The Efavirenz (EFV) Central Nervous System Exposure Sub-study of Encore1

Kirby Institute32 enrolled

Overview

Persistent HIV infection in the central nervous system (CNS) compartment may put subjects at risk of developing HIV-related brain disease. Important factors associated with the development of HIV-related brain disease include therapeutic concentrations of antiretroviral drugs in the CNS. Conflicting evidence regarding the CNS exposure of the antiretroviral drug used for the encore1 study, efavirenz (EFV) have been described in related studies. There were recent study of two small series assessment of EFV exposure in the cerebral spinal fluid (CSF); one group reported small detectable EFV concentrations, while another observed undetectable EFV exposure in the CSF. Also, in a larger reported series comprising of 80 subjects on EFV-containing antiretroviral therapy, a CSF to plasma concentration suggested that there is limited movement of EFV out of the CSF. In HIV-1 infected subjects at steady state, EFV plasma level parameters are dose proportional following 200mg, 400mg, and 600mg daily doses. The CNS exposure of EFV at different daily dosing has not been described.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Enrollment

Conditions

HIV Infection

Interventions

Eligibility

Sex: ALLMin age: 16 Years

Medical Language ↔ Plain English

Inclusion Criteria: * All subjects entering into the main study protocol at participating centres will be eligible to enter this sub-study. Exclusion Criteria: * Existing neurological disease which in the opinion of the investigator would be a contra-indication to lumbar puncture examination * CNS opportunistic infections in the past 12 weeks of randomisation * Bacterial or viral meningitis in the past 12 weeks of randomisation * Head injury requiring medical assessment in the past 12 weeks of randomisation

Locations (5)

Medical Group Practice

Berlin, State of Berlin, Germany

HIVNAT Research Collaboration

Patumwan, Bangkok, Thailand

Khon Kaen University

Khon Kaen, Changwat Khon Kaen, Thailand

Imperial College, St. Mary's Hospital

Clinical Trials Centre, Winston Churchil Wing, London, United Kingdom

Chelsea and Westminster Hospital

Hiv/gum Laboratory 5th Floor Saint Stephen Centre, London, United Kingdom

Outcomes

Primary Outcomes

comparison of mean CSF concentration of EFV from both doses after week 24.

measure the CSF exposure of EFV when dosed at 400mg and 600mg daily. Efavirenz plasma and CSF concentrations will be analysed and CSF:plasma ratios will be compared. Associations between plasma and CSF concentrations and relationship to study clinical parameters will be assessed.

Time frame: 24 weeks

Secondary Outcomes

CSF EFV exposure and plasma exposure (CSF:plasma ratio) using statistical analysis

The relationship between CSF EFV exposure and plasma exposure (CSF:plasma ratio), both for protein bound and free plasma EFV exposure.

Time frame: 24 weeks

The relationship between CSF EFV exposure and neuropsychiatric side effects using questionnaires and medical assessments

Time frame: 24 weeks

The relationship between CSF EFV exposure and other study parameters such as race and sex.

Time frame: 24 weeks

The number of subjects with EFV CSF exposure greater than the postulated CSF IC50 for wild type virus (0.51ng/mL)

Time frame: 24 weeks

CSF HIV RNA measurement after 12 - 24 weeks of study therapy

Time frame: 24 weeks

Relationship between plasma HIV RNA and CSF HIV RNA

Time frame: 24 weeks

CSF biomarker analysis after 12 - 24 weeks of study therapy

Time frame: 24 weeks

comparison between magnetic resonance (MR) spectroscopy findings and CSF HIV RNA and EFV concentration

Time frame: 24 weeks