Clinical trial NCT02503462: Effect of Cobicistat Versus Ritonavir Boosting on the Brain Permeation of Darunavir in HIV-infected Individuals
Official title: Effect of Cobicistat Versus Ritonavir Boosting on the Brain Permeation of Darunavir in HIV-infected Individuals
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE4
Conditions: AIDS-related Dementia Complex
Keywords: HIV
darunavir
ritonavir
cobicistat
CSF
pharmacokinetics
Lead sponsor: University Hospital, Basel, Switzerland
Sponsor class: OTHER
First posted: 2015-07-21
Enrollment: 7
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Cerebrospinal fluid/plasma concentrations (ng/ml) of darunavir/ritonavir versus darunavir/cobicistat
timeFrame: 1 month
Secondary outcomes:
measure: Cerebrospinal fluid concentrations (ng/ml) of darunavir/ritonavir versus darunavir/cobicistat relative to the concentration of darunavir (ng/ml) inhibiting 50% (IC50) or 90% (IC90) of the viral replication
timeFrame: 1 month
measure: Proportion of responders (HIV RNA < 50 copies/ml in CSF) for darunavir/ritonavir versus darunavir/cobicistat
timeFrame: 1 month
Other outcomes:
Locations:
city: Basel
country: Switzerland
facility: Division of Infectious Diseases, University Hospital Basel
state: BS
Study officials:
affiliation: University Hospital, Basel, Switzerland
name: Manuel Battegay
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.