deLIVER: Direct Acting Antiviral Effects on the Liver
Condition: HCV Coinfection; Liver Disease; HIV
MeSH terms: Coinfection; Liver Diseases
Intervention: Sofosbuvir/Velpatasvir/Voxilaprevir [SOF/VEL/VOX]; Sofosbuvir/Velpatasvir (SOF/VEL)
Intervention description: antiviral therapy for HCV; antiviral therapy for HCV
Intervention MeSH terms: Sofosbuvir; Velpatasvir; Sofosbuvir-velpatasvir drug combination
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 15.0
Sex: All
Minimum age: 18 Years
Maximum age: 70 Years
Healthy volunteers: No

Summary:

      Open-label, partially-randomized plasma and liver sampling study to assess hepatitis C virus
      (HCV) kinetics during treatment with two (Sofosbuvir/Velpatasvir) or three
      (Sofosbuvir/Velpatasvir/Voxilaprevir) direct acting antivirals (DAAs)
    

Eligibility criteria:

        Inclusion Criteria Participants must meet all of the following inclusion criteria to be
        eligible for participation

          1. Ability and willingness of participant to provide written informed consent.

          2. Men and women age ≥18 to ≤70 years at study entry

          3. Body mass index (BMI) ≥ 18 kg/m2

          4. HCV RNA ≥ 10,000 IU/mL at Screening

          5. HCV genotype 1a at Screening or within 6 months of screening

          6. Chronic HCV infection (≥ 6 months) documented by prior medical history

          7. HCV treatment-naïve with no prior treatment with any IFN, RBV, or approved or
             experimental HCV-specific DAA

          8. Absence of cirrhosis as defined as transient elastography (FibroScan®) liver stiffness
             measurement < 12.5 kPa within 6 months of screening

          9. The following laboratory values obtained within 42 days prior to study entry. •
             Hemoglobin > 10 g/dL for men and > 9 g/dL for women

             • Platelet count ≥90,000/mm3

             • International normalized ratio (INR) ≤1.5

             • Calculated creatinine clearance (CrCl) ≥ 30 mL/min

             • Alanine aminotransferase (ALT) and aspartate aminotransferase level ≤ 10 x upper
             limit of the normal range (ULN)

             • Total bilirubin <3 mg/dL

             • Albumin ≥3.5 g/dL

               -  CD4+ cell count ≥200 cells/uL and CD4+ cell percentage ≥14% within 42 days of
                  study entry at any US laboratory that has a Clinical Laboratory Improvement
                  Amendments (CLIA) certification [HIV seropositive participants only]

               -  HIV RNA < 400 copies/mL prior to study entry by any US laboratory that has a CLIA
                  certification or its equivalent [HIV seropositive participants only]

         10. On a qualifying antiretroviral therapy (ART) regimen which is permitted with SOF/VEL.
             This allows for antiretroviral regimen that does not include Efavirenz, Nevirapine, or
             Tipranavir.

         11. Women of childbearing potential must have a negative serum pregnancy test at Screening
             and a negative urine pregnancy test on Day 0 prior to liver biopsy

         12. All participants must agree not to participate in a conception process (e.g., active
             attempt to become pregnant or to impregnate, sperm donation, in vitro fertilization).

         13. If participating in sexual activity that could lead to pregnancy, the participant (men
             and women) must also agree to use two reliable methods of contraception simultaneously
             while receiving study treatment and for 30 days after stopping study treatment.

             A combination of TWO of the following contraceptives MUST be used appropriately:

             • Condoms (male or female) with or without a spermicidal agent

             • Diaphragm or cervical cap with spermicide

             • IUD (intrauterine device)

         14. Participants who are not of reproductive potential (women who have been
             post-menopausal for at least 24 consecutive months or have undergone hysterectomy,
             bilateral tubal ligation, and/or bilateral oophorectomy or men who have documented
             azoospermia) are eligible without requiring the use of contraceptives. Acceptable
             documentation of sterilization and menopause is specified below.

             Written or oral documentation communicated by clinician or clinician's staff of one of
             the following:

               -  Physician report/letter

               -  Laboratory report of azoospermia

               -  Follicle stimulating hormone-release factor (FSH) measurement elevated into the
                  menopausal range as established by the reporting laboratory.

         15. Participants must be able to adhere to dosing instructions for study drug
             administration and able to complete the study schedule of assessments, in the opinion
             of the investigator.

        Exclusion Criteria

        Subjects who meet any of the following exclusion criteria are not to be enrolled in this
        study:

          1. Breastfeeding.

          2. Known allergy/sensitivity or any hypersensitivity to components of study drugs or
             their formulation.

          3. Acute or serious illness requiring systemic treatment and/or hospitalization within 42
             days prior to study entry.

          4. Active hepatitis B infection (positive HBsAg) within 42 days prior to study entry.

          5. History of decompensated liver disease (including but not limited to encephalopathy,
             variceal bleeding, or ascites) prior to study entry.

          6. Any cause of liver disease other than chronic HCV infection, including but not limited
             to the following:

             • Hemochromatosis

               -  Alpha-1 antitrypsin deficiency

               -  Wilson's disease

               -  Autoimmune hepatitis

               -  Alcoholic liver disease

               -  Drug-related liver disease

          7. Uncontrolled or active depression or other psychiatric disorder within 24 weeks prior
             to study entry that in the opinion of the investigator might preclude adherence to
             study requirements.

          8. Active drug or alcohol use or dependence that, in the opinion of the investigator,
             would interfere with adherence to study requirements.

          9. Serious illness including uncontrolled seizure disorders, active coronary artery
             disease within 24 weeks prior to study entry, or other chronic medical conditions that
             in the opinion of the investigator might preclude completion of the protocol.

         10. Presence of active or acute AIDS-defining opportunistic infections within 12 weeks
             prior to study entry.

         11. Active or history of malignancy within 2 years prior to study entry other than basal
             cell carcinoma of the skin and/or cutaneous Kaposi's sarcoma (KS) and/or cervical or
             anal dysplasia or carcinoma in situ.

        13. Infection with any HCV genotype other than genotype 1a, or mixed genotype infection any
        time prior to study entry.

        14. History of major organ transplantation with an existing functional graft any time prior
        to study entry.

        15. History of acquired or hereditary bleeding disorder (e.g., hemophilia, warfarin use) or
        any other cause of or tendency toward excessive bleeding time prior to study entry.

        16. Gastrointestinal disorder or post-operative condition that could interfere with the
        absorption of the study drug 17. Difficulty with blood collection and/or poor venous access
        for the purposes of phlebotomy 18. Planning to take any of the following medications or
        supplements from Day -7 to the end of treatment:

          1. Proton pump inhibitors (patients may switch to H2 blockers up to Day -7)

          2. Inducers of P-gp (including, but not limited to, dexamethasone, morphine, ritonavir,
             saquinavir, tipranavir)

          3. Moderate to potent inducers of CYP2B6, CYP2C8, or CYP3A4 (including, but not limited
             to, efavirenz, etavirine, modafinil, rifampin, St. John's Wort, carbamazepine,
             phenytoin) 19. History of taking any dose of amiodarone within 6 months (180 days) of
             Day 0