Clinical trial NCT01978743: Advanced Neuroimaging Evaluation of CNS Changes Associated With Efavirenz Therapy Switch to an Raltegravir-based Regimen
Official title: Advanced Neuroimaging Evaluation of the Central Nervous System Biological Changes Associated With Efavirenz Therapy Switch to an Raltegravir-based Regimen
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: HIV
HIV-associated Neurocognitive Disorder
Neurotoxicity
Keywords: HIV
HIV-associated neurocognitive disorder
neurotoxicity
Lead sponsor: Massachusetts General Hospital
Sponsor class: OTHER
Collaborators: name: Merck Sharp & Dohme LLC
First posted: 2013-11-07
Enrollment: 10
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: BASIC_SCIENCE

Brief summary: 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.

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 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.

Primary outcomes:
measure: Neurometabolites Based on Magnetic Resonance Spectroscopy (MRS)
timeFrame: week 0 and week 8
measure: Neural Activation Networks Using Functional Magnetic Resonance Imaging (fMRI)
timeFrame: week 0 and week 8
Secondary outcomes:
measure: Other Neurometabolite Changes Measured by MRS
timeFrame: week 0 and week 8
measure: Neurocognitive Changes Measured by a Panel of Indexes: WAIS-R, HAMD, DASS-21, FRSBE, STAI
timeFrame: week 0 and week 8
measure: Fasting Lipid Profile
timeFrame: week 0 and week 8
measure: Sleep Quality
timeFrame: week 0 and week 8
measure: ART Regimen Preference
timeFrame: week 0 and week 8
measure: Markers of Immune Activation
timeFrame: week 0 and week 8
measure: Change in Level of EFV and Metabolites
timeFrame: week 0 and week 8
Other outcomes:
Locations:
city: Boston
country: United States
facility: Brigham and Women's hospital
state: Massachusetts
Study officials:
affiliation: Massachusetts General Hospital
name: Nina Lin, MD
role: PRINCIPAL_INVESTIGATOR
References: