Effect of Cobicistat Versus Ritonavir Boosting on the Brain Permeation of Darunavir in HIV-infected Individuals

University Hospital Basel

Status and phase: Terminated; Phase 4

Conditions: AIDS-related Dementia Complex

Treatments: Drug: cobicistat; Drug: Darunavir; Drug: ritonavir

Study type: Interventional

Funder types: Other

Identifiers

NCT02503462

DRVCOBI

Details and patient eligibility

About

The purpose of this study is to assess whether a boosting by cobicistat results in similar concentrations of darunavir in the brain compared to a boosting by ritonavir.

Full description

Cobicistat is a new pharmacokinetic enhancer or booster of the HIV protease inhibitor darunavir. Cobicistat is distinct from the conventional booster ritonavir in that cobicistat presents a more selective inhibition of the enzymes metabolizing drugs. In addition, cobicistat is a weaker inhibitor of the efflux drug transporters expressed at the level of the blood-brain barrier (i.e. P-glycoprotein (P-gp) and breast cancer resistance Protein (BCRP)). A weaker inhibition of these efflux transporters could possibly result in less darunavir entering the brain when boosted by cobicistat as compared to a boosting by ritonavir. Such a difference could potentially be critical in patients with HIV-associated neurocognitive disorders as sufficient drug levels are needed to efficiently inhibit HIV replication inside the brain.

The aim of this study is to determine whether the boosting of darunavir by cobicistat results effectively in lower darunavir concentrations in the CSF as compared to a boosting by ritonavir. The study will be performed in HIV infected patients presenting HIV associated neurocognitive disorders (HAND) and requiring a lumbar puncture for clinical reasons. In addition, the patients will be only eligible if the are treated or if they qualify for a darunavir/ritonavir (800/100 mg once daily) containing regimen. Darunavir concentrations will be measured simultaneously in the CSF and plasma (CSF/plasma ratio) first with the ritonavir boosting and subsequently with the cobicistat boosting.

Enrollment: 7 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• documented HIV infection
• presence of HIV associated neurocognitive disorders requiring a lumbar puncture for clinical reasons
• treatment or qualifying to be treated with a HIV therapy including darunavir/r (800/100 mg once daily)
• ability to comply with the study requirements
• informed consent

Exclusion criteria

• conditions which disrupt the blood-brain barrier and thereby impact the entry of drugs in the brain (meningitis, meningoencephalitis, multiple sclerosis, progressive multifocal leucoencephalopathy)
• co-medications inhibiting/inducing P-glycoprotein and BCRP
• co-medications inhibiting/inducing cytochrome P450 isoenzyme 3A4 (CYP3A4)
• non adherence to Treatment
• pregnancy

Trial design

Primary purpose: Treatment

Allocation: N/A

Interventional model: Single Group Assignment

Masking: None (Open label)

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7 participants in 1 patient group

darunavir/ritonavir vs cobicistat

Experimental group

Description:

All HIV infected patients will be treated with a darunavir/ritonavir (800/100 mg) once daily containing regimen. Darunavir/ritonavir concentrations will be measured simultaneously in CSF and plasma after 1 month of treatment. The treatment will be switched to darunavir/cobicistat (800/150 mg) once daily and darunavir/cobicistat levels will be measured in CSF and plasma after 1 month of treatment.

Treatment:

Drug: ritonavir

Drug: Darunavir

Drug: cobicistat