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

Phase 3

Completed

• Conditions: HIV-1-infection
• Interventions: Drug: Doravirine; Drug: Descovy

• Registration Number: NCT04079452
• Lead Sponsor: Fundación FLS de Lucha Contra el Sida, las Enfermedades Infecciosas y la Promoción de la Salud y la Ciencia

Brief Summary

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

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 Timeline

• Study First Submitted: 2019-09-03
• Study First Submitted QC: 2019-09-03
• Study First Posted: 2019-09-06
• Study Start: 2020-02-18
• Primary Completion: 2020-08-31
• Study Completion: 2020-08-31
• Results First Submitted: 2022-02-27
• Status Verified: 2022-04
• Results First Submitted QC: 2022-04-27
• Last Update Submitted: 2022-04-27
• Results First Posted: 2022-04-28
• Last Update Posted: 2022-04-28

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 15

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Doravirine + Descovy® TAF/FTC	Descovy	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
Doravirine + Descovy® TAF/FTC	Doravirine	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

Primary Outcome Measures

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

Trial Locations

Locations (1)

Hospital Universitari de Bellvitge; 🇪🇸 L'Hospitalet De Llobregat, Barcelona, Spain