Trial Outcomes & Findings for Advanced Neuroimaging Evaluation of CNS Changes Associated With Efavirenz Therapy Switch to an Raltegravir-based Regimen (NCT NCT01978743)
NCT ID: NCT01978743
Last Updated: 2017-07-26
Results Overview
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).
COMPLETED
NA
10 participants
week 0 and week 8
2017-07-26
Participant Flow
Participant milestones
| Measure |
Raltegravir
All participants are switched from Atripla (EFV/FTC/TDF) to raltegravir (RAL) + truvada (FTC/TDF).
Raltegravir will be administered 400mg twice-a-day.
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|---|---|
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Overall Study
STARTED
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10
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Overall Study
COMPLETED
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10
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Overall Study
NOT COMPLETED
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0
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Reasons for withdrawal
Withdrawal data not reported
Baseline Characteristics
Advanced Neuroimaging Evaluation of CNS Changes Associated With Efavirenz Therapy Switch to an Raltegravir-based Regimen
Baseline characteristics by cohort
| Measure |
Raltegravir
n=10 Participants
All 10 participants were switched from Atripla to twice daily Raltegravir and Truvada (FTC/TDF)
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Age, Categorical
<=18 years
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0 Participants
n=5 Participants
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Age, Categorical
Between 18 and 65 years
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10 Participants
n=5 Participants
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Age, Categorical
>=65 years
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0 Participants
n=5 Participants
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Sex: Female, Male
Female
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4 Participants
n=5 Participants
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Sex: Female, Male
Male
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6 Participants
n=5 Participants
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Region of Enrollment
United States
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10 participants
n=5 Participants
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PRIMARY outcome
Timeframe: week 0 and week 8Population: The arbitrary units are expressed as the output from MRS software. While similar to concentration (mM) due to assumptions in the software, it is best expressed as arbitrary units for comparison from week 0 to 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).
Outcome measures
| Measure |
Raltegravir
n=10 Participants
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 switch from Atripla: Switch from Atripla to Raltegravir 400mg BID + Truvada (FTC/TDF) for total of 8 weeks
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Neurometabolites Based on Magnetic Resonance Spectroscopy (MRS)
Post-switch Posterior Cingulate GABA
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5.32 arbitrary units
Standard Deviation 1.85
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Neurometabolites Based on Magnetic Resonance Spectroscopy (MRS)
Pre-switch Posterior Cingulate Creatine
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19.38 arbitrary units
Standard Deviation 1.82
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Neurometabolites Based on Magnetic Resonance Spectroscopy (MRS)
Post-switch Posterior Cingulate Creatine
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18.94 arbitrary units
Standard Deviation 4.01
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Neurometabolites Based on Magnetic Resonance Spectroscopy (MRS)
Pre-switch Posterior Cingulate Glutamate
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27.83 arbitrary units
Standard Deviation 5.06
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Neurometabolites Based on Magnetic Resonance Spectroscopy (MRS)
Post-switch Posterior Cingulate Glutamate
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24.95 arbitrary units
Standard Deviation 4.54
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Neurometabolites Based on Magnetic Resonance Spectroscopy (MRS)
Pre-switch Posterior Cingulate GABA
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5.27 arbitrary units
Standard Deviation 0.74
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Neurometabolites Based on Magnetic Resonance Spectroscopy (MRS)
Pre-switch Anterior Cingulate Creatine
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14.86 arbitrary units
Standard Deviation 2.18
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Neurometabolites Based on Magnetic Resonance Spectroscopy (MRS)
Post-switch Anterior Cingulate Creatine
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14.34 arbitrary units
Standard Deviation 2.92
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Neurometabolites Based on Magnetic Resonance Spectroscopy (MRS)
Pre-switch Anterior Cingulate Glutamate
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19.09 arbitrary units
Standard Deviation 3.83
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Neurometabolites Based on Magnetic Resonance Spectroscopy (MRS)
Post-switch Anterior Cingulate Glutamate
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22.25 arbitrary units
Standard Deviation 6.21
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Neurometabolites Based on Magnetic Resonance Spectroscopy (MRS)
Pre-switch Anterior Cingulate GABA
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4.73 arbitrary units
Standard Deviation 1.55
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Neurometabolites Based on Magnetic Resonance Spectroscopy (MRS)
Post-switch Anterior Cingulate GABA
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3.14 arbitrary units
Standard Deviation 2.12
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PRIMARY outcome
Timeframe: week 0 and week 8Population: 8 of 10 enrolled patients passed QA testing to qualify for final fMRI data analyses. The 3 linear contrasts of Pre-switch/Post-switch/Pre- vs. Post-switch: \[Neg vs.Neu\] x \[No-Go vs. Go\] are reported as z-score (standardized effect size measures with SD=1). Z-score is obtained for each subject, group Z-score is obtained via a mixed-effects model.
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.
Outcome measures
| Measure |
Raltegravir
n=8 Participants
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 switch from Atripla: Switch from Atripla to Raltegravir 400mg BID + Truvada (FTC/TDF) for total of 8 weeks
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Neural Activation Networks Using Functional Magnetic Resonance Imaging (fMRI)
PreVsPostXNegVsNeuXNoGoVsGo: aFP
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3.19 z-score
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Neural Activation Networks Using Functional Magnetic Resonance Imaging (fMRI)
PreVsPostXNegVsNeuXNoGoVsGo: pCG
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3.00 z-score
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Neural Activation Networks Using Functional Magnetic Resonance Imaging (fMRI)
PreVsPostXNegVsNeuXNoGoVsGo: daCG
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-2.53 z-score
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Neural Activation Networks Using Functional Magnetic Resonance Imaging (fMRI)
PreVsPostXNegVsNeuXNoGoVsGo:LHC
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-3.64 z-score
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Neural Activation Networks Using Functional Magnetic Resonance Imaging (fMRI)
Pre: NegVsNeuXNoGoVsGo: aFP
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4.01 z-score
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Neural Activation Networks Using Functional Magnetic Resonance Imaging (fMRI)
Pre: NegVsNeuXNoGoVsGo:pCG
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3.61 z-score
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Neural Activation Networks Using Functional Magnetic Resonance Imaging (fMRI)
Pre: NegVsNeuXNoGoVsGo: daCG
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-2.94 z-score
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Neural Activation Networks Using Functional Magnetic Resonance Imaging (fMRI)
Pre: NegVsNeuXNoGoVsGo: LHC
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-3.07 z-score
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Neural Activation Networks Using Functional Magnetic Resonance Imaging (fMRI)
Post: NegVsNeuXNoGoVsGo: aFP
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-3.03 z-score
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Neural Activation Networks Using Functional Magnetic Resonance Imaging (fMRI)
Post: NegVsNeuXNoGoVsGo: pCG
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-3.13 z-score
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Neural Activation Networks Using Functional Magnetic Resonance Imaging (fMRI)
Post: NegVsNeuXNoGoVsGo: daCG
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3.65 z-score
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Neural Activation Networks Using Functional Magnetic Resonance Imaging (fMRI)
Post: NegVsNeuXNoGoVsGo: LHC
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2.88 z-score
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SECONDARY outcome
Timeframe: week 0 and week 8Population: The arbitrary units are expressed as the output from MRS software. While similar to concentration (mM) due to assumptions in the software, it is best expressed as arbitrary units for comparison from week 0 to 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.
Outcome measures
| Measure |
Raltegravir
n=10 Participants
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 switch from Atripla: Switch from Atripla to Raltegravir 400mg BID + Truvada (FTC/TDF) for total of 8 weeks
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Other Neurometabolite Changes Measured by MRS
Pre-switch Anterior Cingulate Aspartate
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3.15 arbitrary units
Standard Deviation 1.28
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Other Neurometabolite Changes Measured by MRS
Post-switch Anterior Cingulate Aspartate
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2.18 arbitrary units
Standard Deviation 1.61
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Other Neurometabolite Changes Measured by MRS
Pre-switch Posterior Cingulate Glutathione
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5.11 arbitrary units
Standard Deviation 1.18
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Other Neurometabolite Changes Measured by MRS
Post-switch Posterior Cingulate Glutathione
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4.70 arbitrary units
Standard Deviation 1.51
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Other Neurometabolite Changes Measured by MRS
Pre-switch Posterior Cingulate Aspartate
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4.32 arbitrary units
Standard Deviation 0.95
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Other Neurometabolite Changes Measured by MRS
Post-switch Posterior Cingulate Aspartate
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3.31 arbitrary units
Standard Deviation 0.97
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Other Neurometabolite Changes Measured by MRS
Pre-switch Anterior Cingulate Glutathione
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4.25 arbitrary units
Standard Deviation 1.01
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Other Neurometabolite Changes Measured by MRS
Post-switch Anterior Cingulate Glutathione
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3.18 arbitrary units
Standard Deviation 1.08
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SECONDARY outcome
Timeframe: week 0 and week 8Assess 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.
Outcome measures
| Measure |
Raltegravir
n=10 Participants
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 switch from Atripla: Switch from Atripla to Raltegravir 400mg BID + Truvada (FTC/TDF) for total of 8 weeks
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Neurocognitive Changes Measured by a Panel of Indexes: WAIS-R, HAMD, DASS-21, FRSBE, STAI
pre-switch WAIS
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48.1 units on a scale
Standard Deviation 12.53838551
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Neurocognitive Changes Measured by a Panel of Indexes: WAIS-R, HAMD, DASS-21, FRSBE, STAI
post-switch WAIS
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53.5 units on a scale
Standard Deviation 12.00231459
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Neurocognitive Changes Measured by a Panel of Indexes: WAIS-R, HAMD, DASS-21, FRSBE, STAI
pre-switch FRSBE
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79.2 units on a scale
Standard Deviation 13.07074766
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Neurocognitive Changes Measured by a Panel of Indexes: WAIS-R, HAMD, DASS-21, FRSBE, STAI
post-switch FRSBE
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72.4 units on a scale
Standard Deviation 9.834180754
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Neurocognitive Changes Measured by a Panel of Indexes: WAIS-R, HAMD, DASS-21, FRSBE, STAI
pre-switch HAMD
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4.7 units on a scale
Standard Deviation 3.860051813
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Neurocognitive Changes Measured by a Panel of Indexes: WAIS-R, HAMD, DASS-21, FRSBE, STAI
post-switch HAMD
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2.7 units on a scale
Standard Deviation 3.020301677
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Neurocognitive Changes Measured by a Panel of Indexes: WAIS-R, HAMD, DASS-21, FRSBE, STAI
pre-switch DASS depression
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6.4 units on a scale
Standard Deviation 9.834180754
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Neurocognitive Changes Measured by a Panel of Indexes: WAIS-R, HAMD, DASS-21, FRSBE, STAI
post-switch DASS depression
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3.4 units on a scale
Standard Deviation 3.777124126
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Neurocognitive Changes Measured by a Panel of Indexes: WAIS-R, HAMD, DASS-21, FRSBE, STAI
pre-switch STAI
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29.4 units on a scale
Standard Deviation 5.481281278
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Neurocognitive Changes Measured by a Panel of Indexes: WAIS-R, HAMD, DASS-21, FRSBE, STAI
post-switch STAI
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27.2 units on a scale
Standard Deviation 6.528569692
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SECONDARY outcome
Timeframe: week 0 and week 8Population: Change in lipid panel pre- and post-switch to RAL-based regimen
Measure the change in fasting lipid panel prior to and after switching off EFV-based regimen.
Outcome measures
| Measure |
Raltegravir
n=10 Participants
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 switch from Atripla: Switch from Atripla to Raltegravir 400mg BID + Truvada (FTC/TDF) for total of 8 weeks
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Fasting Lipid Profile
pre-switch total cholesterol
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200.9 mg/dL
Standard Deviation 37.02
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Fasting Lipid Profile
post-switch total cholesterol
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176.7 mg/dL
Standard Deviation 26.20
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Fasting Lipid Profile
pre-switch HDL
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58.8 mg/dL
Standard Deviation 9.69
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Fasting Lipid Profile
post-switch HDL
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53.1 mg/dL
Standard Deviation 13.42
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Fasting Lipid Profile
pre-switch LDL
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118.8 mg/dL
Standard Deviation 31.56
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Fasting Lipid Profile
post-switch LDL
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103.5 mg/dL
Standard Deviation 24.08
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Fasting Lipid Profile
pre-switch triglyceride
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116.4 mg/dL
Standard Deviation 69.62
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Fasting Lipid Profile
post-switch triglyceride
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100.6 mg/dL
Standard Deviation 54.52
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SECONDARY outcome
Timeframe: week 0 and week 8Assess 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.
Outcome measures
| Measure |
Raltegravir
n=10 Participants
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 switch from Atripla: Switch from Atripla to Raltegravir 400mg BID + Truvada (FTC/TDF) for total of 8 weeks
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Sleep Quality
pre-switch PSQI index
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5.3 units on a scale
Standard Deviation 3.06
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Sleep Quality
post-switch PSQI index
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3.8 units on a scale
Standard Deviation 1.99
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SECONDARY outcome
Timeframe: week 0 and week 8Population: Each participant was asked a single self-administered question on their ART preference and asked to chose one of the 3 answers; 1. prefer to take Atripla, 2. prefer RAL-based regimen (that they received in study) or 3. no preference.
Evaluate patient preference in ART regimen (Atripla, EFV/FTC/TDF versus RAL + FTC/TDF) through self-administered questionnaires.
Outcome measures
| Measure |
Raltegravir
n=10 Participants
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 switch from Atripla: Switch from Atripla to Raltegravir 400mg BID + Truvada (FTC/TDF) for total of 8 weeks
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ART Regimen Preference
Prefer Raltegravir-based ART
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7 participants
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ART Regimen Preference
Prefer Atripla (EFV-based ART)
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0 participants
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ART Regimen Preference
No preference
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3 participants
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SECONDARY outcome
Timeframe: week 0 and week 8Change in markers of immune activation and inflammation associated with change to RAL (ie, sCD14, IL-6, hsCRP, D-dimer, CRP, LPS, sCD163, EndoCab)
Outcome measures
| Measure |
Raltegravir
n=10 Participants
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 switch from Atripla: Switch from Atripla to Raltegravir 400mg BID + Truvada (FTC/TDF) for total of 8 weeks
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Markers of Immune Activation
pre-switch sCD14
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3652333.6 pg/ml
Standard Deviation 771769.196
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Markers of Immune Activation
post-switch sCD14
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3135828.52 pg/ml
Standard Deviation 791445.1417
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Markers of Immune Activation
pre-switch IP-10
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195.84 pg/ml
Standard Deviation 74.57
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Markers of Immune Activation
post-switch IP-10
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202.85 pg/ml
Standard Deviation 55.58
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Markers of Immune Activation
pre-switch sCD163
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672844 pg/ml
Standard Deviation 281620
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Markers of Immune Activation
post-switch sCD163
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733536 pg/ml
Standard Deviation 378.958
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Markers of Immune Activation
pre-switch MCP-1
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95.578 pg/ml
Standard Deviation 34.14
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Markers of Immune Activation
post-switch MCP-1
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92.794 pg/ml
Standard Deviation 56.25
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Markers of Immune Activation
pre-switch IL-6
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1.49 pg/ml
Standard Deviation 0.68
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Markers of Immune Activation
post-switch IL-6
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1.69 pg/ml
Standard Deviation 0.89
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Markers of Immune Activation
pre-switch TNFR1
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771.18 pg/ml
Standard Deviation 145.46
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Markers of Immune Activation
post-switch TNFR1
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829.12 pg/ml
Standard Deviation 130.66
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SECONDARY outcome
Timeframe: week 0 and week 8Population: 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).
Correlate change in level of EFV and metabolites with neurocognitive and neuroimaging changes
Outcome measures
| Measure |
Raltegravir
n=10 Participants
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 switch from Atripla: Switch from Atripla to Raltegravir 400mg BID + Truvada (FTC/TDF) for total of 8 weeks
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|---|---|
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Change in Level of EFV and Metabolites
pre-switch detectable 7-OH and 8-OH EFV metablites
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9 participants
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Change in Level of EFV and Metabolites
post-switch detectable 7-OH and 8-OH EFVmetaboites
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1 participants
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Adverse Events
Raltegravir
Serious adverse events
Adverse event data not reported
Other adverse events
Adverse event data not reported
Additional Information
Results disclosure agreements
- Principal investigator is a sponsor employee
- Publication restrictions are in place