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

NCT ID: NCT02503462

Last Updated: 2017-02-02

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE4
• Total Enrollment: 7 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-07-31
• Study Completion Date: 2017-01-31

Brief Summary

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.

Detailed 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.

Conditions

AIDS-related Dementia Complex

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

darunavir/ritonavir vs cobicistat

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.

Group Type: EXPERIMENTAL

Darunavir

Intervention Type: DRUG

darunavir 800 mg once daily will be first given together with ritonavir 100 mg once daily for one month (period 1) and then darunavir 800 mg once daily will be given together with cobicistat 150 mg once daily for one month (period 2). Afterwards, all patients will be switched back to darunavir/ritonavir (800/100 mg once daily).

ritonavir

Intervention Type: DRUG

ritonavir 100 mg once daily will be used to boost darunavir 800 mg once daily (period 1).

cobicistat

Intervention Type: DRUG

cobicistat 150 mg once daily will be used to boost darunavir 800 mg once daily (period 2).

Interventions

Darunavir

darunavir 800 mg once daily will be first given together with ritonavir 100 mg once daily for one month (period 1) and then darunavir 800 mg once daily will be given together with cobicistat 150 mg once daily for one month (period 2). Afterwards, all patients will be switched back to darunavir/ritonavir (800/100 mg once daily).

Intervention Type: DRUG

ritonavir

ritonavir 100 mg once daily will be used to boost darunavir 800 mg once daily (period 1).

Intervention Type: DRUG

cobicistat

cobicistat 150 mg once daily will be used to boost darunavir 800 mg once daily (period 2).

Intervention Type: DRUG

Other Intervention Names

Prezista; Norvir; Tybost

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University Hospital, Basel, Switzerland

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Manuel Battegay

Role: PRINCIPAL_INVESTIGATOR

University Hospital, Basel, Switzerland

Locations

Division of Infectious Diseases, University Hospital Basel

Basel, Canton of Basel-City, Switzerland

Countries

Switzerland

References

Bartels H, Decosterd L, Battegay M, Marzolini C. Darunavir concentrations in CSF of HIV-infected individuals when boosted with cobicistat versus ritonavir. J Antimicrob Chemother. 2017 Sep 1;72(9):2574-2577. doi: 10.1093/jac/dkx165.

Reference Type: DERIVED

PMID: 28575323 (View on PubMed)

Other Identifiers

DRVCOBI

Identifier Type: -

Identifier Source: org_study_id