HIV Associated Neurocognitive Disorders (HAND), Human Immunodeficiency Virus (HIV)
Conditions
Keywords
HIV, HAND, Maraviroc, Neurocognitive, Neurology, Human Immunodeficiency Virus, HIV Associated Neurocognitive Disorders
Brief summary
HIV related cognitive impairment still occurs despite highly active antiretroviral therapy (HAART). HIV disease affects the brain in 20-40% of patients with advancing HIV disease; leading to varying degrees of cognitive impairment, recently termed HIV associated neurocognitive disorders (HAND). HAND may occur in patients who are virally suppressed in both blood and CSF. Patients with HIV Associated Neurocognitive Disorders (HAND) who are virally suppressed in both their blood and cerebrospinal fluid (CSF), whilst on a highly active antiretroviral therapy (HAART) regimen may have significant cognitive improvement with HAART intensification with the medication Maraviroc; compared to those who remain on their existing regimen. This study will be a prospective, interventional, randomised and unblinded controlled clinical trial. The aim of this study will be to determine whether HAART intensification with the medication Maraviroc, leads to significant improvement in HIV associated neurocognitive disorders (HAND). Patients with the recent progression (within 6 months) of HAND (validated by neuropsychological assessment) on HAART, who are virally suppressed (\<50 copies per ml) in blood and CSF will be randomised to have their existing HAART regimen intensified with Maraviroc, or not. The control arm will remain on their medication regimen as prescribed. The target is to enrol 70 patients into the control group, and 70 patients into the Maraviroc intensification group. Patients will undergo baseline neuropsychological testing, MRI, blood tests, and cerebrospinal fluid (CSF) tests (via a lumbar puncture). The methods used to determine the effectiveness of adding Maraviroc, will include further neuropsychological assessment at 6 months, and neuropsychological assessment, MRI and CSF assessment again at 12 months. Neuropsychological testing completed at 6 and 12 months will be completed by a blind assessor, in that they will have no knowledge of which arm (treatment or control) the participant is enrolled in. An evaluation (neuropsychological testing) will be performed should the patient deteriorate during the course of the study, as recognised by the patient's managing physician. At the end of the study protocol (12 months) the patient's HAART therapy will be managed by their primary physician.
Interventions
DRUGMaraviroc
Maraviroc oral tablet. Dosage: 150 mg twice daily, 300 mg twice daily, or 600 mg twice daily. Dosing will be dependent on the participant's background HAART therapy, and will be in accordance with the product information sheet.
Sponsors
ViiV Healthcare
Bruce Brew
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* HIV Positive * On HAART, with plasma viral load \< 50 copies/ml for previous 12 months or more * Able to provide informed consent * HAND diagnosis, with symptom progression within previous 6 months
Exclusion criteria
* Non-HIV related neurological disorders and active central nervous system (CNS) opportunistic infection (as assessed by full blood count, electrolytes, creatinine, glucose, liver funciton tests, cryptococcal antigen, venereal disease research laboratory (VDRL), MRI brain scan and CSF analysis for cell count, protein, glucose, culture, VDRL and cryptococcal antigen) * Psychiatric disorders on the psychiatric axis * Current major depression * Current substance use disorder, or severe substance use disorder within 12 months of study entry * Active Hepatitis C Virus (HCV) (detectable HCV RNA) * History of loss of consciousness \> 1 hour * Non-proficient in English * Medications known to pharmacologically interact with antiretrovirals (ARVs) * Currently taking an entry inhibitor * Pregnancy (as assessed by the urine pregnancy test)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Neurocognitive Functioning | Baseline, 6-months and 12-months | Change in overall neurocognitive performance, defined as a global neurocognitive z-score, over the study time-period (baseline, 6-months, 12-months). To derive this score, 1) raw scores obtained from a 5-domain brief neurocognitive battery were converted to age-corrected z-scores (M=0, SD=1) and 2) the set of individual subtest z-scores were averaged to generate a single composite (global) z-score for each subject. Lower (negative) scores therefore indicate greater levels of cognitive impairment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in CSF Neopterin Concentration | Baseline and 12-months | Change in concentration of the CSF neuroinflammatory marker neopterin (measured in nmol/L) from baseline to 12-months. |
| Change in MRS Cerebral Metabolite Ratios in Basal Ganglia | Baseline and 12 months | Change in major cerebral metabolites in the basal ganglia, as measured by 1H-Magnetic Resonance Spectroscopy (MRS), between baseline and 12-months. Spectra were acquired on a Phillips Achieva 3T MRI scanner using point-resolved spectroscopy (PRESS) sequence with short echot time (TE). jMRUI/AMARES algorithm was used to process spectra. Metabolite ratios were calculated for the following metabolites: N-acetyl aspartate (NAA), choline (Cho), creatine (Cr), myo-inositol (mIo), in relation to internal water (H20) as standard. |
| Change in MRS Cerebral Metabolite Ratios in Frontal White Matter | Baseline and 12 months | Change in major cerebral metabolites in the frontal white matter, as measured by 1H-Magnetic Resonance Spectroscopy (MRS), between baseline and 12-months. Spectra were acquired on a Phillips Achieva 3T MRI scanner using point-resolved spectroscopy (PRESS) sequence with short TE. jMRUI/AMARES algorithm was used to process spectra. Metabolite ratios were calculated for the following metabolites: N-acetyl aspartate (NAA), choline (Cho), creatine (Cr), myo-inositol (mIo), glutamate/glutamine complex (Glx), in relation to internal H2O as standard. |
Countries
Australia
Participant flow
Recruitment details
Participants were recruited from St Vincent's Hospital and/or referred from tertiary sexual health centres over the period January 2012 to June 2013.
Pre-assignment details
Two enrolled participants failed screening (1 HCV+, 1 not cognitively impaired)
Participants by arm
| Arm | Count |
|---|---|
| Standard of Care HAART Regimen Participants randomised to this arm of the trial will remain on their usual prescribed HAART regimen. | 5 |
| Maraviroc Participants randomised to this arm will remain on their usual prescribed HAART regimen, with the addition of Maraviroc. Maraviroc will be prescribed according to the Product Information Sheet, with consideration given to background therapy.
Maraviroc: Maraviroc oral tablet. Dosage: 150 mg twice daily, 300 mg twice daily, or 600 mg twice daily. Dosing will be dependent on the participant's background HAART therapy, and will be in accordance with the product information sheet. | 9 |
| Total | 14 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Protocol Violation | 1 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Maraviroc | Total | Standard of Care HAART Regimen |
|---|---|---|---|
| Age, Continuous | 52.2 years STANDARD_DEVIATION 3.7 | 55 years STANDARD_DEVIATION 7.1 | 60 years STANDARD_DEVIATION 9.4 |
| Current CD4 | 499 cells/mm3 | 625.5 cells/mm3 | 980 cells/mm3 |
| Education | 12.3 years STANDARD_DEVIATION 2.8 | 12.1 years STANDARD_DEVIATION 2.6 | 11.6 years STANDARD_DEVIATION 2.3 |
| HAND Status Asymptomatic Neurocognitive Impairment (ANI) | 1 participants | 2 participants | 1 participants |
| HAND Status HIV-Associated Dementia (HAD) | 0 participants | 2 participants | 2 participants |
| HAND Status Mild Neurocognitive Disorder (MND) | 8 participants | 10 participants | 2 participants |
| Nadir cluster of differentiation 4 (CD4) | 150 cells/mm3 | 174.5 cells/mm3 | 310 cells/mm3 |
| Premorbid intelligence quotient (IQ) | 102.2 units on a scale STANDARD_DEVIATION 16.3 | 103 units on a scale STANDARD_DEVIATION 16.6 | 104.4 units on a scale STANDARD_DEVIATION 18.9 |
| Race/Ethnicity, Customized Caucasian | 9 participants | 14 participants | 5 participants |
| Region of Enrollment Australia | 9 participants | 14 participants | 5 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 9 Participants | 14 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 2 / 8 | 5 / 9 |
| serious Total, serious adverse events | 0 / 8 | 0 / 9 |
Outcome results
Primary
Change in Neurocognitive Functioning
Change in overall neurocognitive performance, defined as a global neurocognitive z-score, over the study time-period (baseline, 6-months, 12-months). To derive this score, 1) raw scores obtained from a 5-domain brief neurocognitive battery were converted to age-corrected z-scores (M=0, SD=1) and 2) the set of individual subtest z-scores were averaged to generate a single composite (global) z-score for each subject. Lower (negative) scores therefore indicate greater levels of cognitive impairment.
Time frame: Baseline, 6-months and 12-months
Population: Modified intent-to-treat analysis. All randomized participants were included except for n=2 controls with baseline data only (1 lost to follow-up, 1 withdrew before 6-months) and n=1 control where a protocol violation was noted (randomized without conclusive evidence of neurocognitive impairment - see participant flow section).
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Standard of Care HAART Regimen | Change in Neurocognitive Functioning | Baseline | -0.94 Global Neurocognitive Z-Score | Standard Error 0.3 |
| Standard of Care HAART Regimen | Change in Neurocognitive Functioning | 6 months | -1.03 Global Neurocognitive Z-Score | Standard Error 0.3 |
| Standard of Care HAART Regimen | Change in Neurocognitive Functioning | 12 months | -0.93 Global Neurocognitive Z-Score | Standard Error 0.3 |
| Maraviroc | Change in Neurocognitive Functioning | Baseline | -0.81 Global Neurocognitive Z-Score | Standard Error 0.23 |
| Maraviroc | Change in Neurocognitive Functioning | 6 months | -0.51 Global Neurocognitive Z-Score | Standard Error 0.23 |
| Maraviroc | Change in Neurocognitive Functioning | 12 months | -0.56 Global Neurocognitive Z-Score | Standard Error 0.23 |
Comparison: The primary outcome was analysed using a mixed-effect regression model with arm and time as fixed linear effects, arm\*time interaction as a non-linear fixed effect and participant as a random effect to account for participant attrition.p-value: 0.05Mixed Models Analysis
Comparison: Clinical relevance of the effect size observed at 6-months was assessed by generating Cohen's d statistic and 90% confidence interval (CI) around the estimate.90% CI: [-0.19, 1.71]
Comparison: Clinical relevance of the effect size observed at 12-months was assessed by generating Cohen's d statistic and 90%CI around the estimate.90% CI: [-0.47, 1.55]
Secondary
Change in CSF Neopterin Concentration
Change in concentration of the CSF neuroinflammatory marker neopterin (measured in nmol/L) from baseline to 12-months.
Time frame: Baseline and 12-months
Population: The analysis included all randomized participants who were included in the primary analysis aside from n=1 control and n=2 maraviroc who did not provide a CSF sample at 12-months.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Standard of Care HAART Regimen | Change in CSF Neopterin Concentration | Baseline | 11.5 nmol/L | Standard Error 3.41 |
| Standard of Care HAART Regimen | Change in CSF Neopterin Concentration | 12-months | 13.25 nmol/L | Standard Error 3.41 |
| Maraviroc | Change in CSF Neopterin Concentration | Baseline | 12.57 nmol/L | Standard Error 2.57 |
| Maraviroc | Change in CSF Neopterin Concentration | 12-months | 15.71 nmol/L | Standard Error 2.57 |
Comparison: Change in CSF neopterin levels was analysed using repeated-measures ANOVA with arm, time, and arm\*time interaction as fixed effects.p-value: 0.82ANOVA
Secondary
Change in MRS Cerebral Metabolite Ratios in Basal Ganglia
Change in major cerebral metabolites in the basal ganglia, as measured by 1H-Magnetic Resonance Spectroscopy (MRS), between baseline and 12-months. Spectra were acquired on a Phillips Achieva 3T MRI scanner using point-resolved spectroscopy (PRESS) sequence with short echot time (TE). jMRUI/AMARES algorithm was used to process spectra. Metabolite ratios were calculated for the following metabolites: N-acetyl aspartate (NAA), choline (Cho), creatine (Cr), myo-inositol (mIo), in relation to internal water (H20) as standard.
Time frame: Baseline and 12 months
Population: The analysis included all randomized participants who were included in the primary analysis aside from n=1 control who did not attend MRI appointment at 12-months.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Standard of Care HAART Regimen | Change in MRS Cerebral Metabolite Ratios in Basal Ganglia | Cr Baseline | 3.09 ratio | Standard Error 0.16 |
| Standard of Care HAART Regimen | Change in MRS Cerebral Metabolite Ratios in Basal Ganglia | Cho Baseline | 1.42 ratio | Standard Error 0.14 |
| Standard of Care HAART Regimen | Change in MRS Cerebral Metabolite Ratios in Basal Ganglia | NAA 12 Months | 3.87 ratio | Standard Error 0.16 |
| Standard of Care HAART Regimen | Change in MRS Cerebral Metabolite Ratios in Basal Ganglia | Cho 12 Months | 1.59 ratio | Standard Error 0.14 |
| Standard of Care HAART Regimen | Change in MRS Cerebral Metabolite Ratios in Basal Ganglia | Cr 12 Months | 3.24 ratio | Standard Error 0.16 |
| Standard of Care HAART Regimen | Change in MRS Cerebral Metabolite Ratios in Basal Ganglia | mIo Baseline | 1.10 ratio | Standard Error 0.22 |
| Standard of Care HAART Regimen | Change in MRS Cerebral Metabolite Ratios in Basal Ganglia | mIo 12 Months | 0.88 ratio | Standard Error 0.22 |
| Standard of Care HAART Regimen | Change in MRS Cerebral Metabolite Ratios in Basal Ganglia | NAA Baseline | 3.76 ratio | Standard Error 0.16 |
| Maraviroc | Change in MRS Cerebral Metabolite Ratios in Basal Ganglia | mIo 12 Months | 1.07 ratio | Standard Error 0.15 |
| Maraviroc | Change in MRS Cerebral Metabolite Ratios in Basal Ganglia | mIo Baseline | 1.19 ratio | Standard Error 0.15 |
| Maraviroc | Change in MRS Cerebral Metabolite Ratios in Basal Ganglia | NAA Baseline | 3.96 ratio | Standard Error 0.11 |
| Maraviroc | Change in MRS Cerebral Metabolite Ratios in Basal Ganglia | NAA 12 Months | 3.89 ratio | Standard Error 0.11 |
| Maraviroc | Change in MRS Cerebral Metabolite Ratios in Basal Ganglia | Cr Baseline | 2.91 ratio | Standard Error 0.11 |
| Maraviroc | Change in MRS Cerebral Metabolite Ratios in Basal Ganglia | Cr 12 Months | 3.08 ratio | Standard Error 0.11 |
| Maraviroc | Change in MRS Cerebral Metabolite Ratios in Basal Ganglia | Cho Baseline | 1.45 ratio | Standard Error 0.09 |
| Maraviroc | Change in MRS Cerebral Metabolite Ratios in Basal Ganglia | Cho 12 Months | 1.55 ratio | Standard Error 0.09 |
Comparison: Change in NAA/H20 levels were analysed using repeated-measures ANOVA with arm, time, and arm\*time interaction as fixed effects.p-value: 0.49ANOVA
Comparison: Change in Cr/H20 levels were analysed using repeated-measures ANOVA with arm, time, and arm\*time interaction as fixed effects.p-value: 0.94ANOVA
Comparison: Change in Cho/H20 levels were analysed using repeated-measures ANOVA with arm, time, and arm\*time interaction as fixed effects.p-value: 0.8ANOVA
Comparison: Change in mIo/H20 levels were analysed using repeated-measures ANOVA with arm, time, and arm\*time interaction as fixed effects.p-value: 0.72ANOVA
Secondary
Change in MRS Cerebral Metabolite Ratios in Frontal White Matter
Change in major cerebral metabolites in the frontal white matter, as measured by 1H-Magnetic Resonance Spectroscopy (MRS), between baseline and 12-months. Spectra were acquired on a Phillips Achieva 3T MRI scanner using point-resolved spectroscopy (PRESS) sequence with short TE. jMRUI/AMARES algorithm was used to process spectra. Metabolite ratios were calculated for the following metabolites: N-acetyl aspartate (NAA), choline (Cho), creatine (Cr), myo-inositol (mIo), glutamate/glutamine complex (Glx), in relation to internal H2O as standard.
Time frame: Baseline and 12 months
Population: The analysis included all randomized participants who were included in the primary analysis aside from n=1 control who did not attend MRI appointment at 12-months.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Standard of Care HAART Regimen | Change in MRS Cerebral Metabolite Ratios in Frontal White Matter | NAA Baseline | 4.32 ratio | Standard Error 0.34 |
| Standard of Care HAART Regimen | Change in MRS Cerebral Metabolite Ratios in Frontal White Matter | NAA 12 Months | 4.30 ratio | Standard Error 0.34 |
| Standard of Care HAART Regimen | Change in MRS Cerebral Metabolite Ratios in Frontal White Matter | Cr Baseline | 2.74 ratio | Standard Error 0.21 |
| Standard of Care HAART Regimen | Change in MRS Cerebral Metabolite Ratios in Frontal White Matter | Cr 12 Months | 2.99 ratio | Standard Error 0.21 |
| Standard of Care HAART Regimen | Change in MRS Cerebral Metabolite Ratios in Frontal White Matter | Cho Baseline | 2.19 ratio | Standard Error 0.16 |
| Standard of Care HAART Regimen | Change in MRS Cerebral Metabolite Ratios in Frontal White Matter | Cho 12 Months | 2.19 ratio | Standard Error 0.16 |
| Standard of Care HAART Regimen | Change in MRS Cerebral Metabolite Ratios in Frontal White Matter | mIo Baseline | 1.11 ratio | Standard Error 0.15 |
| Standard of Care HAART Regimen | Change in MRS Cerebral Metabolite Ratios in Frontal White Matter | mIo 12 Months | 1.15 ratio | Standard Error 0.15 |
| Standard of Care HAART Regimen | Change in MRS Cerebral Metabolite Ratios in Frontal White Matter | Glx Baseline | 2.16 ratio | Standard Error 0.23 |
| Standard of Care HAART Regimen | Change in MRS Cerebral Metabolite Ratios in Frontal White Matter | Glx 12 Months | 2.05 ratio | Standard Error 0.23 |
| Maraviroc | Change in MRS Cerebral Metabolite Ratios in Frontal White Matter | mIo 12 Months | 1.35 ratio | Standard Error 0.1 |
| Maraviroc | Change in MRS Cerebral Metabolite Ratios in Frontal White Matter | NAA Baseline | 4.16 ratio | Standard Error 0.23 |
| Maraviroc | Change in MRS Cerebral Metabolite Ratios in Frontal White Matter | Cho 12 Months | 2.24 ratio | Standard Error 0.11 |
| Maraviroc | Change in MRS Cerebral Metabolite Ratios in Frontal White Matter | NAA 12 Months | 4.16 ratio | Standard Error 0.23 |
| Maraviroc | Change in MRS Cerebral Metabolite Ratios in Frontal White Matter | Glx 12 Months | 2.18 ratio | Standard Error 0.15 |
| Maraviroc | Change in MRS Cerebral Metabolite Ratios in Frontal White Matter | Cr Baseline | 2.93 ratio | Standard Error 0.14 |
| Maraviroc | Change in MRS Cerebral Metabolite Ratios in Frontal White Matter | mIo Baseline | 1.07 ratio | Standard Error 0.1 |
| Maraviroc | Change in MRS Cerebral Metabolite Ratios in Frontal White Matter | Cr 12 Months | 3.05 ratio | Standard Error 0.14 |
| Maraviroc | Change in MRS Cerebral Metabolite Ratios in Frontal White Matter | Glx Baseline | 2.27 ratio | Standard Error 0.15 |
| Maraviroc | Change in MRS Cerebral Metabolite Ratios in Frontal White Matter | Cho Baseline | 2.13 ratio | Standard Error 0.11 |
Comparison: Change in NAA/H20 levels were analysed using repeated-measures ANOVA with arm, time, and arm\*time interaction as fixed effects.p-value: 0.95ANOVA
Comparison: Change in Cr/H20 levels were analysed using repeated-measures ANOVA with arm, time, and arm\*time interaction as fixed effects.p-value: 0.66ANOVA
Comparison: Change in Cho/H20 levels were analysed using repeated-measures ANOVA with arm, time, and arm\*time interaction as fixed effects.p-value: 0.56ANOVA
Comparison: Change in mIo/H20 levels were analysed using repeated-measures ANOVA with arm, time, and arm\*time interaction as fixed effects.p-value: 0.29ANOVA
Comparison: Change in Glx/H20 levels were analysed using repeated-measures ANOVA with arm, time, and arm\*time interaction as fixed effects.p-value: 0.95ANOVA