HIV
Conditions
Keywords
HAND, HIV, Neurology, Neurocognitive, Neuro-HAART, HIV Associated Neurocognitive Disorders (HAND)
Brief summary
Patients infected with Human Immunodeficiency Virus (HIV) are at risk of brain related complications despite the use of highly active antiretroviral therapy (HAART). Such complications are termed HIV neurocognitive disorders (HAND) and comprise a spectrum from asymptomatic neurocognitive impairment (ANI), through mild cognitive impairment (MCI) to severe HIV dementia (HAD). Prior to HAART approximately 30% of patients with advanced HIV disease had cognitive impairment; with HAART the incidence of HAND has decreased but its prevalence increased. The reasons for the ongoing development of cognitive impairment in HAART treated patients are not clear. They might relate to virus induced brain injury prior to starting HAART, the onset of a separate neurological process, toxicity related to HAART, or ongoing viral infection in the brain. It is clear that the ability of different antiretroviral drugs to penetrate the brain varies but what is not established is whether these differences between drugs lead to different neurological outcomes. The investigators propose to study HIV infected patients stable on HAART for 12 months; subdividing the groups according to the brain penetrance of their drug combination. Patients would undergo neuropsychological assessment and MRI brain scan at the start of the study and after 12 months. Differences in neuropsychological tests and MRI would be sought between treatment groups to establish whether HAART with better CNS penetration is associated with better outcome and fewer MRI changes.
Interventions
None listed
Sponsors
ViiV Healthcare
St Vincent's Hospital, Sydney
Study design
Observational model
COHORT
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* HIV positive with nadir cluster of differentiation 4 (CD4) count \<350 /microlitre (uL) * Taking HAART with CNS Penetration Effectiveness (CPE) score of either ≤7.0 or ≥7.5 for 1 year or more. Changes in antiretrovirals (ARVs) within the last 12 months are allowed so long as the CPE score does not lead to a change groups * Plasma HIV viral load \<50 copies / mL for preceding 12 months or longer * Informed consent given by participant or legally appointed guardian
Exclusion criteria
* Non-HIV related neurological disorders and active CNS opportunistic infection as assessed by full blood count, electrolytes, creatinine, glucose, liver function tests, cryptococcal antigen, venereal disease reaction level (VDRL), MRI brain scan and cerebrospinal fluid analyses for cell count, protein, glucose, culture, VDRL and cryptococcal antigen. * Psychiatric disorders on the psychotic axis, current major depression, and current substance use disorder as assessed by the Study Enrolment Questionnaire for Eligibility * Severe substance use disorders (within 12 months of study entry) * Active Hepatitis C virus (HCV) (detectable HCV RNA because HCV per se can cause cognitive impairment) * History of loss of consciousness \>1 hour * Non-proficient in English as assessed by the English as a second language questionnaire * Medications known pharmacologically to interact with ARVs * Pregnancy as assessed by the urinary pregnancy test
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Neurocognitive Functioning | Change from baseline Neuropsychological testing at 6 and 12 months | Change in overall neurocognitive performance, defined as a global neurocognitive z-score, after a 12-month period of observation, between HIV positive patients taking antiretroviral regimens categorized as being either of high or low CNS penetration. To derive this score, 1) raw scores obtained from a 5-domain brief neurocognitive battery were converted to age-corrected z-scores (M=0, Standard Deviation=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 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), after a 12 month period of observation. Spectra were acquired on a Phillips Achieva 3T MRI scanner using point-resolved spectroscopy (PRESS) sequence with short echo 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 H20 as standard. |
| Cerebrospinal Fluid | Baseline to 12 Months | To measure plateaux CSF ARV concentrations. This will identify the proportion of patients achieving levels of specific ARVs capable of inhibiting 95% of in vitro viral replication (IC95). |
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.
Participants by arm
| Arm | Count |
|---|---|
| Non Neuro-HAART (Low CNS Penetrance) Participants will be assessed based on their current Highly Active Antiretroviral Treatment (HAART). A scoring system is utilised to determine if their current treatment has high Central Nervous System (CNS) penetrance or low CNS penetrance. This will determine which study cohort they are randomised to. No treatment adjustments or changes will be made, they will remain on their usual HAART regimen. | 5 |
| Neuro-HAART (High CNS Penetrance) Participants will be assessed based on their current Highly Active Antiretroviral Treatment (HAART). A scoring system is utilised to determine if their current treatment has high Central Nervous System (CNS) penetrance or low CNS penetrance. This will determine which study cohort they are randomised to. No treatment adjustments or changes will be made, they will remain on their usual HAART regimen. | 12 |
| Total | 17 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Neuro-HAART (High CNS Penetrance) | Total | Non Neuro-HAART (Low CNS Penetrance) |
|---|---|---|---|
| Age, Continuous | 55.4 years STANDARD_DEVIATION 8.6 | 53.9 years STANDARD_DEVIATION 8.5 | 50.2 years STANDARD_DEVIATION 7.8 |
| Current CD4 | 583 cells/mm3 | 684 cells/mm3 | 943 cells/mm3 |
| Education | 12.2 years STANDARD_DEVIATION 2.7 | 12.8 years STANDARD_DEVIATION 2.7 | 14.4 years STANDARD_DEVIATION 3.4 |
| HIV-Associated Neurocognitive Disorder (HAND) status Asymptomatic Neurocognitive Impairment (ANI) | 7 participants | 9 participants | 2 participants |
| HIV-Associated Neurocognitive Disorder (HAND) status HIV-Associated Dementia (HAD) | 0 participants | 1 participants | 1 participants |
| HIV-Associated Neurocognitive Disorder (HAND) status Mild Neurocognitive Disorder (MND) | 3 participants | 4 participants | 1 participants |
| HIV-Associated Neurocognitive Disorder (HAND) status Normal/Unimpaired | 2 participants | 3 participants | 1 participants |
| Nadir cluster of differentiation 4 (CD4) | 115 cells/mm3 | 200 cells/mm3 | 400 cells/mm3 |
| Premorbid intelligence quotient (IQ) | 102.5 units on a scale STANDARD_DEVIATION 12.6 | 103.0 units on a scale STANDARD_DEVIATION 14.1 | 104.2 units on a scale STANDARD_DEVIATION 18.7 |
| Race/Ethnicity, Customized Asian | 1 participants | 2 participants | 1 participants |
| Race/Ethnicity, Customized Caucasian | 11 participants | 15 participants | 4 participants |
| Region of Enrollment Australia | 12 participants | 17 participants | 5 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 12 Participants | 17 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 / 7 | 5 / 12 |
| serious Total, serious adverse events | 0 / 7 | 0 / 12 |
Outcome results
Primary
Change in Neurocognitive Functioning
Change in overall neurocognitive performance, defined as a global neurocognitive z-score, after a 12-month period of observation, between HIV positive patients taking antiretroviral regimens categorized as being either of high or low CNS penetration. To derive this score, 1) raw scores obtained from a 5-domain brief neurocognitive battery were converted to age-corrected z-scores (M=0, Standard Deviation=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: Change from baseline Neuropsychological testing at 6 and 12 months
Population: Modified intent-to-treat analysis. All enrolled participants were included aside n=2 low CNS penetrance with baseline data only (1 lost to follow-up, 1 withdrew before 6-months).
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Non Neuro-HAART (Low CNS Penetrance) | Change in Neurocognitive Functioning | Baseline | -0.26 Global neurocognitive z-score | Standard Error 0.27 |
| Non Neuro-HAART (Low CNS Penetrance) | Change in Neurocognitive Functioning | 6 months | -0.09 Global neurocognitive z-score | Standard Error 0.27 |
| Non Neuro-HAART (Low CNS Penetrance) | Change in Neurocognitive Functioning | 12 months | -0.07 Global neurocognitive z-score | Standard Error 0.27 |
| Neuro-HAART (High CNS Penetrance) | Change in Neurocognitive Functioning | Baseline | -0.80 Global neurocognitive z-score | Standard Error 0.17 |
| Neuro-HAART (High CNS Penetrance) | Change in Neurocognitive Functioning | 6 months | -0.63 Global neurocognitive z-score | Standard Error 0.17 |
| Neuro-HAART (High CNS Penetrance) | Change in Neurocognitive Functioning | 12 months | -0.61 Global neurocognitive z-score | Standard Error 0.17 |
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: 0.99Mixed Models Analysis
Secondary
Cerebrospinal Fluid
To measure plateaux CSF ARV concentrations. This will identify the proportion of patients achieving levels of specific ARVs capable of inhibiting 95% of in vitro viral replication (IC95).
Time frame: Baseline to 12 Months
Population: Data presented for n=5 participants with detectable CSF ARV concentrations who had lumbar puncture at Baseline and 12 months. The pre-specified analysis was not conducted as nevirapine, raltegravir, and darunavir were the only ARVs detected in CSF, and of these, only nevirapine was detected above the minimum threshold (set at \>50 ug/L).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Non Neuro-HAART (Low CNS Penetrance) | Cerebrospinal Fluid | Nevirapine Baseline | NA ug/L | — |
| Non Neuro-HAART (Low CNS Penetrance) | Cerebrospinal Fluid | Nevirapine 12 months | NA ug/L | — |
| Non Neuro-HAART (Low CNS Penetrance) | Cerebrospinal Fluid | Raltegravir Baseline | 38 ug/L | — |
| Non Neuro-HAART (Low CNS Penetrance) | Cerebrospinal Fluid | Raltegravir 12 months | 32 ug/L | — |
| Non Neuro-HAART (Low CNS Penetrance) | Cerebrospinal Fluid | Darunavir Baseline | 46 ug/L | — |
| Non Neuro-HAART (Low CNS Penetrance) | Cerebrospinal Fluid | Darunavir 12 months | NA ug/L | — |
| Neuro-HAART (High CNS Penetrance) | Cerebrospinal Fluid | Darunavir Baseline | 39 ug/L | — |
| Neuro-HAART (High CNS Penetrance) | Cerebrospinal Fluid | Nevirapine Baseline | 1161.5 ug/L | Standard Error 101.5 |
| Neuro-HAART (High CNS Penetrance) | Cerebrospinal Fluid | Raltegravir 12 months | NA ug/L | — |
| Neuro-HAART (High CNS Penetrance) | Cerebrospinal Fluid | Nevirapine 12 months | 1445 ug/L | Standard Error 234 |
| Neuro-HAART (High CNS Penetrance) | Cerebrospinal Fluid | Darunavir 12 months | 50 ug/L | — |
| Neuro-HAART (High CNS Penetrance) | Cerebrospinal Fluid | Raltegravir Baseline | 39 ug/L | — |
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), after a 12 month period of observation. Spectra were acquired on a Phillips Achieva 3T MRI scanner using point-resolved spectroscopy (PRESS) sequence with short echo 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: n=1 participant in high CNS penetrance arm did not return for 12-months follow-up visit. Their baseline data were therefore excluded from analysis.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Non Neuro-HAART (Low CNS Penetrance) | Change in MRS Cerebral Metabolite Ratios in Basal Ganglia | NAA Baseline | 4.14 Ratio | Standard Error 0.2 |
| Non Neuro-HAART (Low CNS Penetrance) | Change in MRS Cerebral Metabolite Ratios in Basal Ganglia | Cho Baseline | 1.81 Ratio | Standard Error 0.16 |
| Non Neuro-HAART (Low CNS Penetrance) | Change in MRS Cerebral Metabolite Ratios in Basal Ganglia | Cr Baseline | 3.18 Ratio | Standard Error 0.18 |
| Non Neuro-HAART (Low CNS Penetrance) | Change in MRS Cerebral Metabolite Ratios in Basal Ganglia | NAA 12 months | 3.96 Ratio | Standard Error 0.2 |
| Non Neuro-HAART (Low CNS Penetrance) | Change in MRS Cerebral Metabolite Ratios in Basal Ganglia | mIo Baseline | 1.22 Ratio | Standard Error 0.21 |
| Non Neuro-HAART (Low CNS Penetrance) | Change in MRS Cerebral Metabolite Ratios in Basal Ganglia | Cr 12 Months | 3.20 Ratio | Standard Error 0.18 |
| Non Neuro-HAART (Low CNS Penetrance) | Change in MRS Cerebral Metabolite Ratios in Basal Ganglia | mIo 12 Months | 1.12 Ratio | Standard Error 0.21 |
| Non Neuro-HAART (Low CNS Penetrance) | Change in MRS Cerebral Metabolite Ratios in Basal Ganglia | Cho 12 Months | 1.78 Ratio | Standard Error 0.16 |
| Neuro-HAART (High CNS Penetrance) | Change in MRS Cerebral Metabolite Ratios in Basal Ganglia | mIo 12 Months | 1.18 Ratio | Standard Error 0.14 |
| Neuro-HAART (High CNS Penetrance) | Change in MRS Cerebral Metabolite Ratios in Basal Ganglia | NAA Baseline | 4.00 Ratio | Standard Error 0.13 |
| Neuro-HAART (High CNS Penetrance) | Change in MRS Cerebral Metabolite Ratios in Basal Ganglia | NAA 12 months | 3.99 Ratio | Standard Error 0.13 |
| Neuro-HAART (High CNS Penetrance) | Change in MRS Cerebral Metabolite Ratios in Basal Ganglia | Cr Baseline | 3.03 Ratio | Standard Error 0.12 |
| Neuro-HAART (High CNS Penetrance) | Change in MRS Cerebral Metabolite Ratios in Basal Ganglia | Cr 12 Months | 3.27 Ratio | Standard Error 0.12 |
| Neuro-HAART (High CNS Penetrance) | Change in MRS Cerebral Metabolite Ratios in Basal Ganglia | Cho Baseline | 1.79 Ratio | Standard Error 0.11 |
| Neuro-HAART (High CNS Penetrance) | Change in MRS Cerebral Metabolite Ratios in Basal Ganglia | Cho 12 Months | 1.72 Ratio | Standard Error 0.11 |
| Neuro-HAART (High CNS Penetrance) | Change in MRS Cerebral Metabolite Ratios in Basal Ganglia | mIo Baseline | 1.27 Ratio | Standard Error 0.14 |
Comparison: Change in NAA/H20 levels was analysed using repeated-measures ANOVA with arm, time, and arm\*time interaction as fixed effects.p-value: 0.58ANOVA
Comparison: Change in Cr/H20 levels was analysed using repeated-measures ANOVA with arm, time, and arm\*time interaction as fixed effects.p-value: 0.44ANOVA
Comparison: Change in Cho/H20 levels was analysed using repeated-measures ANOVA with arm, time, and arm\*time interaction as fixed effects.p-value: 0.86ANOVA
Comparison: Change in mIo/H20 levels was analysed using repeated-measures ANOVA with arm, time, and arm\*time interaction as fixed effects.p-value: 0.98ANOVA
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 H20 as standard.
Time frame: Baseline and 12 months
Population: n=1 participant in high CNS penetrance arm did not return for 12-months follow-up visit. Their baseline data were therefore excluded from analysis.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Non Neuro-HAART (Low CNS Penetrance) | Change in MRS Cerebral Metabolite Ratios in Frontal White Matter | NAA Baseline | 4.39 Ratio | Standard Error 0.22 |
| Non Neuro-HAART (Low CNS Penetrance) | Change in MRS Cerebral Metabolite Ratios in Frontal White Matter | NAA 12 Months | 4.74 Ratio | Standard Error 0.22 |
| Non Neuro-HAART (Low CNS Penetrance) | Change in MRS Cerebral Metabolite Ratios in Frontal White Matter | Cr Baseline | 2.77 Ratio | Standard Error 0.19 |
| Non Neuro-HAART (Low CNS Penetrance) | Change in MRS Cerebral Metabolite Ratios in Frontal White Matter | Cr 12 Months | 3.29 Ratio | Standard Error 0.19 |
| Non Neuro-HAART (Low CNS Penetrance) | Change in MRS Cerebral Metabolite Ratios in Frontal White Matter | Cho Baseline | 2.25 Ratio | Standard Error 0.13 |
| Non Neuro-HAART (Low CNS Penetrance) | Change in MRS Cerebral Metabolite Ratios in Frontal White Matter | Cho 12 Months | 2.50 Ratio | Standard Error 0.13 |
| Non Neuro-HAART (Low CNS Penetrance) | Change in MRS Cerebral Metabolite Ratios in Frontal White Matter | mIo Baseline | 1.06 Ratio | Standard Error 0.09 |
| Non Neuro-HAART (Low CNS Penetrance) | Change in MRS Cerebral Metabolite Ratios in Frontal White Matter | mIo 12 Months | 1.19 Ratio | Standard Error 0.09 |
| Non Neuro-HAART (Low CNS Penetrance) | Change in MRS Cerebral Metabolite Ratios in Frontal White Matter | Glx Baseline | 2.26 Ratio | Standard Error 0.16 |
| Non Neuro-HAART (Low CNS Penetrance) | Change in MRS Cerebral Metabolite Ratios in Frontal White Matter | Glx 12 Months | 2.13 Ratio | Standard Error 0.19 |
| Neuro-HAART (High CNS Penetrance) | Change in MRS Cerebral Metabolite Ratios in Frontal White Matter | mIo 12 Months | 1.23 Ratio | Standard Error 0.06 |
| Neuro-HAART (High CNS Penetrance) | Change in MRS Cerebral Metabolite Ratios in Frontal White Matter | NAA Baseline | 4.38 Ratio | Standard Error 0.15 |
| Neuro-HAART (High CNS Penetrance) | Change in MRS Cerebral Metabolite Ratios in Frontal White Matter | Cho 12 Months | 2.31 Ratio | Standard Error 0.08 |
| Neuro-HAART (High CNS Penetrance) | Change in MRS Cerebral Metabolite Ratios in Frontal White Matter | NAA 12 Months | 4.32 Ratio | Standard Error 0.15 |
| Neuro-HAART (High CNS Penetrance) | Change in MRS Cerebral Metabolite Ratios in Frontal White Matter | Glx 12 Months | 1.96 Ratio | Standard Error 0.11 |
| Neuro-HAART (High CNS Penetrance) | Change in MRS Cerebral Metabolite Ratios in Frontal White Matter | Cr Baseline | 3.09 Ratio | Standard Error 0.12 |
| Neuro-HAART (High CNS Penetrance) | Change in MRS Cerebral Metabolite Ratios in Frontal White Matter | mIo Baseline | 1.05 Ratio | Standard Error 0.06 |
| Neuro-HAART (High CNS Penetrance) | Change in MRS Cerebral Metabolite Ratios in Frontal White Matter | Cr 12 Months | 3.16 Ratio | Standard Error 0.12 |
| Neuro-HAART (High CNS Penetrance) | Change in MRS Cerebral Metabolite Ratios in Frontal White Matter | Glx Baseline | 2.13 Ratio | Standard Error 0.11 |
| Neuro-HAART (High CNS Penetrance) | Change in MRS Cerebral Metabolite Ratios in Frontal White Matter | Cho Baseline | 2.33 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: 0.16ANOVA
Comparison: Change in Cr/H20 levels were analysed using repeated-measures ANOVA with arm, time, and arm\*time interaction as fixed effects.p-value: 0.09ANOVA
Comparison: Change in Cho/H20 levels were analysed using repeated-measures ANOVA with arm, time, and arm\*time interaction as fixed effects.p-value: 0.06ANOVA
Comparison: Change in mIo/H20 levels were analysed using repeated-measures ANOVA with arm, time, and arm\*time interaction as fixed effects.p-value: 0.68ANOVA
Comparison: Change in Glx/H20 levels were analysed using repeated-measures ANOVA with arm, time, and arm\*time interaction as fixed effects.p-value: 0.58ANOVA