Using Less Neurotoxic Drugs in Patients With HAND (MARAND-X) ((MARAND-X))

MARaviroc-based Treatment Switch in HIV-positive Patients With HAND: Consequences of Reducing Antiretroviral-associated Neurotoxicity

Neurocognitive disorders are still highly prevalent in the HAART era; despite a dramatic reduction in dementia cases, 15-50% of patients may develop mild or asymptomatic neurocognitive disorders (HIV-associated neurocognitive disorders, HAND).

Among other hypothesis neurotoxicity of antiretrovirals has been postulated but its impact is unknown.

Our hypothesis is that using drugs with reduced in vitro neurotoxicity may improve cognition in HIV-positive patients withHAND.

76 patients with HAND will be randomized to either continue their treatment or switch to emtricitabine, darunavir/cobicistat, maraviroc. Patients will be re-tested 6 months later.

Study Overview

• Status: Terminated
• Conditions: Hiv; Neurocognitive Dysfunction
• Intervention / Treatment: Drug: emtricitabine, darunavir/cobicistat, maraviroc

Detailed Description

Scientific Rationale for Study / Scientific Study Objectives:

Neurocognitive disorders are still highly prevalent in the HAART era; despite a dramatic reduction in dementia cases, 15-50% of patients may develop mild or asymptomatic neurocognitive disorders (HIV-associated neurocognitive disorders, HAND). It should be highlighted that patients presenting no abnormalities in everyday living activities (asymptomatic neurocognitive disorders, ANI) are at higher risk of worse results in performance-based tests, adherence-based measures and they show a significant risk of progressing to more severe forms of impairment. Excluding significantly confounding comorbidities, several factors have been associated with this neurocognitive decline including a low nadir CD4+ T-lymphocyte count, a high HIV DNA, a lower compartmental viral control, a lower concentration/penetration effectiveness score, a lower efficacy in macrophage-derived cells and antiretroviral-generated neuronal toxicity. However several data point out that vascular abnormalities, very common in HIV-positive patients, may deeply influence neurocognitive disorders development and severity: of note, intima media thickness, a well recognized proxy of systemic atherosclerosis, was associated with HAND.

In case of HAND diagnosis, the only recommended approach is to optimize treatment according to plasma and cerebrospinal fluid (CSF) resistance tests; no strategy is currently suggested in case of suppressed plasma and CSF HIV RNA or in case of low level CSF HIV RNA (without evidence of genotypic resistance). It has been postulated that antiretrovirals may have neurotoxic effects through different mechanisms and such effects might become evident once the beneficial effect of HIV RNA suppression vanishes. Available data suggest that, in vitro, the drugs associated with the least neurotoxic effect were emtricitabine, tenofovir, darunavir and maraviroc. Furthermore, several pieces of evidence and a small randomized trial suggest that maraviroc, in HAART-treated subjects may have beneficial effects in terms of improved neurocognitive function, reduced CSF inflammatory biomarkers and improved MRI markers of neuronal integrity.

No study has so far investigated the effect of using drugs with a low neurotoxic profile in HAART-treated patients with HAND.

Primary objective of the study is the variation in neurocognitive tests (global deficit score), 6 months after treatment switch while secondary objectives include the improvement in other biomarkers of neuronal and vascular integrity.

Methods:

Study Design: Randomized, controlled, pilot study. HIV-positive patients that fulfill the inclusion criteria and that sign the informed consent will be enrolled. Patients will be randomized 1:1 (block randomization) to either continue their treatment or to switch to once-daily emtricitabine (200 mg) plus darunavir/cobicistat (800/150 mg) plus maraviroc (300 mg). A lumbar puncture will be performed 6 months after treatment switch.

Number of Patients: 76 (38 per arm)

• Study Type: Interventional
• Enrollment (Actual): 38
• Phase: Phase 4

Contacts and Locations

Study Locations

• Italy
  • Torino, Italy
    • University of Torino

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age above >18 years;
• Confirmed HIV-positivity;
• Diagnosed with HAND according to the Frascati Criteria;
• On combination antiretroviral treatment;
• No evidence of major resistance associated mutations on previous plasma or CSF samples;
• Plasma HIV RNA <50 copies/mL;
• CSF HIV RNA <50 copies/mL;
• R5-tropic virus as detected by a genotype or phenotype based test before starting HAART or genotype-based test performed on HIV DNA in the previous 12 months;

Exclusion Criteria:

• the use of drugs having major drug-to-drug interaction with maraviroc (for instance rifampicin);
• the use of efavirenz- or darunavir-containing regimens at baseline;
• confounding comorbidities that may influence or affect the diagnosis of HAND including developmental disability, history of traumatic brain injury or of cerebrovascular accident;
• a previous diagnosis of central nervous system opportunistic, autoimmune, neurodegenerative or neoplastic disease;
• severe untreated depression;
• active alcohol or recreational substance abuse (in the previous 3 months);
• not fluent in Italian or unable to complete the neurocognitive tests.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Standard of care; Continue current antiretroviral regimen
Experimental: Reduced Neurotoxicity Arm; Emtricitabine plus darunavir/cobicistat plus maraviroc	Drug: emtricitabine, darunavir/cobicistat, maraviroc; Treatment change

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
6-month variation in global deficit score in NPZ-8 complete neurocognitive tests according to the study arm;	Global deficit score	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
rs-fMRI	spectroscopic and perfusion markers at MRI as well as the variations in brain connectivity at resting state functional MRI;	6 months
EEG-LORETA	electroencephalographic waves using the LORETA software;	6 months
CSF HIV RNA	changes in CSF HIV RNA in the two arms	6 months
CSF markers	Variation in CSF markers of inflammation or neuronal damage	6 months
Blood Brain Barrier Integrity	Variation in CSAR in the two arms	6 months
IMT	Variation in carotid intima media thickness in the two arms	6 months
TMAO	Variation in trimethylamine-N-oxide in the two arms	6 months

Collaborators and Investigators

• Sponsor: Giovanni Di Perri

Study record dates

Study Major Dates

• Study Start (Actual): May 15, 2017
• Primary Completion (Actual): June 30, 2020
• Study Completion (Actual): June 30, 2020

Study Registration Dates

• First Submitted: May 19, 2017
• First Submitted That Met QC Criteria: May 22, 2017
• First Posted (Actual): May 23, 2017

Study Record Updates

• Last Update Posted (Actual): November 6, 2020
• Last Update Submitted That Met QC Criteria: November 5, 2020
• Last Verified: November 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Neurocognitive Disorders; Cognition Disorders; Cognitive Dysfunction; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Protease Inhibitors; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; HIV Protease Inhibitors; Viral Protease Inhibitors; HIV Fusion Inhibitors; Viral Fusion Protein Inhibitors; CCR5 Receptor Antagonists; Emtricitabine; Cobicistat; Maraviroc; Darunavir; Cobicistat mixture with darunavir
• Other Study ID Numbers: MARAND-X

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No