HIV-1-infection, HIV Associated Neurocognitive Disorder
Conditions
Keywords
CNS Penetration Effectiveness, Global Deficit Score, Cytokines, CSF Inflammation
Brief summary
Prospective study in HIV-1 infected adult subjects with HIV-associated neurocognitive disorders despite effective antiretroviral therapy in plasma for more than one year, analyzing the evolution of cognitive disorders and markers of macrophagic inflammation in blood and cerebrospinal fluid, after a change in HIV treatment with an increased of the new scale CHARTER score ≥ 3 (total treatment score to be ≥ 9)
Detailed description
Neurocognitive disorders are measured using Frascati 3-stage classification and Global Deficit Score, after the following 10 standardized battery test: Grooved Pegboard for dominant and non-dominant hand, Grefex Verbal Fluency, California Verbal Learning Test (CVLT), Digit Span Wechsler Adult Intelligence Scale III, modified Paced Auditory Serial Addition Test (60 items), WAIS III Digit Symbol Test, Trail Making Test A&B, recall of CVLT and Wisconsin Card Sorting Test; and after the Beck Depression Inventory II (BDI), Inventory of Activity Daily Living part II (IADL) and 10-items Cognitive Complaint Questionnaire (CCQ). The global CNS Penetration Effectiveness (CPE) score of ARV treatment are the sum of the scores of each ARV the patient received, according to the last published scoring. For each drug class, we considered treatment intensification only for drugs with CPE score reaching at least 3 (no intensification if switch in same drug class with same CPE score). CPE score was corrected by drugs resistance status, using cumulative genotype interpreted with the 2012 ANRS algorithm (www.hivfrenchresistance.org; v.2012) at inclusion (CPE=0 if resistance).
Interventions
OTHERValidation of Charter score for the CNS diffusion of antiretroviral drugs
IHFB001 (Neuroplustrois) is a pilot study, phase IV, open-label, multicenter in Ile-de-France region, trying to demonstrate the improvement of cognitive change after treatment characterized by its better diffusion in the central nervous system. The characteristics of the change in treatment are (Cn - Ci) ≥ 3 and Cn ≥ 9, where Cn is the Charter score of the new treatment and Ci the Charter score of the initial treatment.
Sponsors
Hospital Ambroise Paré Paris
Hôpital Franco-Britannique-Fondation Cognacq-Jay
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Prospective Pilot study, open-label, multicenter in the Ile-de-France
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
1. Subject (male or female) with HIV-1 infection 2. Subject is ≥ 18 years of age 3. Subject with a plasma viral load (HIV-1 RNA) undetectable for at least one year or with minimal replication \<500 copies/ml for at least one year at the inclusion date 4. Patient with HIV-associated neurocognitive disorders : at least two ability domains, documented by performance of at least 1.0 standard deviation below the mean for age-education appropriate norms on standardized neuropsychological tests 5. Patient is willing and able to understand and provide written informed consent prior to participation in this study
Exclusion criteria
1. Subject with HIV-2 infection 2. Subject with plasma viral load (HIV-1 RNA)\> 500 copies/ml in the past year 3. Subject with acquired impairment in cognitive functioning involving only one ability domain, or involving at least two ability domains but with performance better than 1.0 standard deviation below the mean (no evidence of potential cognitive impairment) 4. Subject unable, according to the investigator, to meet the study requirements, including patients unable to perform cognitive tests 5. Subject with acute intercurrent disease 6. Patient with positive serology for HCV or HBsAg positive 7. Subject with cognitive impairment related to another cause than HIV: other CNS infection, CNS neoplasm, cerebrovascular disease, preexisting neurologic disease or metabolic disorders, severe substance abuse, or systemic disease. 8. Subject with a brain MRI or CSF analysis results that suggest another pathology than HIV associated neurocognitive disorder 9. Subject requires treatment with immunomodulating agents (or may require such treatment during the two years monitoring) such as systemic corticosteroïds, interferons, interleukins, growth factor GM- CSF, or other targeted therapy that may interfere with macrophage markers of the study 10. Subject requires treatment with radiation therapy or cytotoxic chemotherapeutic agents 11. Subject at which the initial lumbar punction can't be achieved 12. Subject ≥65 years at the inclusion date, age with high risk of atherosclerotic disease 13. Subject with significant depression : with a score ≥29 (or score ≥20 without questions 15 to 21) at Beck Depression Inventory II (1996 version), the neuropsychologist doesn't conduct the battery of cognitive tests 14. Subject under curatorship or guardianship 15. Subject at which the initial cerebral MRI can't be achieved
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Demonstrate a significant improvement in HIV associated neurocognitive disorders after ARV intensification with increased CNS Penetration Effectiveness scoring ≥+3 and total CPE score ≥9. | Change from Baseline to Week 96 | HIV associated neurocognitive disorders classification with Frascati 3-stage |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| To evaluate HIV associated neurocognitive disorders and Global Deficit Score change | Change from Baseline to Week 48 | HIV associated neurocognitive disorders are measured with Frascati 3-stage classification. Global Deficit Score (from 0 with no deficit to 5 with high neurocognitive disorder) is calculated with the results of 10 standardized battery tests. |
| To evaluate the evolution of HIV associated neurocognitive disorders with changes in CD4 and CD8 cells in plasma cells, and plasma HIV-1 viral loads | Change from Baseline to Week 48 | HIV associated neurocognitive disorders are measured with Frascati 3-stage classification and Global Deficit Score. CD4 and CD8 cells are measured in plasma with flow cytometry (results in cells/µL). |
| To evaluate the evolution of HIV associated neurocognitive disorders with plasma HIV-1 viral load cells, and plasma HIV-1 viral loads | Change from Baseline to Week 48 | HIV associated neurocognitive disorders are measured with Frascati 3-stage classification and Global Deficit Score. Plasma HIV-1 viral load will be measured with an ultra-sensitive technique with a threshold of 5 copies/mL. |
| To compare HIV associated neurocognitive disorders in HIV-1 infected patients with detectable and undetectable viral load in CSF | Day 0 | HIV associated neurocognitive disorders are measured with Frascati 3-stage classification and Global Deficit Score.Detectable viral load in CSF is defined as a result \>5 copies/mL with ultrasensitive HIV-RNA measure. |
| To evaluate the patterns of viral genotypic resistance in patients with virologic failure in blood or CSF | Week 12 | Virologic failure in the blood is defined as two results \>100 copies/mL within one month. Virologic failure in the CSF is defined as a result \>100 copies/mL |
| To evaluate the evolution of HIV associated neurocognitive disorders with the evolution of markers in CSF: neopterin, neurofilament light chain (NFL), CCL2, IL6, IL8, CXCL10, soluble CD14 | Change from Baseline to Week 48 | HIV associated neurocognitive disorders are measured with Frascati 3-stage classification and Global Deficit Score. CSF biomarkers were obtained using high-performance liquid chromatography coupled with fluorimetric detection for neopterin (nmol/L), using the Quanterix® single molecule array platform for neurofilament light protein (NF-L)(pg/mL), chemokine (C-C-motif) ligand-2 (CCL2)(pg/mL), interleukine 6 (IL6)(pg/mL), interleukine 8 (IL8)(pg/mL), chemokine (C-X-C-motif) ligand-10 (CXCL10)(pg/mL), and using an enzyme-linked immunosorbent assay (Biotechne®) for soluble CD14 (sCD14)(µg/mL) levels. |
| To evaluate the evolution of HIV associated neurocognitive disorders with the evolution of markers in plasma: neopterin, neurofilament light chain (NFL), CCL2, IL6, IL8, CXCL10, soluble CD14 | Change from Baseline to Week 48 | HIV associated neurocognitive disorders are measured with Frascati 3-stage classification and Global Deficit Score. Plasma biomarkers were obtained using high-performance liquid chromatography coupled with fluorimetric detection for neopterin (nmol/L), using the Quanterix® single molecule array platform for neurofilament light protein (NF-L)(pg/mL), chemokine (C-C-motif) ligand-2 (CCL2)(pg/mL), interleukine 6 (IL6)(pg/mL), interleukine 8 (IL8)(pg/mL), chemokine (C-X-C-motif) ligand-10 (CXCL10)(pg/mL), and using an enzyme-linked immunosorbent assay (Biotechne®) for soluble CD14 (sCD14)(µg/mL) levels. |
| To evaluate HIV associated neurocognitive disorders and Brain MRI change | Change from Baseline to Week 48 | HIV associated neurocognitive disorders are measured with Frascati 3-stage classification and Global Deficit Score. Brain MRI is performed before and after ARV change |
| Demonstrate a significant improvement in HIV associated neurocognitive disorders after ARV intensification with increased CNS Penetration Effectiveness scoring ≥+3 and total CPE score ≥9. | Change from Baseline to Week 48 | HIV associated neurocognitive disorders classification with Frascati 3-stage |
| To evaluate regular monitoring of cognitive impairment by 10-items Cognitive Complaint Questionnaire to detect at the earliest possible changes in cognitive status | Change from Baseline to Week 12 | 10-items Cognitive Complaint Questionnaire is altered with a cutoff ≥3 |
| To evaluate regular monitoring of cognitive impairment by Inventory of Activity Daily Living part II to detect at the earliest possible changes in cognitive status | Change from Baseline to Week 12 | Inventory of Activity Daily Living part II is altered with a cutoff ≥2 |
| To evaluate the Quality of Life during the study | Change from Baseline to Week 12 | Quality of Life is measured by Short Form 36 Health Survey |
| To compare HIV associated neurocognitive disorders in patients with great CPE change ≥5 and patients with low CPE change (+3 or +4) | Change from Baseline to Week 48 | HIV associated neurocognitive disorders are measured with Frascati 3-stage classification and Global Deficit Score. CPE changes are analysed with most recent genotypic algorithm (v.2016) |
| To study the incidence and severity of adverse events during the study period | Week 12 | Neurologic or neuropsychologic adverse events are particularly analysed |
| To study the trough levels of antiretroviral drugs in blood and cerebrospinal fluid during the study | Day 0 | ARV concentrations were determined using an ultra-performance liquid chromatography coupled with tandem mass spectrometry |
| To study the trough levels of antiretroviral drugs in blood after ARV change | Week 4 | ARV concentrations were determined using an ultra-performance liquid chromatography coupled with tandem mass spectrometry |
| To study the cardiovascular risk evolution | Change from Baseline to Week 48 | Cardiovascular risk is measured with Framingham score, Systematic Coronary Risk Estimation, and D:A:D study model score |
| To compare sensitivity and specificity of the 2 screening tests (FAB test and Modified - HIV Dementia Scale) for the diagnosis of HAND | Day 0 | HIV associated neurocognitive disorders are measured with Frascati 3-stage classification and Global Deficit Score. Altered Frontal Assessment Battery test is defined with a score ≤15/18 and altered modified-HIV Dementia Scale screening test is defined with a score ≤10/12. |
Countries
France
Outcome results
None listed