HIV
Conditions
Brief summary
The purpose of this study is to find out how well the HIV medication dolutegravir gets into different parts of the body including blood plasma, special blood cells, and rectal tissue. Specifically, investigators want to compare how fast dolutegravir lowers the HIV viral load in these three different sites. In addition, as an exploratory aim, investigators seek to learn if there are any differences in how dolutegravir acts in males and females. Results of this study will provide more information about HIV medications and their limitations. In the future, this could help create better HIV medications that can get into these hard-to-reach places and eventually cure HIV infection.
Detailed description
Emerging evidence indicates that sites outside of blood plasma, such as peripheral blood mononuclear cells (PBMCs) and gut-associated lymphoid tissue, remain reservoirs for HIV and play critical roles in viral persistence despite long-term potent combination antiretroviral therapy (cART). Suboptimal ARV drug concentrations within these reservoirs are thought to contribute to our inability to fully eradicate HIV. In addition, host factors such as sex have been found to impact ARV drug exposure within these sites and effect key outcomes such as time to virologic suppression. The understanding of reservoir site pharmacology and the impact on sex is limited due to several barriers: 1) Difficulty in sampling reservoir sites intensively and 2) Scarcity of women enrolled in HIV clinical research studies. Optimal drug concentrations are ideally determined early in drug development by dose-ranging studies that require intensive blood plasma sampling; this methodology is impractical to employ within tissue sites. To mitigate these barriers, the researchers propose to study the pharmacology of the integrase strand transfer inhibitor dolutegravir (DTG) within three body compartments: blood plasma, PBMCs, and rectal tissue using a novel integrated population pharmacokinetic-viral dynamic (PK-VD) modeling approach. This PK-VD modeling strategy generates concentration-response relationships with limited sampling and dosing simulations ideally suited to reservoir sites. The primary aim of this study is to validate the integrated population PK-VD model that quantitatively describes the relationship between dolutegravir (DTG) exposure and HIV viral decay in blood plasma. The second aim of this study is to develop an integrated population pharmacokinetic-viral dynamic (PK-VD) model to describe the relationship between DTG exposure and HIV viral decay in peripheral blood mononuclear cells and rectal tissue reservoir sites. The third aim is exploratory and will investigate sex differences in DTG penetration into blood plasma, peripheral blood mononuclear cells and rectal tissue reservoirs reservoirs as well as its impact on the rectal microbiome.
Interventions
DRUGdolutegravir
Tivicay is a human immunodeficiency virus type 1 (HIV-1) integrase strand transfer inhibitor (INSTI) indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection. 50 mg of Tivicay (dolutegravir) will be taken orally once a day.
DRUGTriumeq
Triumeq is a fixed-dose combination drug for the treatment of HIV/AIDS. It is a combination of 600 mg abacavir, 50 mg dolutegravir and 300 mg lamivudine. Triumeq will be taken orally once daily.
DRUGTruvada
Truvada is a combination of emtriva and viread, both nucleoside analog HIV-1 reverse transcriptase inhibitors. Truvada is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection. One Truvada tablet (containing 200 mg/300 mg of emtricitabine and tenofovir disoproxil fumarate) will be taken orally once daily.
Sponsors
National Institute of Allergy and Infectious Diseases (NIAID)
Emory University
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* No ARVs in the last 6 months (from date of screening) * No documented or suspected resistance to integrase inhibitors (dolutegravir, elvitegravir, raltegravir, or bictegravir). * Creatinine Clearance \>50 mL/min, as calculated by the Cockcroft-Gault equation within 90 days of screen * Liver function testing, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase \< 5 times upper limit of normal within 90 days of screen * Intact gastrointestinal tract * Able and willing to give informed consent * Willing and eligible to initiate ARV therapy with Triumeq, DTG + Truvada (TDF/FTC), or DTG + Descovy (FTC/TAF) * Agree to receive from their provider and pay for a prescribed supply of the drug, Tivicay® (dolutegravir/DTG), with either Triumeq, or Truvada or Descovy as determined by their primary HIV provider * Agree to take the prescribed medication by mouth * Agree that they (the participant) is responsible for bringing these medications with them to their study visits * Willing to undergo serial blood and rectal tissue sampling * Female participants' must be willing to have a pregnancy test done at each visit. Female participants of childbearing potential (FCB) must agree to either commit to continued abstinence from heterosexual intercourse or to use a reliable form of birth control such as oral contraceptive pills, intrauterine device, Nexplanon, DepoProvera, permanent sterilization, or another acceptable method, as determined by the investigator for the duration of the study. FCB are defined as sexually mature women who have not undergone hysterectomy or bilateral oophorectomy or have not been naturally postmenopausal for at least 24 consecutive months (i.e have had menses at any time in preceding 24 months)
Exclusion criteria
* Pregnant or attempting to conceive now or during the course of the study * Self-reported or documented current anal or rectal disease prohibiting safe anoscopy and biopsies, in investigator's opinion. * Taking concurrent medications that interfere with DTG * Bleeding diathesis * Platelet count \<50,000 mm3 * Medical condition that interferes with conduct of study, in investigator's opinion
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dolutegravir Concentration | Day 84 (hour 0 through 24) | Dolutegravir concentrations in blood plasma are assessed as the maximum dolutegravir concentration (Cmax) and 24 hour trough (lowest) concentration (C24h) of dolutegravir in micrograms per milliliter (µg/mL). Blood samples for pharmacokinetics were obtained prior to dosing (hour 0) and 1, 2, 3, 4, 6, 8, and 24 hours after dosing. |
| Time of Maximum Dolutegravir Concentration | Day 84 (hour 0 through 24) | Time of maximum dolutegravir concentration is assessed in hours for the time periods of after the first dose and during steady state. Blood samples for pharmacokinetics were obtained prior to dosing (hour 0) and 1, 2, 3, 4, 6, 8, and 24 hours after dosing. |
| Area Under the Dolutegravir Plasma Concentration vs Time Curve | Day 84 (hour 0 through 24) | The area under the dolutegravir plasma concentration vs time curve in a 24 hour period (AUC24h) is assessed in hours times micrograms per millimeters (h\* µg/mL) for the time periods of after the first dose and during steady state. Blood samples for pharmacokinetics were obtained prior to dosing (hour 0) and 1, 2, 3, 4, 6, 8, and 24 hours after dosing. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Dolutegravir Exposure in Peripheral Blood Mononuclear Cells (PBMC) | Up to Day 84 | Dolutegravir concentrations in peripheral blood mononuclear cells required for HIV viral load decline. |
| Dolutegravir Concentration in Rectal Tissue | Week 2, Week 6, Week 12 | Rectal dolutegravir concentrations in rectal tissue stratified by virologic suppressors vs non-suppressors. |
Countries
United States
Participant flow
Recruitment details
Participant enrollment began September 2016 and all follow up was complete by September 11, 2019. Participants were enrolled at the Grady Ponce de Leon Center and Grady Health System in Atlanta, Georgia, USA.
Participants by arm
| Arm | Count |
|---|---|
| Anti-retroviral (ARV) Naïve Males Males diagnosed with HIV undergoing serial blood and tissue rectal sampling for twelve weeks after initiating ARV therapy as prescribed by their physician. Participants were treated with either Triumeq (abacavir 600 mg/dolutegravir 50 mg/lamivudine 300 mg), or Truvada (emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg) plus and dolutegravir (50 mg), or Descovy (emtricitabine 200 mg/tenofovir alafenamide 25 mg) plus dolutegravir (50 mg). | 16 |
| Anti-retroviral (ARV) Naïve Females Females diagnosed with HIV undergoing serial blood and tissue rectal sampling for twelve weeks after initiating ARV therapy as prescribed by their physician. Participants were treated with either Triumeq (abacavir 600 mg/dolutegravir 50 mg/lamivudine 300 mg), or Truvada (emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg) plus and dolutegravir (50 mg), or Descovy (emtricitabine 200 mg/tenofovir alafenamide 25 mg) plus dolutegravir (50 mg). | 6 |
| Total | 22 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Participant began ARVs prior to study intervention | 2 | 0 |
| Overall Study | Physician Decision | 2 | 0 |
| Overall Study | Withdrawal by Subject | 3 | 0 |
Baseline characteristics
| Characteristic | Anti-retroviral (ARV) Naïve Males | Total | Anti-retroviral (ARV) Naïve Females |
|---|---|---|---|
| Age, Continuous | 35.2 years STANDARD_DEVIATION 9.8 | 38.0 years STANDARD_DEVIATION 10.3 | 45.6 years STANDARD_DEVIATION 8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 16 Participants | 22 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 14 Participants | 19 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 2 Participants | 3 Participants | 1 Participants |
| Region of Enrollment United States | 16 Participants | 22 Participants | 6 Participants |
| Sex: Female, Male Female | 0 Participants | 6 Participants | 6 Participants |
| Sex: Female, Male Male | 16 Participants | 16 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 16 | 0 / 6 |
| other Total, other adverse events | 9 / 16 | 6 / 6 |
| serious Total, serious adverse events | 0 / 16 | 0 / 6 |
Outcome results
Primary
Area Under the Dolutegravir Plasma Concentration vs Time Curve
The area under the dolutegravir plasma concentration vs time curve in a 24 hour period (AUC24h) is assessed in hours times micrograms per millimeters (h\* µg/mL) for the time periods of after the first dose and during steady state. Blood samples for pharmacokinetics were obtained prior to dosing (hour 0) and 1, 2, 3, 4, 6, 8, and 24 hours after dosing.
Time frame: Day 84 (hour 0 through 24)
Population: This analysis includes participants who completed at least one study visit. Fourteen participants completed all study visits and 2 completed a portion of study visits. Males and females are combined for all primary and secondary analyses and are separated only for exploratory study outcomes.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Anti-retroviral (ARV) Naïve Males and Females | Area Under the Dolutegravir Plasma Concentration vs Time Curve | First-dose pharmacokinetics (AUC24h) | 22.30 h* µg/mL |
| Anti-retroviral (ARV) Naïve Males and Females | Area Under the Dolutegravir Plasma Concentration vs Time Curve | Steady state pharmacokinetics (AUC24h) | 27.24 h* µg/mL |
Primary
Dolutegravir Concentration
Dolutegravir concentrations in blood plasma are assessed as the maximum dolutegravir concentration (Cmax) and 24 hour trough (lowest) concentration (C24h) of dolutegravir in micrograms per milliliter (µg/mL). Blood samples for pharmacokinetics were obtained prior to dosing (hour 0) and 1, 2, 3, 4, 6, 8, and 24 hours after dosing.
Time frame: Day 84 (hour 0 through 24)
Population: This analysis includes participants who completed at least one study visit. Fourteen participants completed all study visits and 2 completed a portion of study visits. Males and females are combined for all primary and secondary analyses and are separated only for exploratory study outcomes.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Anti-retroviral (ARV) Naïve Males and Females | Dolutegravir Concentration | First-dose pharmacokinetics (Cmax) | 2.01 µg/mL |
| Anti-retroviral (ARV) Naïve Males and Females | Dolutegravir Concentration | Steady state pharmacokinetics (Cmax) | 2.34 µg/mL |
| Anti-retroviral (ARV) Naïve Males and Females | Dolutegravir Concentration | Trough dolutegravir concentration (C24h) | 0.56 µg/mL |
Primary
Time of Maximum Dolutegravir Concentration
Time of maximum dolutegravir concentration is assessed in hours for the time periods of after the first dose and during steady state. Blood samples for pharmacokinetics were obtained prior to dosing (hour 0) and 1, 2, 3, 4, 6, 8, and 24 hours after dosing.
Time frame: Day 84 (hour 0 through 24)
Population: This analysis includes participants who completed at least one study visit. Fourteen participants completed all study visits and 2 completed a portion of study visits. Males and females are combined for all primary and secondary analyses and are separated only for exploratory study outcomes.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Anti-retroviral (ARV) Naïve Males and Females | Time of Maximum Dolutegravir Concentration | First-dose pharmacokinetics (Tmax) | 1.5 hours |
| Anti-retroviral (ARV) Naïve Males and Females | Time of Maximum Dolutegravir Concentration | Steady state pharmacokinetics (Tmax) | 3.0 hours |
Secondary
Dolutegravir Concentration in Rectal Tissue
Rectal dolutegravir concentrations in rectal tissue stratified by virologic suppressors vs non-suppressors.
Time frame: Week 2, Week 6, Week 12
Population: This analysis includes the first 12 study participants; the analysis was not extended to subsequent participants due to study findings being sufficient from the first 12 participants. One participant was removed from this analysis because they had undetectable virus in rectal tissue at the baseline assessment.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Anti-retroviral (ARV) Naïve Males and Females | Dolutegravir Concentration in Rectal Tissue | Week 2 | 1606 ng/mL |
| Anti-retroviral (ARV) Naïve Males and Females | Dolutegravir Concentration in Rectal Tissue | Week 6 | 724 ng/mL |
| Anti-retroviral (ARV) Naïve Males and Females | Dolutegravir Concentration in Rectal Tissue | Week 12 | 473 ng/mL |
| HIV RNA Non-suppressors | Dolutegravir Concentration in Rectal Tissue | Week 2 | 749 ng/mL |
| HIV RNA Non-suppressors | Dolutegravir Concentration in Rectal Tissue | Week 6 | 625 ng/mL |
| HIV RNA Non-suppressors | Dolutegravir Concentration in Rectal Tissue | Week 12 | 373 ng/mL |
Secondary
Dolutegravir Exposure in Peripheral Blood Mononuclear Cells (PBMC)
Dolutegravir concentrations in peripheral blood mononuclear cells required for HIV viral load decline.
Time frame: Up to Day 84
Population: Due to lack of viral dynamic decline in PBMCs and inability to measure intracellular dolutegravir consistently with the assays, this secondary outcome could not be assessed.