HIV Infections
Conditions
Keywords
Pre-exposure Prophylaxis, HIV, Kenya, Descovy
Brief summary
The study seeks to assess the safety of and define blood and tissue benchmark concentrations of tenofovir diphosphate (TFV-DP) and emtricitabine triphosphate (FTC-TP) in cisgender women using directly observed oral pre-exposure prophylaxis (PrEP) therapy with tenofovir alafenamide-emtricitabine (TAF-FTC). Cisgender women will be randomly assigned to receive varying frequencies of weekly PrEP doses and followed for up to 18 weeks.These data will help accurate interpretation of efficacy results obtained in HIV prevention trials and programs in cisgender women.
Detailed description
This is an open-label, randomized, three-arm, directly observed therapy (DOT), pharmacokinetics study. HIV-uninfected non-pregnant cisgender women at low risk for HIV acquisition will be randomly assigned to 1 of 3 dosing frequencies of DOT with tenofovir alafenamide-emtricitabine (TAF-FTC) oral PrEP, to help differentiate poor and moderate from perfect adherence. The primary objectives of the study are: 1. To describe the safety of TAF-FTC-based PrEP in HIV-uninfected cisgender women. 2. To define expected blood concentrations and dose-proportionality specific to cisgender women for tenofovir-diphosphate (TFV-DP) in dried blood spots (DBS) and peripheral blood mononuclear cells (PBMCs) using directly observed therapy of TAF-FTC at 2, 4, and 7 doses per week, representing poor, moderate, and perfect adherence, respectively. 3. To establish a model to predict adherence rate to TAF-FTC by level of TFV-DP in DBS for cisgender women. HIV-uninfected non-pregnant cisgender women will be randomly assigned to 1 of 3 dosing frequencies of directly observed therapy of TAF-FTC oral PrEP: 2, 4, or 7 doses/week to differentiate poor and moderate from perfect adherence. The study will be the first to define TAF-FTC-based PrEP adherence-blood concentration thresholds for African cisgender women, a priority population for HIV prevention. The findings will guide accurate interpretation of safety, adherence, and efficacy of planned or ongoing HIV prevention trials in African women.
Interventions
DRUGco-formulated 25mg TAF/ 200mg FTC
Participants will be randomized into 1 of 3 groups to receive a controlled number of doses of a single tablet of co-formulated 25 mg TAF/ 200mg FTC
Sponsors
University of Washington
Kenya Medical Research Institute
University of Colorado, Denver
Gilead Sciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 30 Years
Healthy volunteers
Yes
Inclusion criteria
* Age ≥18 and ≤30 years old * Willing to undergo urine pregnancy tests * Has understood the information provided and has provided written informed consent before any study-related procedures are performed. * HIV uninfected based on negative HIV rapid tests, according to Kenyan national algorithm * Normal renal function (estimated glomerular filtration rate \>60 mL/min) * Hepatitis B surface Ag negative * No active clinically significant medical or psychiatric conditions that, in the opinion of the investigators, would interfere with study participation * Lack of severe anemia (Hemoglobin \>10 g/dL) * Willing to use DOT and come to clinic frequently for DOT PrEP for at least 10 weeks * Willing to have home visits for follow up * Has access to an active smartphone to allow off-site observation of dosing if unable to come to the clinic or as determined by the study staff, the participant resides in close location to clinic to permit home visit if unable to come to the clinic. i.e., potential participants without a smartphone may be enrolled in the study if investigator determines that the participant resides within reasonable distance from the clinic that would permit home visit id the participant misses their visit. * Intention to stay within the study site's catchment area for at least 10 weeks. * Resides or works in catchment area with high speed internet coverage to permit video streaming * Not pregnant or breast feeding * Willing to use effective contraception during the study period. * At low risk for HIV. In Kenya, national guidelines define substantial risk for HIV and recommend PrEP be an option for individuals reporting: partner of HIV-infected person not on ART or on ART for \<6 months, \>1 partner of unknown status, transactional sex, recent STI, recurrent PEP use, inconsistent condom use, or injection drug use. So, non-pregnant cisgender women reporting any of these factors will not be eligible for the study but will be linked for PrEP at clinic of choice including at Thika Site itself. * Willing to be randomized to non-daily PrEP and come to clinic frequently for DOT PrEP * Willingness and ability to be abstinent for at least 7 days after each vaginal biopsy visit.
Exclusion criteria
* Inability to give informed consent * Positive screening HIV+ as determined by standard rapid serologic assays or suspected acute HIV infection in the opinion of the clinician. (example signs and symptoms of acute HIV infection include combinations of fever, headache, fatigue, arthralgia, vomiting, myalgia, diarrhea, pharyngitis, rash, night sweats, and adenopathy cervical or inguinal) * Positive HBV surface antigen test at screening * Calculated creatinine clearance \<60 ml/min. * Any laboratory value or uncontrolled medical conditions that, in the opinion of the investigators, would interfere with the study conditions such as, heart disease and/or cancer. * Prohibited concomitant medications are: investigational agents (within 30 days of enrollment), aminoglycosides, ganciclovir/valganciclovir, chronic high-dose acyclovir/valacyclovir (\>800mg acyclovir or \>500mg valacyclovir for \>7 days), cyclosporine, amphotericin B, foscarnet, and cidofovir, and products with same or similar active ingredients as the study medications including TAF®, TRUVADA®, ATRIPLA®, COMPLERA®, EMTRIVA®, VIREAD®; or drugs containing lamivudine or adefovir, which are close analogs of FTC and tenofovir, respectively. * Current or past use of PrEP (pre-exposure prophylaxis) * Not willing to have home visits * Pregnancy or plan to become pregnant in the next 6 months or unwillingness to use birth control * Current breastfeeding * High risk of HIV infection (for example: sexually active with an HIV infected partner; engages in condomless intercourse with HIV-infected partners or partner of unknown status during the study; females who exchange sex for money, shelter, or gifts; active injection drug use or during the last 12 months; newly diagnosed sexually transmitted infections in last 6 months.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Frequency of Adverse Events | Assessed through the 10 week DOT dosing period | The frequency of graded adverse events by arm, including emergent HIV infection during the study period. |
| Concentrations of Tenofovir Disphosphate (TFV-DP) and Emtricitabine Triphosphate (FTC-TP) Measured at Ten Weeks in Dried Blood Spots (DBS) | Assessed at week 10 | TFV-DP and FTC-TP concentrations observed in dried blood spots (DBS) after ten weeks of directly observed therapy with TAF-FTC oral PrEP, in women randomized to receive 2, 4, or 7 doses per week, representing poor, moderate, or perfect adherence, respectively. |
| Concentrations of Tenofovir Disphosphate (TFV-DP) and Emtricitabine Triphosphate (FTC-TP) Measured at Four Weeks in Peripheral Blood Mononuclear Cells (PBMCs) | Assessed at week 4 | Steady-state TFV-DP and FTC-TP concentrations observed in peripheral blood mononuclear cells (PBMCs) after ten weeks of directly observed therapy with TAF-FTC oral PrEP, in women randomized to receive 2, 4, or 7 doses per week, representing poor, moderate, or perfect adherence, respectively. |
| Fitted Steady-state TFV-DP Concentrations in Dried Blood Spots (DBS) | Assessed through 10 weeks | Fitted steady-state TFV-DP concentrations after ten weeks of directly observed therapy with TAF-FTC oral PrEP, in women randomized to receive 2, 4, or 7 doses per week, representing poor, moderate, or perfect adherence, respectively. |
Countries
Kenya
Contacts
PRINCIPAL_INVESTIGATORKenneth K Mugwanya, MBChB, MS, PhD
University of Washington
PRINCIPAL_INVESTIGATORPeter L Anderson, PharmD
University of Colorado, Denver
Participant flow
Recruitment details
Seventy-one women were screened for study participation starting 28 March 2023 to 11 September 2023 at the Kenya Medical Research Institute, Center for Clinical Research, Thika site in Kenya. The Of these, 54 healthy volunteer women ages 18-30 at low risk of HIV acquisition were enrolled into the study and randomized. The first participant was randomized on 10 April 2023.
Participants by arm
| Arm | Count |
|---|---|
| Poor Adherence Cisgender women will receive a single tablet of coformulated 25 mg TAF/ 200mg FTC twice per week | 18 |
| Moderate Adherence Cisgender women will receive a single tablet of coformulated 25 mg TAF/ 200mg FTC 4 times per week | 18 |
| Perfect Adherence Cisgender women will receive a single tablet of coformulated 25 mg TAF/ 200mg FTC once daily (7 doses per week) | 18 |
| Total | 54 |
Baseline characteristics
| Characteristic | Moderate Adherence | Perfect Adherence | Total | Poor Adherence |
|---|---|---|---|---|
| Age, Customized Median age | 24.5 years | 23 years | 23 years | 22 years |
| Race and Ethnicity Not Collected | — | — | 0 Participants | — |
| Region of Enrollment Kenya | 18 participants | 18 participants | 54 participants | 18 participants |
| Sex: Female, Male Female | 18 Participants | 18 Participants | 54 Participants | 18 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 18 | 0 / 18 | 0 / 18 |
| other Total, other adverse events | 17 / 18 | 17 / 18 | 17 / 18 |
| serious Total, serious adverse events | 0 / 18 | 0 / 18 | 0 / 18 |
Outcome results
Primary
Concentrations of Tenofovir Disphosphate (TFV-DP) and Emtricitabine Triphosphate (FTC-TP) Measured at Four Weeks in Peripheral Blood Mononuclear Cells (PBMCs)
Steady-state TFV-DP and FTC-TP concentrations observed in peripheral blood mononuclear cells (PBMCs) after ten weeks of directly observed therapy with TAF-FTC oral PrEP, in women randomized to receive 2, 4, or 7 doses per week, representing poor, moderate, or perfect adherence, respectively.
Time frame: Assessed at week 4
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Poor Adherence | Concentrations of Tenofovir Disphosphate (TFV-DP) and Emtricitabine Triphosphate (FTC-TP) Measured at Four Weeks in Peripheral Blood Mononuclear Cells (PBMCs) | Observed TFV-DP concentrations | 70 fmol/10^6 cells |
| Poor Adherence | Concentrations of Tenofovir Disphosphate (TFV-DP) and Emtricitabine Triphosphate (FTC-TP) Measured at Four Weeks in Peripheral Blood Mononuclear Cells (PBMCs) | Observed FTC-TP concentrations | 407 fmol/10^6 cells |
| Moderate Adherence | Concentrations of Tenofovir Disphosphate (TFV-DP) and Emtricitabine Triphosphate (FTC-TP) Measured at Four Weeks in Peripheral Blood Mononuclear Cells (PBMCs) | Observed TFV-DP concentrations | 229 fmol/10^6 cells |
| Moderate Adherence | Concentrations of Tenofovir Disphosphate (TFV-DP) and Emtricitabine Triphosphate (FTC-TP) Measured at Four Weeks in Peripheral Blood Mononuclear Cells (PBMCs) | Observed FTC-TP concentrations | 1859 fmol/10^6 cells |
| Perfect Adherence | Concentrations of Tenofovir Disphosphate (TFV-DP) and Emtricitabine Triphosphate (FTC-TP) Measured at Four Weeks in Peripheral Blood Mononuclear Cells (PBMCs) | Observed TFV-DP concentrations | 680 fmol/10^6 cells |
| Perfect Adherence | Concentrations of Tenofovir Disphosphate (TFV-DP) and Emtricitabine Triphosphate (FTC-TP) Measured at Four Weeks in Peripheral Blood Mononuclear Cells (PBMCs) | Observed FTC-TP concentrations | 6402 fmol/10^6 cells |
Primary
Concentrations of Tenofovir Disphosphate (TFV-DP) and Emtricitabine Triphosphate (FTC-TP) Measured at Ten Weeks in Dried Blood Spots (DBS)
TFV-DP and FTC-TP concentrations observed in dried blood spots (DBS) after ten weeks of directly observed therapy with TAF-FTC oral PrEP, in women randomized to receive 2, 4, or 7 doses per week, representing poor, moderate, or perfect adherence, respectively.
Time frame: Assessed at week 10
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Poor Adherence | Concentrations of Tenofovir Disphosphate (TFV-DP) and Emtricitabine Triphosphate (FTC-TP) Measured at Ten Weeks in Dried Blood Spots (DBS) | Observed TFV-DP concentrations | 432 fmol/punches |
| Poor Adherence | Concentrations of Tenofovir Disphosphate (TFV-DP) and Emtricitabine Triphosphate (FTC-TP) Measured at Ten Weeks in Dried Blood Spots (DBS) | Observed FTC-TP concentrations | 261 fmol/punches |
| Moderate Adherence | Concentrations of Tenofovir Disphosphate (TFV-DP) and Emtricitabine Triphosphate (FTC-TP) Measured at Ten Weeks in Dried Blood Spots (DBS) | Observed TFV-DP concentrations | 1214 fmol/punches |
| Moderate Adherence | Concentrations of Tenofovir Disphosphate (TFV-DP) and Emtricitabine Triphosphate (FTC-TP) Measured at Ten Weeks in Dried Blood Spots (DBS) | Observed FTC-TP concentrations | 976 fmol/punches |
| Perfect Adherence | Concentrations of Tenofovir Disphosphate (TFV-DP) and Emtricitabine Triphosphate (FTC-TP) Measured at Ten Weeks in Dried Blood Spots (DBS) | Observed TFV-DP concentrations | 2345 fmol/punches |
| Perfect Adherence | Concentrations of Tenofovir Disphosphate (TFV-DP) and Emtricitabine Triphosphate (FTC-TP) Measured at Ten Weeks in Dried Blood Spots (DBS) | Observed FTC-TP concentrations | 4031 fmol/punches |
Primary
Fitted Steady-state TFV-DP Concentrations in Dried Blood Spots (DBS)
Fitted steady-state TFV-DP concentrations after ten weeks of directly observed therapy with TAF-FTC oral PrEP, in women randomized to receive 2, 4, or 7 doses per week, representing poor, moderate, or perfect adherence, respectively.
Time frame: Assessed through 10 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Poor Adherence | Fitted Steady-state TFV-DP Concentrations in Dried Blood Spots (DBS) | 468 fmol/punch |
| Moderate Adherence | Fitted Steady-state TFV-DP Concentrations in Dried Blood Spots (DBS) | 1010 fmol/punch |
| Perfect Adherence | Fitted Steady-state TFV-DP Concentrations in Dried Blood Spots (DBS) | 2355 fmol/punch |
Primary
Frequency of Adverse Events
The frequency of graded adverse events by arm, including emergent HIV infection during the study period.
Time frame: Assessed through the 10 week DOT dosing period
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Poor Adherence | Frequency of Adverse Events | Emergent HIV infection | 0 Number of adverse events |
| Poor Adherence | Frequency of Adverse Events | Grade 3 or higher adverse events | 0 Number of adverse events |
| Poor Adherence | Frequency of Adverse Events | Grade 2 adverse events | 1 Number of adverse events |
| Poor Adherence | Frequency of Adverse Events | Grade 1 adverse events | 69 Number of adverse events |
| Moderate Adherence | Frequency of Adverse Events | Grade 3 or higher adverse events | 0 Number of adverse events |
| Moderate Adherence | Frequency of Adverse Events | Grade 2 adverse events | 1 Number of adverse events |
| Moderate Adherence | Frequency of Adverse Events | Grade 1 adverse events | 60 Number of adverse events |
| Moderate Adherence | Frequency of Adverse Events | Emergent HIV infection | 0 Number of adverse events |
| Perfect Adherence | Frequency of Adverse Events | Grade 2 adverse events | 0 Number of adverse events |
| Perfect Adherence | Frequency of Adverse Events | Grade 1 adverse events | 62 Number of adverse events |
| Perfect Adherence | Frequency of Adverse Events | Emergent HIV infection | 0 Number of adverse events |
| Perfect Adherence | Frequency of Adverse Events | Grade 3 or higher adverse events | 0 Number of adverse events |