HIV-1 Infected Adult Subjects With HIV-associated Neurocognitive Disorders Despite Effective Antiretroviral Therapy

Study Overview
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Brief Summary
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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
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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).

Official Title
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Prospective Study in HIV-1 Infected Adult Subjects With HIV-associated Neurocognitive Disorders Despite Effective Antiretroviral Therapy in Plasma, After a Change in HIV Treatment With an Increased of CHARTER Score ≥ 3 (Total Score ≥ 9)

Conditions
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HIV-1-infection, HIV Associated Neurocognitive Disorder

Intervention / Treatment
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* Other: Validation of Charter score for the CNS diffusion of antiretroviral drugs


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject (male or female) with HIV-1 infection Subject is ≥ 18 years of age 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 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 Patient is willing and able to understand and provide written informed consent prior to participation in this study Exclusion Criteria: Subject with HIV-2 infection Subject with plasma viral load (HIV-1 RNA)> 500 copies/ml in the past year 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) Subject unable, according to the investigator, to meet the study requirements, including patients unable to perform cognitive tests Subject with acute intercurrent disease Patient with positive serology for HCV or HBsAg positive 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. Subject with a brain MRI or CSF analysis results that suggest another pathology than HIV associated neurocognitive disorder 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 Subject requires treatment with radiation therapy or cytotoxic chemotherapeutic agents Subject at which the initial lumbar punction can't be achieved Subject ≥65 years at the inclusion date, age with high risk of atherosclerotic disease 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 Subject under curatorship or guardianship Subject at which the initial cerebral MRI can't be achieved

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Prospective Pilot study, open-label, multicenter in the Ile-de-France
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: HIV-1 infected adult associated neurocognitiv<br>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 with Global Deficit Score and HAND classification, 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) | Other: Validation of Charter score for the CNS diffusion of antiretroviral drugs<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Demonstrate a significant improvement in HIV associated neurocognitive disorders after ARV intensification with increased CNS Penetration Effectiveness scoring ≥+3 and total CPE score ≥9. | HIV associated neurocognitive disorders classification with Frascati 3-stage | Change from Baseline to Week 96 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Demonstrate a significant improvement in HIV associated neurocognitive disorders after ARV intensification with increased CNS Penetration Effectiveness scoring ≥+3 and total CPE score ≥9. | HIV associated neurocognitive disorders classification with Frascati 3-stage | Change from Baseline to Week 48 | 
| To evaluate HIV associated neurocognitive disorders and Global Deficit Score change | 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. | Change from Baseline to Week 48 | 
| To evaluate HIV associated neurocognitive disorders and Global Deficit Score change | 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. | Change from Baseline to Week 96 | 
| 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 | 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). | Change from Baseline to Week 48 | 
| 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 | 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). | Change from Baseline to Week 96 | 
| To evaluate the evolution of HIV associated neurocognitive disorders with plasma HIV-1 viral load cells, and plasma HIV-1 viral loads | 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. | Change from Baseline to Week 48 | 
| To evaluate the evolution of HIV associated neurocognitive disorders with plasma HIV-1 viral load cells, and plasma HIV-1 viral loads | 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. | Change from Baseline to Week 96 | 
| To compare HIV associated neurocognitive disorders in HIV-1 infected patients with detectable and undetectable viral load in CSF | 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. | Day 0 | 
| To compare HIV associated neurocognitive disorders in HIV-1 infected patients with detectable and undetectable viral load in CSF | 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. | Week 48 | 
| To compare HIV associated neurocognitive disorders in HIV-1 infected patients with detectable and undetectable viral load in CSF | 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. | Week 96 | 
| To evaluate the patterns of viral genotypic resistance in patients with virologic failure in blood or CSF | 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 | Week 12 | 
| To evaluate the patterns of viral genotypic resistance in patients with virologic failure in blood or CSF | 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 | Week 24 | 
| To evaluate the patterns of viral genotypic resistance in patients with virologic failure in blood or CSF | 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 | Week 36 | 
| To evaluate the patterns of viral genotypic resistance in patients with virologic failure in blood or CSF | 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 | Week 48 | 
| To evaluate the patterns of viral genotypic resistance in patients with virologic failure in blood or CSF | 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 | Week 60 | 
| To evaluate the patterns of viral genotypic resistance in patients with virologic failure in blood or CSF | 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 | Week 72 | 
| To evaluate the patterns of viral genotypic resistance in patients with virologic failure in blood or CSF | 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 | Week 84 | 
| To evaluate the patterns of viral genotypic resistance in patients with virologic failure in blood or CSF | 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 | Week 96 | 
| 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 | 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. | Change from Baseline to Week 48 | 
| 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 | 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. | Change from Baseline to Week 96 | 
| 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 | 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. | Change from Baseline to Week 48 | 
| 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 | 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. | Change from Baseline to Week 96 | 
| To evaluate HIV associated neurocognitive disorders and Brain MRI change | HIV associated neurocognitive disorders are measured with Frascati 3-stage classification and Global Deficit Score. Brain MRI is performed before and after ARV change | Change from Baseline to Week 48 | 
| To evaluate HIV associated neurocognitive disorders and Brain MRI change | HIV associated neurocognitive disorders are measured with Frascati 3-stage classification and Global Deficit Score. Brain MRI is performed before and after ARV change | Change from Baseline to Week 96 | 
| To compare sensitivity and specificity of the 2 screening tests (FAB test and Modified - HIV Dementia Scale) for the diagnosis of HAND | 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. | Day 0 | 
| To evaluate regular monitoring of cognitive impairment by 10-items Cognitive Complaint Questionnaire to detect at the earliest possible changes in cognitive status | 10-items Cognitive Complaint Questionnaire is altered with a cutoff ≥3 | Change from Baseline to Week 12 | 
| To evaluate regular monitoring of cognitive impairment by 10-items Cognitive Complaint Questionnaire to detect at the earliest possible changes in cognitive status | 10-items Cognitive Complaint Questionnaire is altered with a cutoff ≥3 | Change from Baseline to Week 24 | 
| To evaluate regular monitoring of cognitive impairment by 10-items Cognitive Complaint Questionnaire to detect at the earliest possible changes in cognitive status | 10-items Cognitive Complaint Questionnaire is altered with a cutoff ≥3 | Change from Baseline to Week 36 | 
| To evaluate regular monitoring of cognitive impairment by 10-items Cognitive Complaint Questionnaire to detect at the earliest possible changes in cognitive status | 10-items Cognitive Complaint Questionnaire is altered with a cutoff ≥3 | Change from Baseline to Week 48 | 
| To evaluate regular monitoring of cognitive impairment by 10-items Cognitive Complaint Questionnaire to detect at the earliest possible changes in cognitive status | 10-items Cognitive Complaint Questionnaire is altered with a cutoff ≥3 | Change from Baseline to Week 60 | 
| To evaluate regular monitoring of cognitive impairment by 10-items Cognitive Complaint Questionnaire to detect at the earliest possible changes in cognitive status | 10-items Cognitive Complaint Questionnaire is altered with a cutoff ≥3 | Change from Baseline to Week 72 | 
| To evaluate regular monitoring of cognitive impairment by 10-items Cognitive Complaint Questionnaire to detect at the earliest possible changes in cognitive status | 10-items Cognitive Complaint Questionnaire is altered with a cutoff ≥3 | Change from Baseline to Week 84 | 
| To evaluate regular monitoring of cognitive impairment by 10-items Cognitive Complaint Questionnaire to detect at the earliest possible changes in cognitive status | 10-items Cognitive Complaint Questionnaire is altered with a cutoff ≥3 | Change from Baseline to Week 96 | 
| 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 | Inventory of Activity Daily Living part II is altered with a cutoff ≥2 | Change from Baseline to Week 12 | 
| 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 | Inventory of Activity Daily Living part II is altered with a cutoff ≥2 | Change from Baseline to Week 24 | 
| 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 | Inventory of Activity Daily Living part II is altered with a cutoff ≥2 | Change from Baseline to Week 36 | 
| 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 | Inventory of Activity Daily Living part II is altered with a cutoff ≥2 | Change from Baseline to Week 48 | 
| 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 | Inventory of Activity Daily Living part II is altered with a cutoff ≥2 | Change from Baseline to Week 60 | 
| 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 | Inventory of Activity Daily Living part II is altered with a cutoff ≥2 | Change from Baseline to Week 72 | 
| 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 | Inventory of Activity Daily Living part II is altered with a cutoff ≥2 | Change from Baseline to Week 84 | 
| 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 | Inventory of Activity Daily Living part II is altered with a cutoff ≥2 | Change from Baseline to Week 96 | 
| To evaluate the Quality of Life during the study | Quality of Life is measured by Short Form 36 Health Survey | Change from Baseline to Week 12 | 
| To evaluate the Quality of Life during the study | Quality of Life is measured by Short Form 36 Health Survey | Change from Baseline to Week 24 | 
| To evaluate the Quality of Life during the study | Quality of Life is measured by Short Form 36 Health Survey | Change from Baseline to Week 36 | 
| To evaluate the Quality of Life during the study | Quality of Life is measured by Short Form 36 Health Survey | Change from Baseline to Week 48 | 
| To evaluate the Quality of Life during the study | Quality of Life is measured by Short Form 36 Health Survey | Change from Baseline to Week 60 | 
| To evaluate the Quality of Life during the study | Quality of Life is measured by Short Form 36 Health Survey | Change from Baseline to Week 72 | 
| To evaluate the Quality of Life during the study | Quality of Life is measured by Short Form 36 Health Survey | Change from Baseline to Week 84 | 
| To evaluate the Quality of Life during the study | Quality of Life is measured by Short Form 36 Health Survey | Change from Baseline to Week 96 | 
| To compare HIV associated neurocognitive disorders in patients with great CPE change ≥5 and patients with low CPE change (+3 or +4) | 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) | Change from Baseline to Week 48 | 
| To compare HIV associated neurocognitive disorders in patients with great CPE change ≥5 and patients with low CPE change (+3 or +4) | 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) | Change from Baseline to Week 96 | 
| To study the incidence and severity of adverse events during the study period | Neurologic or neuropsychologic adverse events are particularly analysed | Week 12 | 
| To study the incidence and severity of adverse events during the study period | Neurologic or neuropsychologic adverse events are particularly analysed | Week 24 | 
| To study the incidence and severity of adverse events during the study period | Neurologic or neuropsychologic adverse events are particularly analysed | Week 36 | 
| To study the incidence and severity of adverse events during the study period | Neurologic or neuropsychologic adverse events are particularly analysed | Week 48 | 
| To study the incidence and severity of adverse events during the study period | Neurologic or neuropsychologic adverse events are particularly analysed | Week 60 | 
| To study the incidence and severity of adverse events during the study period | Neurologic or neuropsychologic adverse events are particularly analysed | Week 72 | 
| To study the incidence and severity of adverse events during the study period | Neurologic or neuropsychologic adverse events are particularly analysed | Week 84 | 
| To study the incidence and severity of adverse events during the study period | Neurologic or neuropsychologic adverse events are particularly analysed | Week 96 | 
| To study the trough levels of antiretroviral drugs in blood and cerebrospinal fluid during the study | ARV concentrations were determined using an ultra-performance liquid chromatography coupled with tandem mass spectrometry | Day 0 | 
| To study the trough levels of antiretroviral drugs in blood after ARV change | ARV concentrations were determined using an ultra-performance liquid chromatography coupled with tandem mass spectrometry | Week 4 | 
| To study the trough levels of antiretroviral drugs in blood and cerebrospinal fluid during the study | ARV concentrations were determined using an ultra-performance liquid chromatography coupled with tandem mass spectrometry | Week 48 | 
| To study the trough levels of antiretroviral drugs in blood and cerebrospinal fluid during the study | ARV concentrations were determined using an ultra-performance liquid chromatography coupled with tandem mass spectrometry | Week 96 | 
| To study the cardiovascular risk evolution | Cardiovascular risk is measured with Framingham score, Systematic Coronary Risk Estimation, and D:A:D study model score | Change from Baseline to Week 48 | 
| To study the cardiovascular risk evolution | Cardiovascular risk is measured with Framingham score, Systematic Coronary Risk Estimation, and D:A:D study model score are calcul | Change from Baseline to Week 96 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CNS Penetration Effectiveness, Global Deficit Score, Cytokines, CSF Inflammation