Part A: Drug Interaction Study of Sofosbuvir and Antiretroviral Therapy (ART) Combinations in HIV and Hepatitis C Virus (HCV) Co-infected Patients. Part B: Efficacy and Safety of Sofosbuvir for 12 Weeks in HIV/HCV Co-infected Patients.

Study Overview
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Brief Summary
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This study consists of 2 parts, Part A and Part B. Part A, the Phase 1 drug interaction/early viral kinetic study, will evaluate the effect of selected antiretroviral therapies on the safety, viral kinetics, and pharmacokinetics of sofosbuvir (GS-7977; PSI-7977) and its metabolites in participants with HIV and hepatitis C virus (HCV) coinfection. Part B, the Phase 2 treatment study, will investigate the efficacy and safety of sofosbuvir, pegylated interferon alpha (PEG) and ribavirin (RBV) in participants with HIV/HCV coinfection.

Official Title
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Part A: Drug Interaction Study Between GS-7977 and Antiretroviral Therapy (ARV) Combinations of Efavirenz, Tenofovir and Emtricitabine; Efavirenz, Zidovudine and Lamivudine; Atazanavir/Ritonavir, Tenofovir and Emtricitabine; Darunavir/Ritonavir, Tenofovir and Emtricitabine; Raltegravir, Tenofovir and Emtricitabine in Human Immunodeficiency Virus and Hepatitis C Virus (HIV/HCV) Co-infected Patients. Part B: A Phase 2, Open-Label Study to Investigate the Efficacy and Safety of GS-7977 With Peginterferon Alfa 2a and Ribavirin for 12 Weeks in Treatment-Naïve HIV/HCV Co-infected Patients.

Conditions
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Hepatitis C, HIV

Intervention / Treatment
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* Drug: SOF
* Drug: EFV/FTC/TDF
* Drug: EFV
* Drug: ZDV/3TC
* Drug: ATV
* Drug: Ritonavir
* Drug: FTC/TDF
* Drug: DRV
* Drug: RAL
* Drug: PEG
* Drug: RBV


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy according to medical history and physical examination with exception of HCV and HIV diagnoses Confirmation of Chronic HCV infection Confirmation of Chronic HIV-1 infection On a stable protocol approved HIV antiretroviral (ARV) regimen with undetectable HIV-RNA Agree to use two forms of highly effective contraception for the duration of the study and 6 months after the last dose of study medication Subjects must be naive to treatment for chronic HCV infection Exclusion Criteria: Known or suspected cirrhosis History of any other clinically significant chronic liver disease A history consistent with decompensated liver disease. Use of any prohibited medications as defined by the protocol Pregnant or nursing female or male with pregnant female partner Contraindication to PEG or RBV therapy (for Part B) Clinically relevant drug or alcohol abuse

Ages Eligible for Study
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Minimum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A: SOF+EFV/FTC/TDF (Cohort 1)<br>Participants with a prestudy regimen of EFV/FTC/TDF will receive SOF+EFV/FTC/TDF FDC for 7 days, followed by EFV/FTC/TDF FDC (or EFV+FTC/TDF) for 7 days, coadministered once daily in the evening under fasting conditions. | Drug: SOF<br>* Sofosbuvir (SOF) 400 mg (1 × 400 mg tablet or 2 × 200 mg tablets) administered orally once daily<br>* Other names: PSI-7977;Drug: EFV/FTC/TDF<br>* Efavirenz (EFV) 600 mg/emtricitabine (FTC) 200 mg/tenofovir disoproxil fumarate (TDF) 300 mg fixed-dose combination (FDC) tablet administered orally once daily<br>* Other names: Atripla®;|
| Experimental: Part A: SOF+EFV+ZDV/3TC (Cohort 2)<br>Participants with a prestudy regimen of EFV+ZDV/3TC will receive SOF+EFV+ZDV/3TC for 7 days followed by EFV+ZDV/3TC for 7 days. Sofosbuvir and EFV will be administered once daily in the evening under fasting conditions; ZDV/3TC will be administered twice daily, in the morning without regard to food and in the evening on an empty stomach. | Drug: SOF<br>* Sofosbuvir (SOF) 400 mg (1 × 400 mg tablet or 2 × 200 mg tablets) administered orally once daily<br>* Other names: PSI-7977;Drug: EFV<br>* Efavirenz (EFV) 600 mg tablet administered orally once daily<br>* Other names: Sustiva®;Drug: ZDV/3TC<br>* Zidovudine (ZDV) 300 mg/lamivudine (3TC) 150 mg FDC tablet administered orally twice daily<br>* Other names: Combivir®;|
| Experimental: Part A: SOF+RTV+ATV+FTC/TDF (Cohort 3)<br>Participants with a prestudy regimen of RTV+ATV+FTC/TDF will receive SOF+RTV+ATV+FTC/TDF for 7 days followed by RTV+ATV+FTC/TDF for 7 days coadministered once daily in the morning with food. | Drug: SOF<br>* Sofosbuvir (SOF) 400 mg (1 × 400 mg tablet or 2 × 200 mg tablets) administered orally once daily<br>* Other names: PSI-7977;Drug: ATV<br>* Atazanavir (ATV) 400 mg tablet administered orally once daily<br>Drug: Ritonavir<br>* Ritonavir (RTV) 100 mg tablet administered orally once daily<br>Drug: FTC/TDF<br>* FTC/TDF (200/300 mg) FDC tablet administered orally once daily<br>* Other names: Truvada®;|
| Experimental: Part A: SOF+RTV+DRV+FTC/TDF (Cohort 4)<br>Participants with a prestudy regimen of RTV+DRV+FTC/TDF will receive SOF+RTV+DRV+FTC/TDF for 7 days followed by RTV+DRV+FTC/TDF for 7 days coadministered once daily in the morning with food. | Drug: SOF<br>* Sofosbuvir (SOF) 400 mg (1 × 400 mg tablet or 2 × 200 mg tablets) administered orally once daily<br>* Other names: PSI-7977;Drug: Ritonavir<br>* Ritonavir (RTV) 100 mg tablet administered orally once daily<br>Drug: FTC/TDF<br>* FTC/TDF (200/300 mg) FDC tablet administered orally once daily<br>* Other names: Truvada®;Drug: DRV<br>* Darunavir (DRV) 800 mg (2 × 400 mg tablets) administered orally once daily<br>|
| Experimental: Part A: SOF+RAL+FTC/TDF (Cohort 5)<br>Participants with a prestudy regimen of RAL+FTC/TDF will receive SOF+RAL+FTC/TDF for 7 days followed by RAL+FTC/TDF for 7 days. Sofosbuvir and FTC/TDF will be administered once daily in the morning with food; RAL will be administered twice daily, in the morning with food and in the evening without regard to food. | Drug: SOF<br>* Sofosbuvir (SOF) 400 mg (1 × 400 mg tablet or 2 × 200 mg tablets) administered orally once daily<br>* Other names: PSI-7977;Drug: FTC/TDF<br>* FTC/TDF (200/300 mg) FDC tablet administered orally once daily<br>* Other names: Truvada®;Drug: RAL<br>* Raltegravir (RAL) 400 mg administered administered orally twice daily<br>|
| Experimental: Part B: SOF+PEG+RBV<br>Participants will receive SOF+PEG+RBV for 12 weeks. | Drug: SOF<br>* Sofosbuvir (SOF) 400 mg (1 × 400 mg tablet or 2 × 200 mg tablets) administered orally once daily<br>* Other names: PSI-7977;Drug: PEG<br>* Pegylated interferon alfa (PEG) 180 μg administered once weekly by subcutaneous injection<br>* Other names: Pegasys®;Drug: RBV<br>* Ribavirin (RBV) tablets administered orally in a divided daily dose according to package insert weight-based dosing recommendations (< 75kg = 1000 mg and ≥ 75 kg = 1200 mg)<br>* Other names: Ribasphere®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Plasma Pharmacokinetics of SOF, EFV, Tenofovir (TFV), and FTC: AUCtau at Day 7 | AUCtau: concentration of drug over time (area under the plasma concentration versus time curve over the dosing interval). Data for this outcome measure were collected for participants in Part A only. | Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 hours postdose | 
| Part A: Plasma Pharmacokinetics of SOF, EFV, TFV, and FTC: Cmax at Day 7 | Cmax: maximum observed concentration of drug in plasma. Data for this outcome measure were collected for participants in Part A only. | Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 hours postdose | 
| Part B: Percentage of Participants With Sustained Virologic Response (SVR) at 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. Data for this outcome measure were collected for participants in Part B only. | Posttreatment Week 12 | 
| Incidence of Adverse Events Leading to Permanent Discontinuation of Study Drug(s) | The percentage of participants discontinuing any study drug due to an adverse event was summarized. | Up to 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part B: Percentage of Participants With Sustained Virologic Response at 4 and 24 Weeks After Discontinuation of Therapy (SVR4 and SVR24) | SVR4 and SVR24 was defined as HCV RNA < LLOQ at 4 and 24 weeks following the last dose of study drug, respectively. Data for this outcome measure were collected for participants in Part B only. | Posttreatment Weeks 4 and 24 | 
| Part B: Percentage of Participants Experiencing Viral Breakthrough or Viral Relapse | Viral breakthrough was defined as having confirmed detectable HCV RNA levels (HCV RNA > LLOQ) on treatment after having previously had undetectable HCV RNA levels (HCV RNA < LLOQ) while on treatment. Viral relapse was defined as having achieved undetectable HCV RNA levels (HCV RNA < LLOQ) at end of treatment, but did not achieve an SVR. Data for this outcome measure were collected for participants in Part B only. | Posttreatment Weeks 4 and 24 |