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

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.

Study Overview

• Status: Completed
• Conditions: HIV-1-infection
• Intervention / Treatment: Drug: Doravirine; Drug: Descovy

Detailed Description

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

• Study Type: Interventional
• Enrollment (Actual): 15
• Phase: Phase 3

Contacts and Locations

Study Locations

• Spain
  • Barcelona
    • L'Hospitalet De Llobregat, Barcelona, Spain, 08907
      • Hospital Universitari de Bellvitge

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Asymptomatic, HIV-1 infected individuals ≥ 18 years of age
2. 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.
3. Plasma HIV-1 RNA at screening <40 copies/mL for at least 3 months at the Screening visit.
4. Signed and dated written informed consent prior to inclusion.
5. 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:

1. Severe hepatic impairment (Child-Pugh Class C)
2. Ongoing malignancy
3. Active opportunistic infection
4. 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.
5. Any verified Grade 4 laboratory abnormality
6. ALT or AST ≥ 3xULN and/or bilirubin ≥ 1.5xULN
7. Adequate renal function: Estimated glomerular filtration rate ≥ 50 mL/min
8. Females who are pregnant (as confirmed by positive serum pregnancy test) or breastfeeding.
9. Current treatment with antiaggregant or anticoagulant therapy.
10. History of any neurologic disease/condition/treatment may alter the blood brain barrier permeability.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Doravirine + Descovy® TAF/FTC; 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; Doravirine 100 mg tablet; Other Names: MK-1439; Drug: Descovy; Tenofovir alafenamide 25 mg / emtricitabine 200 mg tablet; Other Names: TAF/FTC

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Fundación FLS de Lucha Contra el Sida, las Enfermedades Infecciosas y la Promoción de la Salud y la Ciencia
• Collaborators: Institut d'Investigació Biomèdica de Bellvitge; Hospital Universitari de Bellvitge
• Investigators: Principal Investigator: Daniel Podzamczer, PhD Chief, Hospital Universitari de Bellvitge

Study record dates

Study Major Dates

• Study Start (Actual): February 18, 2020
• Primary Completion (Actual): August 31, 2020
• Study Completion (Actual): August 31, 2020

Study Registration Dates

• First Submitted: September 3, 2019
• First Submitted That Met QC Criteria: September 3, 2019
• First Posted (Actual): September 6, 2019

Study Record Updates

• Last Update Posted (Actual): April 28, 2022
• Last Update Submitted That Met QC Criteria: April 27, 2022
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Keywords: Doravirine
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Emtricitabine tenofovir alafenamide
• Other Study ID Numbers: DORACeNeS; 2018-003915-24 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No