This site became the new ClinicalTrials.gov on June 19th. Learn more.
Show more
ClinicalTrials.gov Menu IMPORTANT: Listing of a study on this site does not reflect endorsement by the National Institutes of Health. Talk with a trusted healthcare professional before volunteering for a study. Read more...
ClinicalTrials.gov Menu IMPORTANT: Talk with a trusted healthcare professional before volunteering for a study. Read more...
ClinicalTrials.gov Menu
Give us feedback

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

This study has been completed.
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: July 26, 2017
Last verified: July 2017
  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: Intervention Model: Single Group Assignment
Intervention Model Description:
Treatment switch study
Masking: None (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 Nina Lin, MD, Massachusetts General Hospital:

Primary Outcome Measures:
  • Change in Neurometabolites Based on Magnetic Resonance Spectroscopy (MRS) [ Time Frame: week 0 to week 8 ]
    Assess the change in levels of neuro-metabolites measured by MRS from week 0 (before switching to the efavirenz-based therapy) and then at week 8 (after completing 9 weeks of integrase-inhibitor based regimen with Stribild). Two areas of the brain: 1) posterior cingulate gyrus and 2) anterior cingulate will be assessed for the levels of brain Cr, GABA and 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 efavirenz-based therapy using fMRI employing an Emotional Word/Go-NoGo task paradigm that probes affective symptomatologies typical with EFV use, specifically 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-switch / Post-switch / 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.


Secondary Outcome Measures:
  • Change in Other Neurometabolite Measured by MRS Between Week 0 and Week 8 [ Time Frame: week 0 to week 8 ]
    Use MRS to evaluate a fuller panel of known neurometabolites (in addition to the primary endpoints) between week 0 and week 8 to identify prominent and significant changes associated with EFV use.

  • Neurocognitive Changes [ 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 damage, 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

    6. 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: 8 weeks ]
    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; minimum Score = 0 (better); maximum Score = 21 (worse).

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

  • Markers of Immune Activation [ Time Frame: week 0 and week 8 ]
    Change in markers of immune activation and inflammation associated with change to Stibild: sCD14, IP-10,sCD163, IL-6)

  • Effect of EFV and Its Metabolites [ Time Frame: week 0 and week 8 ]
    Level of EFV (efavirenz) in Atripla and its two known metabolites known to cause cerebral side effects, 7-hydroxy (OH) EFV and 8-OH EFV, were measured in the plasma prior to switch off Atripla and after 8 weeks of RAL-based regimen (no EFV).


Enrollment: 10
Actual Study Start Date: January 2014
Study Completion Date: October 2015
Primary Completion Date: October 2015 (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 65 Years   (Adult)
Sexes Eligible for Study:   All
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 - 65

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

Locations
United States, Massachusetts
Brigham and Women's Hospital
Boston, Massachusetts, United States, 02115
Sponsors and Collaborators
Massachusetts General Hospital
Brigham and Women's Hospital
Gilead Sciences
  More Information

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
Results First Received: March 27, 2017
Last Updated: July 26, 2017

Keywords provided by Nina Lin, MD, Massachusetts General Hospital:
HIV
neurocognitive symptoms
efavirenz
elvitegravir
neurometabolites

Additional relevant MeSH terms:
Acquired Immunodeficiency Syndrome
HIV Infections
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
Tenofovir
Emtricitabine
Efavirenz
Cobicistat
Elvitegravir, Cobicistat, Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination
Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination
Antiviral Agents
Anti-Infective Agents
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-Retroviral Agents
Anti-HIV Agents
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

ClinicalTrials.gov processed this record on September 25, 2017