Doravirine Concentrations and Antiviral Activity in Cerebrospinal Fluid in HIV-1 Infected Individuals

Study Overview
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Brief Summary
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Doravirine is a new HIV-1 non-nucleoside reverse transcriptase inhibitor (NNRTI) that has demonstrated a good efficacy and safety profile in clinical trials. It functions by inhibiting viral replication of both wild-type virus and most common NNRTI variants. It is dosed orally once daily and always given in combination with other HIV-1 active agents as part of highly active antiretroviral therapy. Initial pharmacokinetic studies demonstrated not extensive binding to plasma proteins, which may be crucial determinant for penetration to different reservoirs such as the central nervous system (CNS). This study will address two important issues: The pharmacokinetic profile of Doravirine in cerebrospinal fluid (CSF) as well as the maintenance of HIV suppression in CSF. The assessment of concentrations as well as the antiviral activity of new antiretroviral drugs in compartments such as CNS is relevant to avoid HIV-related neurocognitive disorders as well as for future cure strategies. In addition, the role of unbound ARV drug concentrations has been scarcely evaluated.

Detailed Description
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15 asymptomatic, virologically suppressed, HIV infected patients will be offered to switch their antiretroviral treatment to Doravirine+Emtricitabine/TAF. After 4 weeks of treatment all subjects will undergo lumbar puncture and bloods in order to assess CSF and plasma (total and unbound) Doravirine concentrations. HIV RNA also will be assessed. All subjects will complete a follow up visit 4 weeks after

Official Title
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Doravirine Concentrations and Antiviral Activity in Cerebrospinal Fluid in HIV-1 Infected Individuals

Conditions
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HIV-1-infection

Intervention / Treatment
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* Drug: Doravirine
* Drug: Descovy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Asymptomatic, HIV-1 infected individuals ≥ 18 years of age Be on a stable ART continously or ≥3 consecutive months preceding the screening visit. Patients already receiving TAF/FTC+DoravirineC for at least three consecutive months will be eligible. Plasma HIV-1 RNA at screening <40 copies/mL for at least 3 months at the Screening visit. Signed and dated written informed consent prior to inclusion. Subjects must agree to utilize a highly effective method of contraception during heterosexual intercourse from the screening visit throughout the duration of the study. Exclusion Criteria: Severe hepatic impairment (Child-Pugh Class C) Ongoing malignancy Active opportunistic infection Primary resistance to any of the ARV included in the study or history of virologic failure with risk of resistance selection to any of the study drugs. Any verified Grade 4 laboratory abnormality ALT or AST ≥ 3xULN and/or bilirubin ≥ 1.5xULN Adequate renal function: Estimated glomerular filtration rate ≥ 50 mL/min Females who are pregnant (as confirmed by positive serum pregnancy test) or breastfeeding. Current treatment with antiaggregant or anticoagulant therapy. History of any neurologic disease/condition/treatment may alter the blood brain barrier permeability.

Ages Eligible for Study
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Minimum Age: 18 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Doravirine + Descovy® TAF/FTC<br>Doravirine (MK-1439) 100 mg administered orally once daily in combination with Tenofovir alafenamide (TAF) and emtricitabine (FTC) coformulated as single tablet (Descovy® TAF/FTC 25/200 mg) and administered orally once daily during 4 weeks | Drug: Doravirine<br>* Doravirine 100 mg tablet<br>* Other names: MK-1439;Drug: Descovy<br>* Tenofovir alafenamide 25 mg / emtricitabine 200 mg tablet<br>* Other names: TAF/FTC;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total Doravirine Concentrations in Cerebrospinal Fluid | Total Doravirine concentrations in cerebrospinal fluid in HIV-1 infected individual receiving ART with Doravirine+FTC/TAF | 4 Weeks | 
| Total Doravirine Concentrations in Blood Plasma | Total Doravirine concentrations in blood plasma | 4 Weeks | 
| Total Doravirine Concentration CSF/Plasma Ratio | total Doravirine CSF/plasma ratio | 4 Weeks | 
| HIV-1 RNA in Cerebrospinal Fluid | Number of patients with HIV-1 RNA cerebrospinal fluid <40 copies/ml | 4 Weeks | 
| HIV-1 RNA in Blood Plasma | Number of patients with HIV-1 RNA in blood plasma <40 copies/ml | 4 Weeks | 
| Unbound Doravirine Concentrations in CSF | Unbound Doravirine concentrations in cerebrospinal fluid in HIV-1 infected individual receiving ART with Doravirine+FTC/TAF | 4 Weeks | 
| Doravirine Concentrations in Blood Plasma | Unbound Doravirine concentrations in blood plasma | 4 Weeks | 
| Unbound Doravirine Concentration CSF/Plasma Ratio | Unbound Doravirine CSF/plasma ratio | 4 Weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Doravirine