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

Study Overview
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Brief Summary
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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.

Official Title
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The EFV Central Nervous System Exposure Sub-study of Encore1: A Randomised, Double-blind, Placebo-controlled, Clinical Trial to Compare the Safety and Efficacy of Reduced Dose Efavirenz (EFV) With Standard Dose EFV Plus Two Nucleotide Reverse Transcriptase Inhibitors (N(t)RTI) in Antiretroviral-naïve HIV-infected Individuals Over 96 Weeks

Conditions
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HIV Infection

Intervention / Treatment
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* Drug: Efavirenz
* Drug: Efavirenz


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 16 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Reduced dose Efavirenz arm<br>Patient's on main study that was randomised to receive TDF (300mg qd)/FTC (200mg qd) + EFV (400mg qd; 2 x 200mg + 1 x 200mg placebo qd). | Drug: Efavirenz<br>* 400mg qd; 2 x 200mg<br>|
| Active Comparator: Normal Efavirenz dose arm<br>Patient's on main study randomised to receive tenofovir (TDF) (300mg qd)/emtricitabine (FTC) (200mg qd) + EFV (600mg qd; 3 x 200mg qd) | Drug: Efavirenz<br>* 600mg qd; 3 x 200mg qd<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 24 weeks | 
| The relationship between CSF EFV exposure and neuropsychiatric side effects using questionnaires and medical assessments |  | 24 weeks | 
| The relationship between CSF EFV exposure and other study parameters such as race and sex. |  | 24 weeks | 
| The number of subjects with EFV CSF exposure greater than the postulated CSF IC50 for wild type virus (0.51ng/mL) |  | 24 weeks | 
| CSF HIV RNA measurement after 12 - 24 weeks of study therapy |  | 24 weeks | 
| Relationship between plasma HIV RNA and CSF HIV RNA |  | 24 weeks | 
| CSF biomarker analysis after 12 - 24 weeks of study therapy |  | 24 weeks | 
| comparison between magnetic resonance (MR) spectroscopy findings and CSF HIV RNA and EFV concentration |  | 24 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV, Efavirenz, Central Nervous System (CNS), Lumbar puncture, Dose reduction