changes Associated With Efavirenz Therapy and Switch to an Elvitegravir-based Regimen

Resource links provided by NLM:


Further study details as provided by Massachusetts General Hospital:

Primary Outcome Measures:
  • Neurometabolites based on MRS [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
    Assess the changes in levels of neuro-metabolites measured by MRS while on and off the efavirenz-based therapy. Two areas of the brain; 1) posterior cingulate gyrus and 2) anterior cingulate will be assessed for change in levels of brain Cr, GABA and GLU between week 0 and 8 of switch to an elvitegravir-based regimen.

  • Neural activation networks using fMRI [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
    Assess changes in neural activation correlated with affective disturbances associated with efavirenz-based therapy using fMRI employing a paradigm that probes affective symptomatologies typical with EFV use, specifically anxiety/dysphoria and affective dysregulation and their association with changes in cognitive function.


Secondary Outcome Measures:
  • Other neurometabolite changes measured by MRS [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
    Use MRS to evaluate a fuller panel of known neurometabolites (in addition to the primary endpoints) to evaluate for prominent and significant changes associated with EFV use.

  • Neurocognitive changes [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
    Assess for changes in cognitive and affective function prior to and after switching off EFV-based regimen.

  • Fasting lipid profile [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
    Measure the change in fasting lipid panel prior to and after switching off EFV-based regimen.

  • Sleep quality [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
    Assess for changes in sleep pattern and quality prior to and after switching off EFV-based regimen through self-administered questionnaires.

  • ART regimen preference [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
    Evaluate patient preference in ART regimen (Atripla, EFV/FTC/TDF versus EVG/COBI/FTC/TDF) through self-administered questionnaires.

  • Markers of immune activation [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
    Change in markers of immune activation and inflammation associated with change to RAL (ie, sCD14, IL-6, hsCRP, D-dimer, CRP, LPS, sCD163, EndoCab)


Estimated Enrollment: 10
Study Start Date: October 2013
Estimated Study Completion Date: October 2014
Estimated Primary Completion Date: May 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Drug switching
Single-arm with switch from baseline antiretroviral therapy with Atripla to Stribild for total of 8 weeks.
Drug: Stribild (elvitegravir, cobicistat, emtricitabine and tenofovir)
Switch from Atripla (efavirenz, emtricitabine and tenofovir) to Stribild (elvitegravir, cobicistat, emtricitabine and tenofovir)for total of 8 weeks

  Eligibility

Ages Eligible for Study:   18 Years to 75 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Chronic HIV-infected individuals on suppressive regimen with EFV/FTC/TDF, for at least 6 months
  • Undetectable HIV-1 RNA virus load for at least 6 months
  • No co-infections with active hepatitis B and C
  • Presence of at least moderate symptoms on 2 out of 3 subcores on the DASS
  • No known active HIV-related and non-HIV related CNS infections
  • Estimated glomerular filtration rate (EGFR) >60 ml/min
  • Consent to switching to EVG/COBI/FTC/TDF
  • Ages 18 - 75

Exclusion Criteria:

  • History of CNS opportunistic infections or active CNS infections
  • History of severe psychiatric disorder (excluding depression and anxiety)
  • History of chronic neurological disorders, such as epilepsy or multiple sclerosis
  • History of or current significant substance abuse or dependence and/or heavy alcohol use (>12 oz/wk)
  • Any women who may be pregnant (positive urine pregnancy test or unprotected sex in 2 weeks prior to scan) or known to be pregnant
  • Contraindications to undergoing fMRI, including metallic implants, claustrophobia, and medical conditions or medications that significantly affect cerebral blood flow or function.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01929759

Contacts
Contact: Nina Lin, MD 617-768-8479 nhlin@partners.org

Locations
United States, Massachusetts
Brigham and Women's Hospital Not yet recruiting
Boston, Massachusetts, United States, 02115
Contact: Nina Lin, MD    617-768-8479    nhlin@partners.org   
Sponsors and Collaborators
Massachusetts General Hospital
Brigham and Women's Hospital
Gilead Sciences
  More Information

No publications provided

Responsible Party: Nina Lin, MD, Instructor in Medicine, Massachusetts General Hospital
ClinicalTrials.gov Identifier: NCT01929759     History of Changes
Other Study ID Numbers: NeuroHIV001
Study First Received: August 23, 2013
Last Updated: August 27, 2013
Health Authority: United States: Parters Human Research Committee

Keywords provided by Massachusetts General Hospital:
HIV
neurocognitive symptoms
efavirenz
elvitegravir
neurometabolites

Additional relevant MeSH terms:
Acquired Immunodeficiency Syndrome
HIV Infections
Tenofovir
Tenofovir disoproxil
Emtricitabine
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Slow Virus Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Efavirenz
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Therapeutic Uses
Anti-HIV Agents

ClinicalTrials.gov processed this record on September 15, 2014