Hepatitis C, HIV Coinfection
Conditions
Brief summary
This study will evaluate the effect of ledipasvir/sofosbuvir (LDV/SOF) treatment on the pharmacokinetics (PK) and renal safety of tenofovir in the form of tenofovir alafenamide (TAF). Subjects living with human immunodeficiency virus (HIV) who are receiving tenofovir-based antiretroviral therapy (in the form of tenofovir disoproxil fumarate \[TDF\]), and are also taking a ritonavir- or cobicistat-boosted protease inhibitor will be invited to participate. The study will consist of five visits: a screening visit, three abbreviated 4-hour pharmacokinetic visits, and one end-of-study follow-up visit. Subjects will also be asked to use a Wisepill device, which will track medication adherence throughout the study.
Interventions
DRUGTDF with a boosted protease inhibitor
Participants who are already taking tenofovir disoproxil fumarate 300 mg (in the form of Viread or Truvada) in combination with either a ritonavir- or cobicistat-boosted protease inhibitor for HIV treatment will continue to take their prescribed treatment for 12 weeks after enrollment. Other: Blood draws for tenofovir PK, renal function assessment
DRUGTAF with a boosted protease inhibitor
Participants will be switched from tenofovir disoproxil fumarate to tenofovir alafenamide 25 mg/emtricitabine 200 mg with a boosted protease inhibitor. Other: Blood draws for tenofovir PK, renal function assessment
DRUGTAF with a boosted protease inhibitor and LDV/SOF
After taking tenofovir alafenamide/emtricitabine for 12 weeks, participants will then start taking ledipasvir 90 mg/sofosbuvir 400 mg (Harvoni) in combination with the tenofovir alafenamide 25 mg/emtricitabine 200 mg (Descovy) and a boosted protease inhibitor for 4 weeks. Subjects will then return to taking tenofovir alafenamide 25 mg/emtricitabine 200 mg (Descovy) and a boosted protease inhibitor for the final 12 weeks. Other: Blood draws for tenofovir PK, renal function assessment
Sponsors
University of Colorado, Denver
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Between 18-70 years of age * Have been taking TDF and a ritonavir- or cobicistat-boosted protease inhibitor as part of standard care for treatment of HIV
Exclusion criteria
* eGFR \< 30 mL/min * Pregnant or planning pregnancy * Breastfeeding * Any medical, social, or mental-health issue(s) that, in the opinion of the investigators, could interfere with study participation or the study outcomes * Signs or symptoms of decompensated liver disease * Hepatitis B infection * Medications that may cause unwanted drug interactions with ledipasvir/sofosbuvir or emtricitabine/tenofovir alafenamide * Unwillingness or inability to comply with study procedures * Chronic hepatitis C infection
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Week 12 Plasma Tenofovir Area Under the Plasma Concentration vs. Time Curve From Time 0 to 24 Hours (AUC0-24) at 24 and 28 Weeks | 12 weeks and 24 weeks and 28 weeks | Compare plasma tenofovir AUC0-24 between TAF with boosted PI vs. TDF with boosted PI (Phase 2 vs. 1), and between TAF with boosted PI and LDV/SOF vs. TDF with boosted PI (Phase 3 vs. 1) |
| Change From Week 12 Tenofovir-diphosphate (TFV-DP) in Peripheral Blood Mononuclear Cells (PBMCs) at 24 and 28 Weeks | 12 weeks, and 24 weeks and 28 weeks | Compare tenofovir-diphosphate (TFV-DP) in peripheral blood mononuclear cells (PBMCs) between TAF with a boosted PI vs. TDF with a boosted PI (Phase 2 vs. 1), and TAF with a boosted PI and LDV/SOF vs. TDF with a boosted PI (Phase 3 vs. 1). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Week 12 Tenofovir-diphosphate (TFV-DP) in Dried Blood Spots (DBS) | 12 weeks and 24 and 28 weeks | Compare tenofovir diphosphate (TFV-DP) in dried blood spots (DBS) between TAF with a boosted PI vs. TDF with a boosted PI (Phase 2 vs. 1), and TAF with a boosted PI and LDV/SOF vs. TDF with a boosted PI (Phase 3 vs. 1) |
| Change in Estimated Glomerular Filtration Rate (eGFR) and Renal Biomarkers: eGFR | 12 weeks, 24 weeks, and 28 weeks | Change in estimated glomerular filtration rate (eGFR) |
| Change in Estimated Glomerular Filtration Rate (eGFR) and Renal Biomarkers: UPCR | 12 weeks, 24 weeks, and 28 weeks | Change in estimated glomerular filtration rate (eGFR) and renal biomarkers: Urine protein to creatinine ratio (UPCR) |
| Change in Estimated Glomerular Filtration Rate (eGFR) and Renal Biomarkers: B2M/Cr Ratio, and RBP/Cr Ratio | 12 weeks, 24 weeks, and 28 weeks | Change in renal biomarkers: urinary beta-2 microglobulin (B2M)/creatinine (Cr) ratio, and urinary retinol binding protein (RBP)/Cr ratio |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| TAF With a Boosted PI and LDV/SOF Subjects who are already taking tenofovir disoproxil fumarate 300 mg (in the form of Viread or Truvada) in combination with either a ritonavir- or cobicistat-boosted protease inhibitor for HIV treatment will continue to take their prescribed treatment for 12 weeks after enrollment.
Subjects will be switched from tenofovir disoproxil fumarate to tenofovir alafenamide (TAF) 25 mg/emtricitabine (FTC) 200 mg (Descovy) with a boosted protease inhibitor for the next 12 weeks.
After taking TAF/FTC for 12 weeks, subjects will then start taking ledipasvir 90mg/sofosbuvir 400mg (Harvoni) in combination with TAF/FTC and a boosted protease inhibitor for 4 weeks.
Subjects will then return to taking TAF/FTC with a boosted protease inhibitor for the final 12 weeks of the study.
TDF with a boosted protease inhibitor: Subjects who are already taking tenofovir disoproxil fumarate 300 mg (in the form of Viread or Truvada) in combination with either a ritonavir- or cobicistat-boosted protease | 10 |
| Total | 10 |
Baseline characteristics
| Characteristic | TAF With a Boosted PI and LDV/SOF |
|---|---|
| Age, Continuous | 50 years STANDARD_DEVIATION 12.3 |
| eGFR | 91.5 mL/min/1.73^m2 STANDARD_DEVIATION 26.6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 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 | 9 Participants |
| Region of Enrollment United States | 10 participants |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 9 Participants |
| Weight | 88.8 kg STANDARD_DEVIATION 16.6 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 10 | 0 / 10 |
| other Total, other adverse events | 2 / 10 | 2 / 10 | 1 / 10 |
| serious Total, serious adverse events | 0 / 10 | 0 / 10 | 0 / 10 |
Outcome results
Primary
Change From Week 12 Plasma Tenofovir Area Under the Plasma Concentration vs. Time Curve From Time 0 to 24 Hours (AUC0-24) at 24 and 28 Weeks
Compare plasma tenofovir AUC0-24 between TAF with boosted PI vs. TDF with boosted PI (Phase 2 vs. 1), and between TAF with boosted PI and LDV/SOF vs. TDF with boosted PI (Phase 3 vs. 1)
Time frame: 12 weeks and 24 weeks and 28 weeks
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| TDF With a Boosted PI | Change From Week 12 Plasma Tenofovir Area Under the Plasma Concentration vs. Time Curve From Time 0 to 24 Hours (AUC0-24) at 24 and 28 Weeks | 3466 ng*h/mL | Geometric Coefficient of Variation 51.4 |
| TAF With a Boosted PI | Change From Week 12 Plasma Tenofovir Area Under the Plasma Concentration vs. Time Curve From Time 0 to 24 Hours (AUC0-24) at 24 and 28 Weeks | 743 ng*h/mL | Geometric Coefficient of Variation 35.8 |
| TAF With a Boosted PI and LDV/SOF | Change From Week 12 Plasma Tenofovir Area Under the Plasma Concentration vs. Time Curve From Time 0 to 24 Hours (AUC0-24) at 24 and 28 Weeks | 868 ng*h/mL | Geometric Coefficient of Variation 40.8 |
Primary
Change From Week 12 Tenofovir-diphosphate (TFV-DP) in Peripheral Blood Mononuclear Cells (PBMCs) at 24 and 28 Weeks
Compare tenofovir-diphosphate (TFV-DP) in peripheral blood mononuclear cells (PBMCs) between TAF with a boosted PI vs. TDF with a boosted PI (Phase 2 vs. 1), and TAF with a boosted PI and LDV/SOF vs. TDF with a boosted PI (Phase 3 vs. 1).
Time frame: 12 weeks, and 24 weeks and 28 weeks
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| TDF With a Boosted PI | Change From Week 12 Tenofovir-diphosphate (TFV-DP) in Peripheral Blood Mononuclear Cells (PBMCs) at 24 and 28 Weeks | 83.0 fmol/10^6 cells | Geometric Coefficient of Variation 66.6 |
| TAF With a Boosted PI | Change From Week 12 Tenofovir-diphosphate (TFV-DP) in Peripheral Blood Mononuclear Cells (PBMCs) at 24 and 28 Weeks | 926 fmol/10^6 cells | Geometric Coefficient of Variation 23.4 |
| TAF With a Boosted PI and LDV/SOF | Change From Week 12 Tenofovir-diphosphate (TFV-DP) in Peripheral Blood Mononuclear Cells (PBMCs) at 24 and 28 Weeks | 1129 fmol/10^6 cells | Geometric Coefficient of Variation 34.9 |
Secondary
Change From Week 12 Tenofovir-diphosphate (TFV-DP) in Dried Blood Spots (DBS)
Compare tenofovir diphosphate (TFV-DP) in dried blood spots (DBS) between TAF with a boosted PI vs. TDF with a boosted PI (Phase 2 vs. 1), and TAF with a boosted PI and LDV/SOF vs. TDF with a boosted PI (Phase 3 vs. 1)
Time frame: 12 weeks and 24 and 28 weeks
Population: Comparisons between study phases were controlled for 3-month adherence. Results reported
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| TDF With a Boosted PI | Change From Week 12 Tenofovir-diphosphate (TFV-DP) in Dried Blood Spots (DBS) | 36014 fmol/2x7mm punches | Geometric Coefficient of Variation 46.4 |
| TAF With a Boosted PI | Change From Week 12 Tenofovir-diphosphate (TFV-DP) in Dried Blood Spots (DBS) | 6735 fmol/2x7mm punches | Geometric Coefficient of Variation 45 |
| TAF With a Boosted PI and LDV/SOF | Change From Week 12 Tenofovir-diphosphate (TFV-DP) in Dried Blood Spots (DBS) | 6100 fmol/2x7mm punches | Geometric Coefficient of Variation 41 |
Secondary
Change in Estimated Glomerular Filtration Rate (eGFR) and Renal Biomarkers: B2M/Cr Ratio, and RBP/Cr Ratio
Change in renal biomarkers: urinary beta-2 microglobulin (B2M)/creatinine (Cr) ratio, and urinary retinol binding protein (RBP)/Cr ratio
Time frame: 12 weeks, 24 weeks, and 28 weeks
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| TDF With a Boosted PI | Change in Estimated Glomerular Filtration Rate (eGFR) and Renal Biomarkers: B2M/Cr Ratio, and RBP/Cr Ratio | β2M:Cr ratio | 419 ug/g | Geometric Coefficient of Variation 176 |
| TDF With a Boosted PI | Change in Estimated Glomerular Filtration Rate (eGFR) and Renal Biomarkers: B2M/Cr Ratio, and RBP/Cr Ratio | RBP:Cr ratio | 436 ug/g | Geometric Coefficient of Variation 174 |
| TAF With a Boosted PI | Change in Estimated Glomerular Filtration Rate (eGFR) and Renal Biomarkers: B2M/Cr Ratio, and RBP/Cr Ratio | β2M:Cr ratio | 224 ug/g | Geometric Coefficient of Variation 167 |
| TAF With a Boosted PI | Change in Estimated Glomerular Filtration Rate (eGFR) and Renal Biomarkers: B2M/Cr Ratio, and RBP/Cr Ratio | RBP:Cr ratio | 242 ug/g | Geometric Coefficient of Variation 180 |
| TAF With a Boosted PI and LDV/SOF | Change in Estimated Glomerular Filtration Rate (eGFR) and Renal Biomarkers: B2M/Cr Ratio, and RBP/Cr Ratio | β2M:Cr ratio | 178 ug/g | Geometric Coefficient of Variation 156 |
| TAF With a Boosted PI and LDV/SOF | Change in Estimated Glomerular Filtration Rate (eGFR) and Renal Biomarkers: B2M/Cr Ratio, and RBP/Cr Ratio | RBP:Cr ratio | 146 ug/g | Geometric Coefficient of Variation 91.6 |
Secondary
Change in Estimated Glomerular Filtration Rate (eGFR) and Renal Biomarkers: eGFR
Change in estimated glomerular filtration rate (eGFR)
Time frame: 12 weeks, 24 weeks, and 28 weeks
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| TDF With a Boosted PI | Change in Estimated Glomerular Filtration Rate (eGFR) and Renal Biomarkers: eGFR | 86.7 mL/min/1.73 m^2 | Geometric Coefficient of Variation 27.6 |
| TAF With a Boosted PI | Change in Estimated Glomerular Filtration Rate (eGFR) and Renal Biomarkers: eGFR | 91.0 mL/min/1.73 m^2 | Geometric Coefficient of Variation 23 |
| TAF With a Boosted PI and LDV/SOF | Change in Estimated Glomerular Filtration Rate (eGFR) and Renal Biomarkers: eGFR | 88.1 mL/min/1.73 m^2 | Geometric Coefficient of Variation 24.9 |
Secondary
Change in Estimated Glomerular Filtration Rate (eGFR) and Renal Biomarkers: UPCR
Change in estimated glomerular filtration rate (eGFR) and renal biomarkers: Urine protein to creatinine ratio (UPCR)
Time frame: 12 weeks, 24 weeks, and 28 weeks
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| TDF With a Boosted PI | Change in Estimated Glomerular Filtration Rate (eGFR) and Renal Biomarkers: UPCR | 134 mg/g | Geometric Coefficient of Variation 65.7 |
| TAF With a Boosted PI | Change in Estimated Glomerular Filtration Rate (eGFR) and Renal Biomarkers: UPCR | 118 mg/g | Geometric Coefficient of Variation 50.2 |
| TAF With a Boosted PI and LDV/SOF | Change in Estimated Glomerular Filtration Rate (eGFR) and Renal Biomarkers: UPCR | 97.3 mg/g | Geometric Coefficient of Variation 41 |