Hepatitis C Virus, HIV
Conditions
Keywords
genotype 1, genotype 4, HIV
Brief summary
This study will evaluate the antiviral efficacy, safety, and tolerability of ledipasvir/sofosbuvir (LDV/SOF) fixed-dose combination (FDC) administered for 12 weeks in hepatitis C virus (HCV) treatment-naive and treatment-experienced (including treatment intolerant) participants with chronic genotype 1 or 4 HCV infection who are co-infected with HIV-1. Participants who experience confirmed post-treatment virologic failure (relapse) at or before Posttreatment Week 24 may be eligible to be enrolled in the Retreatment Substudy to receive LDV/SOF plus ribavirin (RBV) for 24 weeks.
Interventions
DRUGLDV/SOF
90/400 mg FDC tablet administered orally once daily
DRUGRBV
Tablets administered orally in a divided daily dose according to package insert weight-based dosing recommendations (\< 75 kg = 1000 mg and ≥ 75 kg = 1200 mg)
Sponsors
Gilead Sciences
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* HCV RNA ≥ 10,000 IU/mL at screening * HCV genotype 1 or 4 * HIV-1 infection * Cirrhosis determination, a fibroscan or liver biopsy may be required * Screening laboratory values within defined thresholds * Use of protocol specified method(s) of contraception if female of childbearing potential or sexually active male
Exclusion criteria
* Clinically-significant illness (other than HCV or HIV) or any other major medical disorder that may interfere with subject treatment, assessment, or compliance with the protocol * Current or prior history of clinical hepatic decompensation, hepatocellular carcinoma (HCC), or other malignancy (with the exception of certain resolved skin cancers) * Hepatitis B virus (HBV) infection * Pregnant or nursing female * Chronic use of systemically administered immunosuppressive agents
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Sustained Virologic Response (SVR) 12 Weeks After Discontinuation of Therapy (SVR12) | Posttreatment Week 12 | SVR12 was defined as HCV RNA \< the lower limit of quantitation (LLOQ; ie, 25 IU/mL) at 12 weeks after stopping study treatment. |
| Percentage of Participants Who Permanently Discontinued Any Study Drug Due to an Adverse Event | Up to 12 weeks | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With HCV RNA < LLOQ at Weeks 1, 2, 4, 6, 8, 10, and 12 | Weeks 1, 2, 4, 6, 8, 10, and 12 | — |
| Percentage of Participants With SVR at 4 and 24 Weeks After Discontinuation of Therapy (SVR4 and SVR24) | Posttreatment Weeks 4 and 24 | SVR4 and SVR 24 were defined as HCV RNA \< LLOQ at 4 and 24 weeks after stopping study treatment, respectively. |
| Change From Baseline in HCV RNA at Weeks 1, 2, 4, 6, and 8 | Baseline; Weeks 1, 2, 4, 6, and 8 | — |
| Percentage of Participants With Virologic Failure | Up to Posttreatment Week 24 | Virologic failure was defined as: * On-treatment virologic failure: * Breakthrough (confirmed HCV RNA ≥ LLOQ after having previously had HCV RNA \< LLOQ while on treatment), or * Rebound (confirmed \> 1 log10 IU/mL increase in HCV RNA from nadir while on treatment), or * Non-response (HCV RNA persistently ≥ LLOQ through 8 weeks of treatment) * Virologic relapse: * Confirmed HCV RNA ≥ LLOQ during the posttreatment period having achieved HCV RNA \< LLOQ at last on-treatment visit. |
| Percentage of Participants That Maintain HIV-1 RNA < 50 Copies/mL While on HCV Treatment | Weeks 4, 8, and 12 | — |
| Change From Baseline in Serum Creatinine at the End of Treatment (Week 12) and at Posttreatment Weeks 12 and 24 | Baseline; Week 12, Posttreatment Weeks 12 and 24 | — |
| For Participants in the Retreatment Substudy, Percentage of Participants With SVR at 4, 12, and 24 Weeks After Discontinuation of Therapy (SVR4, SVR12, and SVR24) | Posttreatment Weeks 4, 12, and 24 of Retreatment Substudy | SVR4, SVR12, and SVR 24 were defined as HCV RNA \< LLOQ at 4, 12, and 24 weeks after stopping study treatment, respectively. |
| For Participants in the Retreatment Substudy, Percentage of Participants With HCV RNA < LLOQ at Retreatment Weeks 2, 4, 8, 12, 16, 20, and 24 | Weeks 2, 4, 8, 12, 16, 20, and 24 of the Retreatment Substudy | — |
| For Participants in the Retreatment Substudy, Change From Baseline in HCV RNA at Retreatment Weeks 2, 4, and 8 | Baseline; Weeks 2, 4, and 8 of Retreatment Substudy | — |
| For Participants in the Retreatment Substudy, Percentage of Participants With Virologic Failure | Up to Posttreatment Week 24 of Retreatment Substudy | Virologic failure was defined as: * On-treatment virologic failure: * Breakthrough (confirmed HCV RNA ≥ LLOQ after having previously had HCV RNA \< LLOQ while on treatment), or * Rebound (confirmed \> 1 log10 IU/mL increase in HCV RNA from nadir while on treatment), or * Non-response (HCV RNA persistently ≥ LLOQ through 8 weeks of treatment) * Virologic relapse: * Confirmed HCV RNA ≥ LLOQ during the posttreatment period having achieved HCV RNA \< LLOQ at last on-treatment visit. |
Countries
Canada, New Zealand, Puerto Rico, United States
Participant flow
Recruitment details
Participants were enrolled at study sites in the United States (including Puerto Rico), Canada, and New Zealand. The first participant was screened on 24 February 2014. The last study visit occurred on 01 December 2015.
Pre-assignment details
429 participants were screened.
Participants by arm
| Arm | Count |
|---|---|
| LDV/SOF 12 Weeks Ledipasvir/sofosbuvir (LDV/SOF) (90/400 mg) fixed-dose combination (FDC) tablet once daily for up to 12 weeks. | 335 |
| Total | 335 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Primary Study | Death | 1 |
| Primary Study | Lost to Follow-up | 6 |
| Primary Study | Withdrew Consent | 1 |
Baseline characteristics
| Characteristic | LDV/SOF 12 Weeks |
|---|---|
| Age, Continuous | 52 years STANDARD_DEVIATION 8 |
| Baseline CD4 Count | 662 cells/uL STANDARD_DEVIATION 293.8 |
| Baseline HCV RNA | 6.7 log10 IU/mL STANDARD_DEVIATION 0.64 |
| Baseline HCV RNA Category < 800,000 IU/mL | 36 participants |
| Baseline HCV RNA Category ≥ 800,000 IU/mL | 299 participants |
| Baseline Serum Creatinine | 1.00 mg/dL STANDARD_DEVIATION 0.21 |
| Cirrhosis Status No | 268 participants |
| Cirrhosis Status Yes | 67 participants |
| Estimated Glomerular Filtration Rate Using the Cockcroft-Gault Equation | 101.6 mL/min STANDARD_DEVIATION 30.78 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 56 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 276 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants |
| HCV Genotype Genotype 1a | 250 participants |
| HCV Genotype Genotype 1b | 77 participants |
| HCV Genotype Genotype 4 | 8 participants |
| IL28b Status CC | 81 participants |
| IL28b Status CT | 185 participants |
| IL28b Status TT | 69 participants |
| Prior HCV Treatment Treatment-Experienced with DAA+Peg-IFN+RBV | 53 participants |
| Prior HCV Treatment Treatment-Experienced with DAA+RBV | 14 participants |
| Prior HCV Treatment Treatment-Experienced with Other | 5 participants |
| Prior HCV Treatment Treatment-Experienced with Peg-IFN+RBV | 113 participants |
| Prior HCV Treatment Treatment-Naive | 150 participants |
| Race/Ethnicity, Customized American Indian/ Alaska Native | 2 participants |
| Race/Ethnicity, Customized Asian | 6 participants |
| Race/Ethnicity, Customized Black or African American | 115 participants |
| Race/Ethnicity, Customized Not Disclosed | 3 participants |
| Race/Ethnicity, Customized Other | 6 participants |
| Race/Ethnicity, Customized White | 203 participants |
| Region of Enrollment Canada | 26 participants |
| Region of Enrollment New Zealand | 9 participants |
| Region of Enrollment Puerto Rico | 10 participants |
| Region of Enrollment United States | 290 participants |
| Sex: Female, Male Female | 59 Participants |
| Sex: Female, Male Male | 276 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 179 / 335 | 9 / 9 |
| serious Total, serious adverse events | 8 / 335 | 0 / 9 |
Outcome results
Primary
Percentage of Participants Who Permanently Discontinued Any Study Drug Due to an Adverse Event
Time frame: Up to 12 weeks
Population: Safety Analysis Set: participants who enrolled and received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LDV/SOF 12 Weeks | Percentage of Participants Who Permanently Discontinued Any Study Drug Due to an Adverse Event | 0 percentage of participants |
Primary
Percentage of Participants With Sustained Virologic Response (SVR) 12 Weeks After Discontinuation of Therapy (SVR12)
SVR12 was defined as HCV RNA \< the lower limit of quantitation (LLOQ; ie, 25 IU/mL) at 12 weeks after stopping study treatment.
Time frame: Posttreatment Week 12
Population: Full Analysis Set: participants who enrolled and received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LDV/SOF 12 Weeks | Percentage of Participants With Sustained Virologic Response (SVR) 12 Weeks After Discontinuation of Therapy (SVR12) | 96.1 percentage of participants |
Secondary
Change From Baseline in HCV RNA at Weeks 1, 2, 4, 6, and 8
Time frame: Baseline; Weeks 1, 2, 4, 6, and 8
Population: Participants in the Full Analysis Set with available data were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LDV/SOF 12 Weeks | Change From Baseline in HCV RNA at Weeks 1, 2, 4, 6, and 8 | Change at Week 1 (N = 331) | -4.68 log10 IU/mL | Standard Deviation 0.674 |
| LDV/SOF 12 Weeks | Change From Baseline in HCV RNA at Weeks 1, 2, 4, 6, and 8 | Change at Week 2 (N = 334) | -5.21 log10 IU/mL | Standard Deviation 0.654 |
| LDV/SOF 12 Weeks | Change From Baseline in HCV RNA at Weeks 1, 2, 4, 6, and 8 | Change at Week 4 (N = 335) | -5.30 log10 IU/mL | Standard Deviation 0.743 |
| LDV/SOF 12 Weeks | Change From Baseline in HCV RNA at Weeks 1, 2, 4, 6, and 8 | Change at Week 6 (N = 334) | -5.30 log10 IU/mL | Standard Deviation 0.772 |
| LDV/SOF 12 Weeks | Change From Baseline in HCV RNA at Weeks 1, 2, 4, 6, and 8 | Change at Week 8 (N = 333) | -5.33 log10 IU/mL | Standard Deviation 0.645 |
Secondary
Change From Baseline in Serum Creatinine at the End of Treatment (Week 12) and at Posttreatment Weeks 12 and 24
Time frame: Baseline; Week 12, Posttreatment Weeks 12 and 24
Population: Participants in the Safety Analysis Set with available data were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LDV/SOF 12 Weeks | Change From Baseline in Serum Creatinine at the End of Treatment (Week 12) and at Posttreatment Weeks 12 and 24 | Change at Week 12 (N = 320) | 0.05 mg/dL | Standard Deviation 0.111 |
| LDV/SOF 12 Weeks | Change From Baseline in Serum Creatinine at the End of Treatment (Week 12) and at Posttreatment Weeks 12 and 24 | Change at Posttreatment Week 12 (N = 325) | 0.03 mg/dL | Standard Deviation 0.143 |
| LDV/SOF 12 Weeks | Change From Baseline in Serum Creatinine at the End of Treatment (Week 12) and at Posttreatment Weeks 12 and 24 | Change at Posttreatment Week 24 (N = 313) | -0.02 mg/dL | Standard Deviation 0.134 |
Secondary
For Participants in the Retreatment Substudy, Change From Baseline in HCV RNA at Retreatment Weeks 2, 4, and 8
Time frame: Baseline; Weeks 2, 4, and 8 of Retreatment Substudy
Population: Participants in the Full Analysis Set who entered the Retreatment Substudy were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LDV/SOF 12 Weeks | For Participants in the Retreatment Substudy, Change From Baseline in HCV RNA at Retreatment Weeks 2, 4, and 8 | Change at Week 2 Retreatment | -5.01 log10 IU/mL | Standard Deviation 0.775 |
| LDV/SOF 12 Weeks | For Participants in the Retreatment Substudy, Change From Baseline in HCV RNA at Retreatment Weeks 2, 4, and 8 | Change at Week 4 Retreatment | -5.04 log10 IU/mL | Standard Deviation 0.802 |
| LDV/SOF 12 Weeks | For Participants in the Retreatment Substudy, Change From Baseline in HCV RNA at Retreatment Weeks 2, 4, and 8 | Change at Week 8 Retreatment | -5.04 log10 IU/mL | Standard Deviation 0.802 |
Secondary
For Participants in the Retreatment Substudy, Percentage of Participants With HCV RNA < LLOQ at Retreatment Weeks 2, 4, 8, 12, 16, 20, and 24
Time frame: Weeks 2, 4, 8, 12, 16, 20, and 24 of the Retreatment Substudy
Population: Participants in the Full Analysis Set who entered the Retreatment Substudy were analyzed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LDV/SOF 12 Weeks | For Participants in the Retreatment Substudy, Percentage of Participants With HCV RNA < LLOQ at Retreatment Weeks 2, 4, 8, 12, 16, 20, and 24 | Week 2 Retreatment | 88.9 percentage of participants |
| LDV/SOF 12 Weeks | For Participants in the Retreatment Substudy, Percentage of Participants With HCV RNA < LLOQ at Retreatment Weeks 2, 4, 8, 12, 16, 20, and 24 | Week 4 Retreatment | 100.0 percentage of participants |
| LDV/SOF 12 Weeks | For Participants in the Retreatment Substudy, Percentage of Participants With HCV RNA < LLOQ at Retreatment Weeks 2, 4, 8, 12, 16, 20, and 24 | Week 8 Retreatment | 100.0 percentage of participants |
| LDV/SOF 12 Weeks | For Participants in the Retreatment Substudy, Percentage of Participants With HCV RNA < LLOQ at Retreatment Weeks 2, 4, 8, 12, 16, 20, and 24 | Week 12 Retreatment | 100.0 percentage of participants |
| LDV/SOF 12 Weeks | For Participants in the Retreatment Substudy, Percentage of Participants With HCV RNA < LLOQ at Retreatment Weeks 2, 4, 8, 12, 16, 20, and 24 | Week 16 Retreatment | 100.0 percentage of participants |
| LDV/SOF 12 Weeks | For Participants in the Retreatment Substudy, Percentage of Participants With HCV RNA < LLOQ at Retreatment Weeks 2, 4, 8, 12, 16, 20, and 24 | Week 20 Retreatment | 100.0 percentage of participants |
| LDV/SOF 12 Weeks | For Participants in the Retreatment Substudy, Percentage of Participants With HCV RNA < LLOQ at Retreatment Weeks 2, 4, 8, 12, 16, 20, and 24 | Week 24 Retreatment | 100.0 percentage of participants |
Secondary
For Participants in the Retreatment Substudy, Percentage of Participants With SVR at 4, 12, and 24 Weeks After Discontinuation of Therapy (SVR4, SVR12, and SVR24)
SVR4, SVR12, and SVR 24 were defined as HCV RNA \< LLOQ at 4, 12, and 24 weeks after stopping study treatment, respectively.
Time frame: Posttreatment Weeks 4, 12, and 24 of Retreatment Substudy
Population: Participants in the Full Analysis Set who entered the Retreatment Substudy were analyzed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LDV/SOF 12 Weeks | For Participants in the Retreatment Substudy, Percentage of Participants With SVR at 4, 12, and 24 Weeks After Discontinuation of Therapy (SVR4, SVR12, and SVR24) | SVR4 | 88.9 percentage of participants |
| LDV/SOF 12 Weeks | For Participants in the Retreatment Substudy, Percentage of Participants With SVR at 4, 12, and 24 Weeks After Discontinuation of Therapy (SVR4, SVR12, and SVR24) | SVR12 | 88.9 percentage of participants |
| LDV/SOF 12 Weeks | For Participants in the Retreatment Substudy, Percentage of Participants With SVR at 4, 12, and 24 Weeks After Discontinuation of Therapy (SVR4, SVR12, and SVR24) | SVR24 | 88.9 percentage of participants |
Secondary
For Participants in the Retreatment Substudy, Percentage of Participants With Virologic Failure
Virologic failure was defined as: * On-treatment virologic failure: * Breakthrough (confirmed HCV RNA ≥ LLOQ after having previously had HCV RNA \< LLOQ while on treatment), or * Rebound (confirmed \> 1 log10 IU/mL increase in HCV RNA from nadir while on treatment), or * Non-response (HCV RNA persistently ≥ LLOQ through 8 weeks of treatment) * Virologic relapse: * Confirmed HCV RNA ≥ LLOQ during the posttreatment period having achieved HCV RNA \< LLOQ at last on-treatment visit.
Time frame: Up to Posttreatment Week 24 of Retreatment Substudy
Population: Participants in the Full Analysis Set who entered the Retreatment Substudy were analyzed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LDV/SOF 12 Weeks | For Participants in the Retreatment Substudy, Percentage of Participants With Virologic Failure | On-Treatment Virologic Failure | 0 percentage of participants |
| LDV/SOF 12 Weeks | For Participants in the Retreatment Substudy, Percentage of Participants With Virologic Failure | Virologic Relapse | 11.1 percentage of participants |
Secondary
Percentage of Participants That Maintain HIV-1 RNA < 50 Copies/mL While on HCV Treatment
Time frame: Weeks 4, 8, and 12
Population: Participants in the Safety Analysis Set with available data were analyzed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LDV/SOF 12 Weeks | Percentage of Participants That Maintain HIV-1 RNA < 50 Copies/mL While on HCV Treatment | Week 4 (N = 335) | 98.5 percentage of participants |
| LDV/SOF 12 Weeks | Percentage of Participants That Maintain HIV-1 RNA < 50 Copies/mL While on HCV Treatment | Week 8 (N = 334) | 98.2 percentage of participants |
| LDV/SOF 12 Weeks | Percentage of Participants That Maintain HIV-1 RNA < 50 Copies/mL While on HCV Treatment | Week 12 (N = 334) | 97.9 percentage of participants |
Secondary
Percentage of Participants With HCV RNA < LLOQ at Weeks 1, 2, 4, 6, 8, 10, and 12
Time frame: Weeks 1, 2, 4, 6, 8, 10, and 12
Population: Participants in the Full Analysis Set with available data were analyzed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LDV/SOF 12 Weeks | Percentage of Participants With HCV RNA < LLOQ at Weeks 1, 2, 4, 6, 8, 10, and 12 | Week 1 (N = 335) | 29.3 percentage of participants |
| LDV/SOF 12 Weeks | Percentage of Participants With HCV RNA < LLOQ at Weeks 1, 2, 4, 6, 8, 10, and 12 | Week 2 (N = 335) | 81.2 percentage of participants |
| LDV/SOF 12 Weeks | Percentage of Participants With HCV RNA < LLOQ at Weeks 1, 2, 4, 6, 8, 10, and 12 | Week 4 (N = 335) | 98.8 percentage of participants |
| LDV/SOF 12 Weeks | Percentage of Participants With HCV RNA < LLOQ at Weeks 1, 2, 4, 6, 8, 10, and 12 | Week 6 (N = 335) | 99.1 percentage of participants |
| LDV/SOF 12 Weeks | Percentage of Participants With HCV RNA < LLOQ at Weeks 1, 2, 4, 6, 8, 10, and 12 | Week 8 (N = 334) | 99.4 percentage of participants |
| LDV/SOF 12 Weeks | Percentage of Participants With HCV RNA < LLOQ at Weeks 1, 2, 4, 6, 8, 10, and 12 | Week 10 (N = 332) | 100.0 percentage of participants |
| LDV/SOF 12 Weeks | Percentage of Participants With HCV RNA < LLOQ at Weeks 1, 2, 4, 6, 8, 10, and 12 | Week 12 (N = 332) | 100.0 percentage of participants |
Secondary
Percentage of Participants With SVR at 4 and 24 Weeks After Discontinuation of Therapy (SVR4 and SVR24)
SVR4 and SVR 24 were defined as HCV RNA \< LLOQ at 4 and 24 weeks after stopping study treatment, respectively.
Time frame: Posttreatment Weeks 4 and 24
Population: Full Analysis Set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LDV/SOF 12 Weeks | Percentage of Participants With SVR at 4 and 24 Weeks After Discontinuation of Therapy (SVR4 and SVR24) | SVR4 | 96.7 percentage of participants |
| LDV/SOF 12 Weeks | Percentage of Participants With SVR at 4 and 24 Weeks After Discontinuation of Therapy (SVR4 and SVR24) | SVR24 | 96.1 percentage of participants |
Secondary
Percentage of Participants With Virologic Failure
Virologic failure was defined as: * On-treatment virologic failure: * Breakthrough (confirmed HCV RNA ≥ LLOQ after having previously had HCV RNA \< LLOQ while on treatment), or * Rebound (confirmed \> 1 log10 IU/mL increase in HCV RNA from nadir while on treatment), or * Non-response (HCV RNA persistently ≥ LLOQ through 8 weeks of treatment) * Virologic relapse: * Confirmed HCV RNA ≥ LLOQ during the posttreatment period having achieved HCV RNA \< LLOQ at last on-treatment visit.
Time frame: Up to Posttreatment Week 24
Population: Participants in the Full Analysis Set with available data were analyzed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LDV/SOF 12 Weeks | Percentage of Participants With Virologic Failure | On-Treatment Virologic Failure (N = 335) | 0.6 percentage of participants |
| LDV/SOF 12 Weeks | Percentage of Participants With Virologic Failure | Virologic Relapse (N = 333) | 3.0 percentage of participants |