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

NCT01929759 | Completed Results

• 1 other identifier: NeuroHIV001
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

Brief Summary

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. 1.Determine changes in neurometabolites measured by MRS in the brain associated with long-term EFV use
2. 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. 3.Determine changes in emotion, cognition and sleep quality after switching from EFV to STR, and how they correlate with subject treatment preference.

Conditions

HIV Disease

Keywords

HIV; neurocognitive symptoms; efavirenz; elvitegravir; neurometabolites

Outcome Measures

Primary Outcomes (2)

• Change in Neurometabolites Based on Magnetic Resonance Spectroscopy (MRS)

  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.

  week 0 to week 8

• Neural Activation Networks Using Functional Magnetic Resonance Imaging (fMRI)

  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.

  week 0 and week 8

Secondary Outcomes (7)

• Change in Other Neurometabolite Measured by MRS Between Week 0 and Week 8

  week 0 to week 8

• Neurocognitive Changes

  week 0 and week 8

• Fasting Lipid Profile

  8 weeks

• Sleep Quality

  week 0 and week 8

• ART Regimen Preference

  week 0 and week 8

Study Arms (1)

Drug switching

OTHER

Single-arm with switch from baseline antiretroviral therapy with Atripla to Stribild for total of 8 weeks.

Drug: Stribild (elvitegravir, cobicistat, emtricitabine and tenofovir)

Interventions

Stribild (elvitegravir, cobicistat, emtricitabine and tenofovir) DRUG

Switch from Atripla (efavirenz, emtricitabine and tenofovir) to Stribild (elvitegravir, cobicistat, emtricitabine and tenofovir)for total of 8 weeks

Drug switching

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Massachusetts General Hospital: lead
• Brigham and Women's Hospital: collaborator
• Gilead Sciences: collaborator

Study Sites (1)

Brigham and Women's Hospital

Boston, Massachusetts, 02115, United States

Location

MeSH Terms

Conditions

Acquired Immunodeficiency Syndrome

Interventions

Elvitegravir, Cobicistat, Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; elvitegravir; Cobicistat; Emtricitabine; Tenofovir

Condition Hierarchy (Ancestors)

HIV Infections; Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Slow Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Intervention Hierarchy (Ancestors)

Carbamates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Organophosphonates; Organophosphorus Compounds; Thiazoles; Sulfur Compounds; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Adenine; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Drug Combinations; Pharmaceutical Preparations

Limitations and Caveats

One participant did not have repeat fMRI because the pre-switch fMRI was not done correctly. The patient did not fully understand the tasks to be performed, therefore no repeat follow up fMRI was done without the comparator study.

Results Point of Contact

• Title: Dr. Nina Lin
• Organization: Boston Medical Center, Boston University School of Medicine

nina.lin@bmc.org

617-414-5242

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Instructor in Medicine

Model Details: Treatment switch study

Study Record Dates

• First Submitted: August 23, 2013
• First Posted: August 28, 2013
• Study Start: January 1, 2014
• Primary Completion: October 1, 2015
• Study Completion: October 1, 2015
• Last Updated: July 28, 2017
• Results First Posted: July 28, 2017

Record last verified: 2017-07

Locations

US (1)