ART, HIV
Conditions
Keywords
PrEP, PEP, MSM, Short-course regimen, Pharmacokinetics
Brief summary
The study seeks to understand how anti-HIV drug Biktarvy, which contains the drugs tenofovir alafenamide (TAF), emtricitabine (FTC), and bictegravir (BIC) is absorbed and how long it persists in different body compartments, including mucosal tissues, as it may be considered for PrEP or PEP regimens in the future.
Detailed description
Men who have sex with men (MSM) continue to be disproportionately affected by HIV. The majority of MSM acquire HIV after exposure to the rectal mucosa through receptive anal intercourse without condoms. Pre-exposure prophylaxis (PrEP) and post-exposure prophylaxis (PEP) are recommended for MSM who may be exposed to HIV to prevent infection. Current recommendations for PrEP are to take the combination anti-HIV drug, tenofovir+emtricitabine (TDF/FTC), on a daily basis for the duration of someone's HIV risk exposure period, which could be months or years. For PEP, a three-drug anti-HIV medication is recommended within 72 hours of a possible exposure for a 28-day course. While PrEP and PEP are effective, some people find it difficult to follow the recommended regimen. Therefore, additional short-course dosing regimens for PrEP and PEP are being considered for future development. The study drug provided in this study will not protect participants from HIV or treat any active infection. This proposal seeks to understand how other anti-HIV medications are absorbed and how long they persist in different body compartments, including mucosal tissues, as they may be considered for PrEP or PEP regimens in the future. Participants will be sequentially enrolled into study arms. All participants will take two doses of Biktarvy and then will have biological samples collected at different time points. Blood will be collected at three different time points and a rectal biopsy will occur once. Participants may participate in more than one study arm or subgroup; however, at least 6 weeks must lapse after completion of one study arm or subgroup, before entry into another. Median drug levels of TAF, FTC, and BIC in plasma, peripheral blood mononuclear cells (PBMCs) and rectal tissues will be calculated at baseline, 24 hours after the first dose and 120 hours after the first dose as the primary outcomes of this study. Samples collected at other time points will be stored for future exploratory analyses.
Interventions
DRUGBiktarvy
Participants will be given two doses of the oral fixed dose combination anti-HIV medication Biktarvy (BIC/FTC/TAF) separated by 24 hours. The first dose is given in the clinic and participants are instructed to take the second dose at home, 24 hours after the first dose.
Sponsors
Emory University
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to 49 Years
Healthy volunteers
No
Inclusion criteria
1. HIV-negative man who reports receptive anal sex with another man in the last 6 months 2. Aged 18-49 years 3. Not currently taking PrEP and no plans to initiate during study 4. Not currently taking PEP 5. Able to provide informed consent in English 6. No plans for relocation in the next 3 months 7. Willing to undergo peripheral blood, penile swabs, urine, and rectal biopsy sampling 8. Willing to use study products as directed 9. Willing to abstain from receptive anal intercourse 3 days prior to starting study product and for the duration of the study and for 7 days after any rectal biopsy procedure. 10. Hepatitis B surface antigen (HBsAg) must be negative (screening lab test) 11. Creatine clearance \>60 ml/min
Exclusion criteria
1. History of inflammatory bowel disease or other inflammatory, infiltrative, infectious or vascular condition involving the lower gastrointestinal tract that, in the judgment of the investigators, may be worsened by study procedures or may significantly distort the anatomy of the distal large bowel 2. Currently infected with hepatitis virus and/ or have liver disease 3. Current or chronic history of kidney disease 4. Significant laboratory abnormalities at baseline visit, including but not limited to: 1. Hgb ≤ 10 g/dL 2. partial thromboplastin time (PTT) \> 1.5x upper limit of normal (ULN) or international normalized ratio (INR) \> 1.5x ULN 3. Platelet count \<100,000 4. Creatinine clearance \<60 5. HBsAg reactive 5. Any known medical condition that, in the judgment of the investigators, increases the risk of local or systemic complications of endoscopic procedures or pelvic examination, including but not limited to: 1. Uncontrolled or severe cardiac arrhythmia 2. Recent major abdominal, cardiothoracic, or neurological surgery 3. History of uncontrolled bleeding diathesis 4. History of colonic, rectal, fistula, or malignancy 5. History or evidence on clinical examination of ulcerative, suppurative, or proliferative lesions of the anorectal mucosa, or untreated sexually transmitted disease with mucosal involvement 6. Continued need for, or use during the 14 days prior to enrollment, of the following medications: 1. Aspirin or more than 4 doses of NSAIDs 2. Warfarin, heparin (low-molecular weight or unfractionated), platelet aggregation inhibitors, or fibrinolytic agents 3. Any form of rectally administered agent besides lubricants or douching used for sexual intercourse 7. Continued need for, or use during the 90 days prior to enrollment, of the following medications: 1. Systemic immunomodulatory agents 2. Supraphysiologic doses of steroids (short course steroids less than 7 days duration, allowable at the discretion of the investigators) 3. Experimental medications, vaccines, or biologicals 8. Intent to use HIV antiretroviral pre/post-exposure prophylaxis (PrEP or PEP) during the study, outside of the study procedures 9. Symptoms of an untreated rectal sexually transmitted infection (e.g. rectal pain, discharge, bleeding, etc.) 10. Current use of hormonal therapy 11. Any other clinical condition or prior therapy that, in the opinion of the investigator, would make the patient unsuitable for the study or unable to comply with the study requirements. 12. Participants taking potent inhibitors (e.g. itraconazole, diltiazem) or inducers (e.g. rifampin, phenytoin) of the CYP3A4 enzyme will be excluded from the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Median Drug Levels in Plasma | Baseline (pre-dosing), 24 hours after the first dose, and 120 hours after first dose | Median drug levels of tenofovir (TFV), emtricitabine (FTC), and bictegravir (BIC) in plasma were determined. Concentrations below the limit of quantification (LOQ) are assigned a value of zero. The prespecified outcomes of interest are plasma concentrations of the components of Biktarvy at 24 and 120 hours after the initial dose. All other time points of sample collection are for future exploratory analyses and have not been analyzed. Only the time points of sample collection that were prespecified as primary study outcomes are presented here. |
| Median Drug Concentration in Peripheral Blood Mononuclear Cells (PBMCs) | Baseline (pre-dosing), 24 hours after the first dose, and 120 hours after first dose | Median drug concentrations of tenofovir-diphosphate (TFV-DP) and emtricitabine-triphosphate (FTC-TP) in PBMCs were determined. Concentrations below the limit of quantification (LOQ) are assigned a value of zero. The prespecified outcomes of interest are PBMC concentrations of the components of Biktarvy at 24 and 120 hours after the initial dose. All other time points of sample collection are for future exploratory analyses and have not been analyzed. Only the time points of sample collection that were prespecified as primary study outcomes are presented here. |
| Median Drug Levels in Rectal Tissues | Baseline (pre-dosing), 24 hours after the first dose, and 120 hours after first dose | Median drug levels of TFV, FTC, and BIC in rectal tissue were determined. Concentrations below the limit of quantification (LOQ) are assigned a value of zero. The prespecified outcomes of interest are rectal tissue concentrations of the components of Biktarvy at 24 and 120 hours after the initial dose. All other time points of sample collection are for future exploratory analyses and have not been analyzed. Only the time points of sample collection that were prespecified as primary study outcomes are presented here. |
Countries
United States
Participant flow
Recruitment details
Enrollment began on September 30, 2019 and all follow-up with participants was complete by August 28, 2020. Participants were enrolled at the Hope Clinic in Atlanta, Georgia, USA.
Pre-assignment details
Enrollment began sequentially in Arm A, followed by Arms B and C. Arms A, B, and C were further broken down into two different sub-groups, determining the timing of the rectal biopsy procedure. Enrollment ended prior to enrolling Arm C.2. Participants were able to take part in multiple study arms, with at least 6 weeks after completion of one study arm before beginning another one. In total, 20 participants enrolled. Two individuals participated three times and one individual participated twice.
Participants by arm
| Arm | Count |
|---|---|
| Biktarvy Participants were given two doses of the oral fixed dose combination anti-HIV medication Biktarvy (BIC/FTC/TAF) separated by 24 hours, and had specimens collected at different time points. | 20 |
| Total | 20 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Lost to Follow-up | 1 |
Baseline characteristics
| Characteristic | Biktarvy |
|---|---|
| Age, Continuous | 29.11 years STANDARD_DEVIATION 7.67 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 19 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 15 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 | 4 Participants |
| Region of Enrollment United States | 20 participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 12 | 0 / 8 | 0 / 5 |
| other Total, other adverse events | 0 / 12 | 0 / 8 | 0 / 5 |
| serious Total, serious adverse events | 0 / 12 | 0 / 8 | 0 / 5 |
Outcome results
Primary
Median Drug Concentration in Peripheral Blood Mononuclear Cells (PBMCs)
Median drug concentrations of tenofovir-diphosphate (TFV-DP) and emtricitabine-triphosphate (FTC-TP) in PBMCs were determined. Concentrations below the limit of quantification (LOQ) are assigned a value of zero. The prespecified outcomes of interest are PBMC concentrations of the components of Biktarvy at 24 and 120 hours after the initial dose. All other time points of sample collection are for future exploratory analyses and have not been analyzed. Only the time points of sample collection that were prespecified as primary study outcomes are presented here.
Time frame: Baseline (pre-dosing), 24 hours after the first dose, and 120 hours after first dose
Population: This analysis includes participants with usable samples at the indicated time points. Only the collection times of 24 and 120 hours post-dosing were prespecified for reporting. Technical difficulties precluded the TFV-DP and FTC-TP measures in PBMCs for a large number of samples and therefore, data are not available for all drugs for all participants at these time points.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Sample Collection 2, 48, and 96 Hours After First Dose of Biktarvy | Median Drug Concentration in Peripheral Blood Mononuclear Cells (PBMCs) | TFV-DP at Baseline (pre-dosing) | 0 fmol/10^6 cells |
| Sample Collection 2, 48, and 96 Hours After First Dose of Biktarvy | Median Drug Concentration in Peripheral Blood Mononuclear Cells (PBMCs) | FTC-TP at Baseline (pre-dosing) | 0 fmol/10^6 cells |
| Sample Collection 4, 26, and 120 Hours After First Dose of Biktarvy | Median Drug Concentration in Peripheral Blood Mononuclear Cells (PBMCs) | TFV-DP at Baseline (pre-dosing) | 0 fmol/10^6 cells |
| Sample Collection 4, 26, and 120 Hours After First Dose of Biktarvy | Median Drug Concentration in Peripheral Blood Mononuclear Cells (PBMCs) | TFV-DP at 120 hours after first dose | 189 fmol/10^6 cells |
| Sample Collection 4, 26, and 120 Hours After First Dose of Biktarvy | Median Drug Concentration in Peripheral Blood Mononuclear Cells (PBMCs) | FTC-TP at 120 hours after first dose | 1966 fmol/10^6 cells |
| Sample Collection 4, 26, and 120 Hours After First Dose of Biktarvy | Median Drug Concentration in Peripheral Blood Mononuclear Cells (PBMCs) | FTC-TP at Baseline (pre-dosing) | 0 fmol/10^6 cells |
| Sample Collection 24, 28, and 72 Hours After First Dose of Biktarvy | Median Drug Concentration in Peripheral Blood Mononuclear Cells (PBMCs) | TFV-DP at Baseline (pre-dosing) | 0 fmol/10^6 cells |
| Sample Collection 24, 28, and 72 Hours After First Dose of Biktarvy | Median Drug Concentration in Peripheral Blood Mononuclear Cells (PBMCs) | TFV-DP at 24 hours after the first dose | 98 fmol/10^6 cells |
| Sample Collection 24, 28, and 72 Hours After First Dose of Biktarvy | Median Drug Concentration in Peripheral Blood Mononuclear Cells (PBMCs) | FTC-TP at Baseline (pre-dosing) | 0 fmol/10^6 cells |
| Sample Collection 24, 28, and 72 Hours After First Dose of Biktarvy | Median Drug Concentration in Peripheral Blood Mononuclear Cells (PBMCs) | FTC-TP at 24 hours after the first dose | 3450 fmol/10^6 cells |
Primary
Median Drug Levels in Plasma
Median drug levels of tenofovir (TFV), emtricitabine (FTC), and bictegravir (BIC) in plasma were determined. Concentrations below the limit of quantification (LOQ) are assigned a value of zero. The prespecified outcomes of interest are plasma concentrations of the components of Biktarvy at 24 and 120 hours after the initial dose. All other time points of sample collection are for future exploratory analyses and have not been analyzed. Only the time points of sample collection that were prespecified as primary study outcomes are presented here.
Time frame: Baseline (pre-dosing), 24 hours after the first dose, and 120 hours after first dose
Population: This analysis includes participants with usable samples at the indicated time points. Only the collection times of 24 and 120 hours post-dosing were prespecified for reporting.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Sample Collection 2, 48, and 96 Hours After First Dose of Biktarvy | Median Drug Levels in Plasma | FTC at Baseline (pre-dosing) | 0 ng/mL |
| Sample Collection 2, 48, and 96 Hours After First Dose of Biktarvy | Median Drug Levels in Plasma | TFV at Baseline (pre-dosing) | 0 ng/mL |
| Sample Collection 2, 48, and 96 Hours After First Dose of Biktarvy | Median Drug Levels in Plasma | BIC at Baseline (pre-dosing) | 0 ng/mL |
| Sample Collection 4, 26, and 120 Hours After First Dose of Biktarvy | Median Drug Levels in Plasma | BIC at 120 hours after first dose | 267 ng/mL |
| Sample Collection 4, 26, and 120 Hours After First Dose of Biktarvy | Median Drug Levels in Plasma | FTC at 120 hours after first dose | 0 ng/mL |
| Sample Collection 4, 26, and 120 Hours After First Dose of Biktarvy | Median Drug Levels in Plasma | TFV at Baseline (pre-dosing) | 0 ng/mL |
| Sample Collection 4, 26, and 120 Hours After First Dose of Biktarvy | Median Drug Levels in Plasma | FTC at Baseline (pre-dosing) | 0 ng/mL |
| Sample Collection 4, 26, and 120 Hours After First Dose of Biktarvy | Median Drug Levels in Plasma | BIC at Baseline (pre-dosing) | 0 ng/mL |
| Sample Collection 4, 26, and 120 Hours After First Dose of Biktarvy | Median Drug Levels in Plasma | TFV at 120 hours after first dose | 0 ng/mL |
| Sample Collection 24, 28, and 72 Hours After First Dose of Biktarvy | Median Drug Levels in Plasma | FTC at Baseline (pre-dosing) | 0 ng/mL |
| Sample Collection 24, 28, and 72 Hours After First Dose of Biktarvy | Median Drug Levels in Plasma | FTC at 24 hours after the first dose | 33 ng/mL |
| Sample Collection 24, 28, and 72 Hours After First Dose of Biktarvy | Median Drug Levels in Plasma | BIC at 24 hours after the first dose | 1296 ng/mL |
| Sample Collection 24, 28, and 72 Hours After First Dose of Biktarvy | Median Drug Levels in Plasma | TFV at Baseline (pre-dosing) | 0 ng/mL |
| Sample Collection 24, 28, and 72 Hours After First Dose of Biktarvy | Median Drug Levels in Plasma | TFV at 24 hours after the first dose | 0 ng/mL |
| Sample Collection 24, 28, and 72 Hours After First Dose of Biktarvy | Median Drug Levels in Plasma | BIC at Baseline (pre-dosing) | 0 ng/mL |
Primary
Median Drug Levels in Rectal Tissues
Median drug levels of TFV, FTC, and BIC in rectal tissue were determined. Concentrations below the limit of quantification (LOQ) are assigned a value of zero. The prespecified outcomes of interest are rectal tissue concentrations of the components of Biktarvy at 24 and 120 hours after the initial dose. All other time points of sample collection are for future exploratory analyses and have not been analyzed. Only the time points of sample collection that were prespecified as primary study outcomes are presented here.
Time frame: Baseline (pre-dosing), 24 hours after the first dose, and 120 hours after first dose
Population: This analysis includes participants with usable samples at the indicated time points. Only the collection times of 24 and 120 hours post-dosing were prespecified for reporting. Technical difficulties precluded the drug measures in rectal tissues for a large number of samples and therefore, data are not available for all drugs for all participants at these time points.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Sample Collection 2, 48, and 96 Hours After First Dose of Biktarvy | Median Drug Levels in Rectal Tissues | TFV at Baseline (pre-dosing) | 0 ng/mg |
| Sample Collection 2, 48, and 96 Hours After First Dose of Biktarvy | Median Drug Levels in Rectal Tissues | FTC at Baseline (pre-dosing) | 0 ng/mg |
| Sample Collection 2, 48, and 96 Hours After First Dose of Biktarvy | Median Drug Levels in Rectal Tissues | BIC at Baseline (pre-dosing) | 0 ng/mg |
| Sample Collection 4, 26, and 120 Hours After First Dose of Biktarvy | Median Drug Levels in Rectal Tissues | FTC at Baseline (pre-dosing) | 0 ng/mg |
| Sample Collection 4, 26, and 120 Hours After First Dose of Biktarvy | Median Drug Levels in Rectal Tissues | BIC at 120 hours after first dose | 0.020 ng/mg |
| Sample Collection 4, 26, and 120 Hours After First Dose of Biktarvy | Median Drug Levels in Rectal Tissues | TFV at Baseline (pre-dosing) | 0 ng/mg |
| Sample Collection 4, 26, and 120 Hours After First Dose of Biktarvy | Median Drug Levels in Rectal Tissues | TFV at 120 hours after first dose | 0 ng/mg |
| Sample Collection 4, 26, and 120 Hours After First Dose of Biktarvy | Median Drug Levels in Rectal Tissues | FTC at 120 hours after first dose | 0.064 ng/mg |
| Sample Collection 4, 26, and 120 Hours After First Dose of Biktarvy | Median Drug Levels in Rectal Tissues | BIC at Baseline (pre-dosing) | 0 ng/mg |
| Sample Collection 24, 28, and 72 Hours After First Dose of Biktarvy | Median Drug Levels in Rectal Tissues | BIC at 24 hours after the first dose | 0.105 ng/mg |
| Sample Collection 24, 28, and 72 Hours After First Dose of Biktarvy | Median Drug Levels in Rectal Tissues | TFV at 24 hours after the first dose | 0 ng/mg |
| Sample Collection 24, 28, and 72 Hours After First Dose of Biktarvy | Median Drug Levels in Rectal Tissues | TFV at Baseline (pre-dosing) | 0 ng/mg |
| Sample Collection 24, 28, and 72 Hours After First Dose of Biktarvy | Median Drug Levels in Rectal Tissues | BIC at Baseline (pre-dosing) | 0 ng/mg |
| Sample Collection 24, 28, and 72 Hours After First Dose of Biktarvy | Median Drug Levels in Rectal Tissues | FTC at Baseline (pre-dosing) | 0 ng/mg |
| Sample Collection 24, 28, and 72 Hours After First Dose of Biktarvy | Median Drug Levels in Rectal Tissues | FTC at 24 hours after the first dose | 0.233 ng/mg |