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Advanced Neuroimaging Evaluation of CNS Changes Associated With Efavirenz Therapy Switch to an Raltegravir-based Regimen

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT01978743
First Posted: November 7, 2013
Last Update Posted: July 26, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
Nina Lin, MD, Boston University
  Purpose
In this study investigators 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.

Condition Intervention
HIV HIV-associated Neurocognitive Disorder Neurotoxicity Drug: Raltegravir

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: Advanced Neuroimaging Evaluation of the Central Nervous System Biological Changes Associated With Efavirenz Therapy Switch to an Raltegravir-based Regimen

Resource links provided by NLM:


Further study details as provided by Nina Lin, MD, Boston University:

Primary Outcome Measures:
  • Neurometabolites Based on Magnetic Resonance Spectroscopy (MRS) [ Time Frame: week 0 and week 8 ]
    Assess the levels of neuro-metabolites measured by MRS at week 0 before switching to the efavirenz-based therapy. Two areas of the brain: 1) posterior cingulate gyrus and 2) anterior cingulate will be assessed for the levels of brain creatine (Cr), gamma-aminobutyric acid (GABA) and glutathione (GLU).

  • Neural Activation Networks Using Functional Magnetic Resonance Imaging (fMRI) [ Time Frame: week 0 and week 8 ]
    Assess changes in neural activation correlated with affective disturbances associated with EFV vs. RAL using fMRI employing a paradigm that probes affective symptomatologies typical with EFV use; anxiety/dysphoria and affective dysregulation, and their association with changes in cognitive function. Four brain regions of interests (ROIs) are specified to show the differential frontal-limbic activation patterns in the task-evoked neural responses to the 3 linear contrasts of Pre-/Post-/ Pre-vs. Post-switch: [Negative Word vs. Neutral Word] x [No-Go Trial Block vs. Go Trial Block]: anterior Frontal Pole (aFP), posterior Cingulate Gyrus (pCG), dorsal anterior Cingulate Gyrus (daCG), Left Hippocampus (LHC). A linear mixed-effects model is utilized to examine the effect sizes of the key Regimen/Condition contrasts, with the Subject factor as the random-effect, and Age incorporated as a co-variate of no interest. A z-score is the Mean with a SD=1 and Measure of Dispersion equal to 1.


Secondary Outcome Measures:
  • Other Neurometabolite Changes Measured by MRS [ Time Frame: week 0 and week 8 ]
    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 Measured by a Panel of Indexes: WAIS-R, HAMD, DASS-21, FRSBE, STAI [ Time Frame: week 0 and week 8 ]

    Assess for changes in cognitive and affective function prior to and after switching off EFV-based regimen. Indexes used to access neurocognitive changes included:

    1. Wechsler Adult Intelligence Scale (WAIS-R) Digital Symbol Substitution Test: sensitive to brain dmamage, dementia, age and depressive changes. Range of 0-100, the higher the score the better the person's performance
    2. Hamilton Rating Scale for Depression (HAMD): Measure of depression. Score of 0-7 is normal, score of >20 is moderate/severe depression
    3. Depression Anxiety Stress Scale (DASS-21) the lower the score, the less severe depression, anxiety and stress. Scale range of 0-63
    4. Frontal Systems Behavior Scale (FRSBE): Increased score indicates greater behavioral impairment associated with frontal systems, range 37.2 to 186
    5. Spielberger state trait anxiety inventory (STAI): the higher the score the greater then anxiety level, range of 20 to 80.

  • Fasting Lipid Profile [ Time Frame: week 0 and week 8 ]
    Measure the change in fasting lipid panel prior to and after switching off EFV-based regimen.

  • Sleep Quality [ Time Frame: week 0 and week 8 ]
    Assess for changes in sleep pattern and quality prior to and after switching off EFV-based regimen through a self-administered Pittsburg Sleep Quality Index (PSQI). Measure consists of 19 items with each weighted on 0-3 scale and the sum produces a total score, which ranges from 0-21. The lower the score the healthier the sleep quality.

  • ART Regimen Preference [ Time Frame: week 0 and week 8 ]
    Evaluate patient preference in ART regimen (Atripla, EFV/FTC/TDF versus RAL + FTC/TDF) through self-administered questionnaires.

  • Markers of Immune Activation [ Time Frame: week 0 and week 8 ]
    Change in markers of immune activation and inflammation associated with change to RAL (ie, sCD14, IL-6, hsCRP, D-dimer, CRP, LPS, sCD163, EndoCab)

  • Change in Level of EFV and Metabolites [ Time Frame: week 0 and week 8 ]
    Correlate change in level of EFV and metabolites with neurocognitive and neuroimaging changes


Enrollment: 10
Actual Study Start Date: January 2014
Study Completion Date: January 2017
Primary Completion Date: September 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Raltegravir
Switch from Atripla (EFV/FTC/TDF) to raltegravir (RAL) + Truvada (FTC/TDF). Raltegravir will be administered 400mg twice-a-day with Truvada for 8 weeks.
Drug: Raltegravir
Switch from Atripla to Raltegravir 400mg BID + Truvada (FTC/TDF) for total of 8 weeks
Other Name: Raltegravir (Isentress) 400mg BID

Detailed Description:

In a cohort of HIV-infected patients who are clinically stable on the commonly use regimen of EFV/emtricitabine (FTC)/truvada (TDF) or Atripla, investigators propose to replace the EFV component with an integrase inhibitor, Raltegravir (RAL), given as the RAL and FTC/TDF to evaluate the EFV-related neural alterations. This is a multidisciplinary study which will be lead by Dr. Nina Lin, in collaboration with the research teams of Dr. Alexander Lin, Director of the Center for Clinical Spectroscopy, and Dr. Emily Stern, Director of the Functional Neuroimaging Laboratory, both members of the Brigham and Women's Department of Radiology at Harvard Medical School, as well as Dr. Jane Epstein, a researcher in Dr. Stern's research group. Dr. Epstein is a staff psychiatrist at Brigham and Women's hospital with extensive experience and expertise in research on abnormalities of affective and motivational processing in the context of neuropsychiatric disorders. Investigators 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. Investigators 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 RAL 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 RAL, 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.

  Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 65 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Chronic HIV-infected individuals on suppressive regimen with EFV/FTC/TDF, for at least 6 months
  2. Undetectable HIV-1 RNA virus load for at least 6 months
  3. No co-infections with active hepatitis B and C
  4. Presence of at least moderate symptoms on 2 out of 3 subcores on the DASS
  5. No known active HIV-related and non-HIV related CNS infections
  6. Estimated glomerular filtration rate (EGFR) >60 ml/min
  7. Consent to switching to EVG/COBI/FTC/TDF
  8. Ages 18 - 65

Exclusion Criteria:

  1. History of CNS opportunistic infections or active CNS infections
  2. History of severe psychiatric disorder (excluding depression and anxiety)
  3. History of chronic neurological disorders, such as epilepsy or multiple sclerosis
  4. History of or current significant substance abuse or dependence and/or heavy alcohol use (>12 oz/wk)
  5. Any women who may be pregnant (positive urine pregnancy test or unprotected sex in 2 weeks prior to scan) or known to be pregnant
  6. Contraindications to undergoing fMRI, including metallic implants, claustrophobia, and medical conditions or medications that significantly affect cerebral blood flow or function.
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01978743


Locations
United States, Massachusetts
Brigham and Women's hospital
Boston, Massachusetts, United States, 02115
Sponsors and Collaborators
Massachusetts General Hospital
Merck Sharp & Dohme Corp.
Investigators
Principal Investigator: Nina Lin, MD Massachusetts General Hospital
  More Information

Responsible Party: Nina Lin, MD, Assistant Professor in Medicine, Boston University
ClinicalTrials.gov Identifier: NCT01978743     History of Changes
Other Study ID Numbers: NeuroHIV002
First Submitted: October 20, 2013
First Posted: November 7, 2013
Results First Submitted: June 8, 2017
Results First Posted: July 26, 2017
Last Update Posted: July 26, 2017
Last Verified: July 2017

Keywords provided by Nina Lin, MD, Boston University:
HIV
HIV-associated neurocognitive disorder
neurotoxicity

Additional relevant MeSH terms:
Neurotoxicity Syndromes
Neurocognitive Disorders
Nervous System Diseases
Poisoning
Chemically-Induced Disorders
Mental Disorders
Raltegravir Potassium
Efavirenz
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
HIV Integrase Inhibitors
Integrase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors
Cytochrome P-450 CYP2C9 Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Cytochrome P-450 CYP2C19 Inhibitors
Cytochrome P-450 CYP2B6 Inducers
Cytochrome P-450 Enzyme Inducers
Cytochrome P-450 CYP3A Inducers