HIV-1-infection
Conditions
Keywords
Doravirine
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
Interventions
DRUGDoravirine
Doravirine 100 mg tablet
DRUGDescovy
Tenofovir alafenamide 25 mg / emtricitabine 200 mg tablet
Sponsors
Institut d'Investigació Biomèdica de Bellvitge
Hospital Universitari de Bellvitge
Fundación FLS de Lucha Contra el Sida, las Enfermedades Infecciosas y la Promoción de la Salud y la Ciencia
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| HIV-1 RNA in Blood Plasma | 4 Weeks | Number of patients with HIV-1 RNA in blood plasma \<40 copies/ml |
| 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 |
| 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 |
Countries
Spain
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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
Doravirine: Doravirine 100 mg tablet
Descovy: Tenofovir alafenamide 25 mg / emtricitabine 200 mg tablet | 15 |
| Total | 15 |
Baseline characteristics
| Characteristic | Doravirine + Descovy® TAF/FTC |
|---|---|
| Age, Continuous | 47 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 15 Participants |
| Region of Enrollment Spain | 15 participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 15 |
| other Total, other adverse events | 1 / 15 |
| serious Total, serious adverse events | 0 / 15 |
Outcome results
Primary
Doravirine Concentrations in Blood Plasma
Unbound Doravirine concentrations in blood plasma
Time frame: 4 Weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Doravirine+TAF/FTC Arm (Single Arm) | Doravirine Concentrations in Blood Plasma | 53.5 CSF Unbound DORAVIRINE conc. ng/ml |
Primary
HIV-1 RNA in Blood Plasma
Number of patients with HIV-1 RNA in blood plasma \<40 copies/ml
Time frame: 4 Weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Doravirine+TAF/FTC Arm (Single Arm) | HIV-1 RNA in Blood Plasma | 14 Participants |
Primary
HIV-1 RNA in Cerebrospinal Fluid
Number of patients with HIV-1 RNA cerebrospinal fluid \<40 copies/ml
Time frame: 4 Weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Doravirine+TAF/FTC Arm (Single Arm) | HIV-1 RNA in Cerebrospinal Fluid | 13 Participants |
Primary
Total Doravirine Concentration CSF/Plasma Ratio
total Doravirine CSF/plasma ratio
Time frame: 4 Weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Doravirine+TAF/FTC Arm (Single Arm) | Total Doravirine Concentration CSF/Plasma Ratio | 0.13 ratio |
Primary
Total Doravirine Concentrations in Blood Plasma
Total Doravirine concentrations in blood plasma
Time frame: 4 Weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Doravirine+TAF/FTC Arm (Single Arm) | Total Doravirine Concentrations in Blood Plasma | 417.6 ng/ml |
Primary
Total Doravirine Concentrations in Cerebrospinal Fluid
Total Doravirine concentrations in cerebrospinal fluid in HIV-1 infected individual receiving ART with Doravirine+FTC/TAF
Time frame: 4 Weeks
Population: Descriptive analysis was performed for all participants (15), defining median and IQR of Doravirine concentrations in CSF
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Doravirine+TAF/FTC Arm (Single Arm) | Total Doravirine Concentrations in Cerebrospinal Fluid | 58.6 ng/ml |
Primary
Unbound Doravirine Concentration CSF/Plasma Ratio
Unbound Doravirine CSF/plasma ratio
Time frame: 4 Weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Doravirine+TAF/FTC Arm (Single Arm) | Unbound Doravirine Concentration CSF/Plasma Ratio | 0.99 ratio |
Primary
Unbound Doravirine Concentrations in CSF
Unbound Doravirine concentrations in cerebrospinal fluid in HIV-1 infected individual receiving ART with Doravirine+FTC/TAF
Time frame: 4 Weeks
Population: Descriptive analysis was performed for all participants (15), defining median and IQR of Doravirine concentrations in CSF
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Doravirine+TAF/FTC Arm (Single Arm) | Unbound Doravirine Concentrations in CSF | 44.6 ng/ml |