HIV Associated Neurocognitive Disorders (HAND), Human Immunodeficiency Virus (HIV)
Conditions
Keywords
HIV, HAND, Human Immunodeficiency Virus, Raltegravir, HIV Associated Neurocognitive Disorders, Neuro-HAART, Neurocognitive, Neurology
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 Neurological 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 Raltegravir; 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 Raltegravir, leads to significant improvement in HIV associated neurological 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 raltegravir 400mg twice daily, or not. The control arm will remain on their medication regimen as prescribed. The target is to enrol 110 patients into the control group, and 110 patients into the Raltegravir intensification group. Patients will undergo baseline neuropsychological testing, MRI, blood tests, and cerebral spinal fluid (CSF) tests (via a lumbar puncture). The methods used to determine the effectiveness of adding Raltegravir, will include further neuropsychological testing at 6 months; and neuropsychological testing, MRI and CSF assessment 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. The decision of the Antiretroviral medication regimen to be used in such a case will be determined by the managing physician. At the end of the study protocol (12 months) the patient's HAART therapy will be managed by their primary physician.
Interventions
DRUGRaltegravir
Oral raltegravir, 400 mg tablet, twice daily for one year.
Sponsors
Merck Sharp & Dohme LLC
St Vincent's Hospital, Sydney
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 HIV 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 (while on existing HAART regimen)
Exclusion criteria
* Non-HIV related neurological disorders and active CNS opportunistic infection (as assessed by full blood count, electrolytes, creatinine, glucose, LFT's, cryptococcal antigen, VDRL, MRI brain scan and CSF fluid analysis for cell count, protein, glucose, culture, VDRL and cryptococcal antigen) * Psychiatric disorders on the psychotic axis * Current major depression * Current substance use disorder, or severe substance use disorders within 12 months of study entry * Active HCV (detectable HCV RNA) * History of loss of consciousness \> 1 hour * Non-proficient in English * Medications known to pharmacologically interact with ARV's * Currently taking an Integrase Inhibitor * Pregnancy (as assessed by the urine pregnancy test)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Neurocognitive Function | 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 |
|---|---|---|
| Cerebrospinal Fluid | Baseline and 12 months | To determine if there is improvement in CSF neopterin concentrations with the addition of Raltegravir. |
Countries
Australia
Participant flow
Recruitment details
Recruitment period from October 2011 to October 2013. Participants were known patients of the PI or referred from local tertiary sexual health clinics by associate investigators.
Participants by arm
| Arm | Count |
|---|---|
| Raltegravir Participants randomised to this arm will remain on their standard of care Highly Active Antiretroviral Therapy (HAART) with the addition of Raltegravir 400 mg twice daily (BID).
Raltegravir : Oral raltegravir, 400 mg tablet, twice daily for one year. | 3 |
| Standard of Care HAART Participants randomised to this arm will remain on their standard of care Highly Active Antiretroviral Therapy (HAART). | 3 |
| Total | 6 |
Baseline characteristics
| Characteristic | Raltegravir | Standard of Care HAART | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 3 Participants | 6 Participants |
| Age, Continuous | 52.0 years STANDARD_DEVIATION 8.7 | 59.3 years STANDARD_DEVIATION 4.9 | 55.7 years STANDARD_DEVIATION 7.5 |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 3 Participants | 3 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 1 / 3 | 1 / 3 |
| serious Total, serious adverse events | 0 / 3 | 0 / 3 |
Outcome results
Primary
Neurocognitive Function
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: Study was terminated prematurely with an incomplete study dataset any before any meaningful statistical analysis of the data (including change over the study time-points) could be performed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Raltegravir | Neurocognitive Function | Baseline | -0.83 Global Neurocognitive Z-Score | Standard Error 0.29 |
| Raltegravir | Neurocognitive Function | 6 months | -0.55 Global Neurocognitive Z-Score | Standard Error 0.12 |
| Raltegravir | Neurocognitive Function | 12 months | -0.47 Global Neurocognitive Z-Score | Standard Error 0.46 |
| Standard of Care HAART | Neurocognitive Function | 6 months | -0.48 Global Neurocognitive Z-Score | Standard Error 0.45 |
| Standard of Care HAART | Neurocognitive Function | 12 months | -0.54 Global Neurocognitive Z-Score | Standard Error 0.32 |
| Standard of Care HAART | Neurocognitive Function | Baseline | -0.39 Global Neurocognitive Z-Score | Standard Error 0.2 |
Secondary
Cerebrospinal Fluid
To determine if there is improvement in CSF neopterin concentrations with the addition of Raltegravir.
Time frame: Baseline and 12 months
Population: Study was terminated prematurely with an incomplete study dataset before any meaningful analyses of the data could be conducted. CSF was not collected at 12 months for n=1 raltegravir and n=1 control who refused lumbar puncture.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Raltegravir | Cerebrospinal Fluid | 12 months | 17.00 nmol/L | Standard Error 7 |
| Raltegravir | Cerebrospinal Fluid | Baseline | 11.67 nmol/L | Standard Error 2.91 |
| Standard of Care HAART | Cerebrospinal Fluid | 12 months | 12.00 nmol/L | Standard Error 3 |
| Standard of Care HAART | Cerebrospinal Fluid | Baseline | 34.00 nmol/L | Standard Error 16.26 |