Sofosbuvir Based DAA Therapy in HIV/HCV Coinfected Pre or Post Liver Transplant
Condition: HIV; Hepatitis C; Cirrhosis
MeSH terms: Hepatitis A; Hepatitis C; Hepatitis
Intervention: Harvoni
Intervention description: Treatment of Hepatitis C with sofosbuvir based HCC therapy
Intervention MeSH terms: Ledipasvir, sofosbuvir drug combination
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 68.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: HIV; Hepatitis C; Liver Disease; HCV Treatment; transplant

Summary:

      Retrospective/Prospective, open-label study using sofosbuvir based DAA therapy to treat
      HIV/HCV coinfected pre or post liver transplant participants
    

Eligibility criteria:

        RETROSPECTIVE ARM INCLUSION CRITERIA

        The intent of the Retrospective Arm is to capture all HIV/HCV coinfected patients exposed
        to sofosbuvir based DAA therapy since 2014, to mirror the population enrolled in the
        Prospective Arm.

        Liver transplant candidates (listed) and decompensated cirrhotics (not listed) for liver
        transplant

          1. Treated with sofosbuvir based DAA for any duration since 2014

          2. Age >18 years at time of treatment

          3. Pre-treatment Child's Pugh score of 7 or greater

          4. Pre-treatment laboratory MELD >=6 and <=0

          5. Survived at least 12 weeks after start of treatment

          6. HIV-positive on stable ART for at least 4 weeks pre-treatment

          7. Chronic HCV infection with at least one measurement of plasma HCV RNA >= 1,000 IU/mL
             prior to treatment with sofosbuvir based DAA therapy

          8. HCV genotype 1, 4, 5 or 6

        Liver transplant recipients

          1. Treated with sofosbuvir based DAA post liver transplant for any duration since 2014

          2. Liver transplant from 2000 to current

          3. Age >18 years at time of treatment

          4. Treated initiated at least 1 month post-liver transplant

          5. Post-LT stage of liver disease documented within the prior year of treatment start
             date by standard of care methods of liver staging

          6. Survived at least 12 weeks after start of treatment

          7. HIV-positive on stable ART for at least 4 weeks pre-treatment

          8. Chronic HCV infection with at least one measurement of plasma HCV RNA >= 1,000 IU/mL
             prior to treatment with sofosbuvir based DAA therapy

          9. Fibrosis staging done within 1 year of start of DAA therapy

         10. HCV genotype 1, 4, 5 or 6

        PROSPECTIVE ARM INCLUSION/EXCLUSION CRITERIA

        Pre-liver transplant candidates

          -  Enrollment will be targeted to occur at least 12 weeks prior to anticipated transplant
             date.

          -  Screening laboratory MELD >=6 and <=20 (NIH) or <=30 (non-NIH sites)

        Post-liver transplant recipients

          -  Recipients with evidence of recurrent HCV viremia

          -  Subjects with compensated and decompensated liver disease

          -  Screening laboratory MELD >=6 and <=20 (NIH) or <=30 (non-NIH sites)

          -  Life expectation of >12 weeks

        Inclusion Criteria

          1. Over 18 years of age at screening

          2. Female participants of child bearing potential must have a negative urine pregnancy
             test at day 0 prior to dosing.

          3. Has received a liver transplant for HCV or has decompensated cirrhosis (Child's Pugh
             score of 7 or greater)

          4. Have HIV-1 infection and either:

               1. On HIV medications (antiretrovirals) for at least 4 weeks WITH

                    -  An HIV viral load less than the level of detection OR

               2. On no HIV medications for at least 8 weeks WITH:

                    -  A CD4 count of 500 cells/mm3 or more OR

                    -  HIV viral load of < 500 copies/mL with a stable CD4 count for at least 3
                       months

          5. Chronic HCV infection as documented by at least one measurement of plasma HCV RNA >=
             1,000 IU/mL during screening and at least one of the following:

             A positive anti-HCV antibody, HCV RNA, or an HCV genotype test at least 12 months
             prior to baseline (Day 0) visit together with positive HCV RNA test

          6. HCV genotype 1, 4, 5 or 6

          7. The use of an anti-HCV positive donor is allowed for participants who have detectable
             HCV RNA at the time of transplant.

          8. The use of an HIV+ donor is allowed if the participant is enrolled in an IRB approved
             HOPE Act protocol at the transplant site. If the HIV+ donor is also HCV co-infected,
             then the recipient must have detectable HCV RNA at the time of transplant.

          9. Able to effectively communicate with the Investigator and other center personnel.

         10. Willing to give written informed consent and comply with the study restrictions and
             requirements.

         11. Willingness to allow stored blood or tissue samples to be used in the future for
             studying liver disease and immune function.

         12. Willingness to permit HLA typing to be performed.

         13. Have a transplant team available for all primary and transplant-related care.

         14. If not yet transplanted: expected to be at least 12 weeks prior to transplant in order
             to complete treatment course.

         15. If not yet transplanted: Must have prior standard of care liver staging consistent
             with F4.

         16. If not yet transplanted: For pre-LT patients with HCC, they must meet Milan criteria
             at time of enrollment to be eligible

         17. If post-liver transplant, must be at least 1 month since transplant procedure to begin
             treatment.

         18. If post-liver transplant, liver disease staging must be documented within the prior
             year by standard of care methods of liver staging

        Exclusion Criteria

          1. Positive HBsAg at screening.

          2. History of any other clinically active chronic liver disease (e.g., hemochromatosis,
             autoimmune hepatitis, Wilson's disease, >=1 antitrypsin deficiency, alcoholic liver
             disease, and toxin exposures).

          3. Treatment with unlicensed herbal/natural remedies suggested to be taken for hepatitis
             treatment, such as Milk thistle, St. Johns Wort or Cats Claw, within 28 days of start
             of treatment

          4. Treatment with IFN, RBV, telaprevir or boceprevir or any other approved or
             experimental medication with known anti-HCV activity within 1 month prior to screening
             date

          5. Any prior exposure to an HCV NS5a specific inhibitor

          6. A personal history of or first degree relative with a history of Torsade de pointes.

          7. Abnormal hematological and biochemical parameters, including:

               1. Hemoglobin < 8g/dL

               2. Estimated GFR, calculated by the CKD-EPI equation, <30 mL/min/ per 1.73 m2

               3. Sodium <120 mmol/L

          8. History of major organ transplantation other than liver or kidney transplantation.

          9. Difficulty with blood collection/poor venous access for phlebotomy that would prevent
             the collection of study required samples

         10. Infection requiring systemic antibiotics at the time of screening

         11. Active or recent history (≤ 6 months) of drug or alcohol abuse

         12. Gastrointestinal disorder or post-operative condition that could interfere with the
             absorption of the study drug.

         13. Donation or loss of more than 400 mL blood within 8 weeks prior to first dose
             administration.

         14. Any medications prohibited (see table 2 in section 8.11) within 28 days prior to Day 0
             visit and likely required during study treatment period

         15. History of clinically significant drug allergy to nucleoside/nucleotide analogs.

         16. History or current evidence of psychiatric illness, endocrine, immunologic disorder,
             pulmonary, cardiac disease, seizure disorder, cancer or other conditions that in the
             opinion of the investigator makes the patient unsuitable for the study. Chronic
             medical conditions, especially if treated with medications (such as hypertension),
             must be stable at the time of screening. No new therapies should be started within 28
             days prior to the study that may confound the assessment of study drug safety.

         17. Participation in a clinical study (other than an IRB approved HOPE Act protocol
             involving the utilization of an HIV+ donor) in which an investigational drug,
             biologic, or device was received within 12 weeks prior to first dose administration.

         18. Pregnant/Breastfeeding women