AIDS-related Dementia Complex
Conditions
Keywords
HIV, darunavir, ritonavir, cobicistat, CSF, pharmacokinetics
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.
Interventions
DRUGDarunavir
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).
DRUGritonavir
ritonavir 100 mg once daily will be used to boost darunavir 800 mg once daily (period 1).
DRUGcobicistat
cobicistat 150 mg once daily will be used to boost darunavir 800 mg once daily (period 2).
Sponsors
University Hospital, Basel, Switzerland
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cerebrospinal fluid/plasma concentrations (ng/ml) of darunavir/ritonavir versus darunavir/cobicistat | 1 month | darunavir concentrations (ng/ml) in the cerebrospinal fluid when coadministered with ritonavir versus cobicistat relative to the corresponding concentrations of darunavir in the plasma |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | 1 month | darunavir concentrations (ng/ml) in the cerebrospinal fluid when coadministered with ritonavir versus cobicistat relative to darunavir concentrations (ng/ml) suppressing HIV replication by 50% and 90% (IC50 and IC90) |
| Proportion of responders (HIV RNA < 50 copies/ml in CSF) for darunavir/ritonavir versus darunavir/cobicistat | 1 month | — |
Countries
Switzerland
Outcome results
None listed