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

Approximately fifty HIV/HCV coinfected patients with decompensated liver disease will be enrolled in the study. Ten (up to twenty) subjects will be treated with FDC SOF/LDV pre or post liver transplant and followed prospectively. Forty + subjects will be enrolled retrospectively with the intent to capture all patients who have been exposed to sofosbuvir based DAA therapies at participating sites since 1/2014, and to mirror the population being enrolled prospectively.

In addition, participants in the retrospective arm will be contacted to consent to one prospective study visit for liver staging to determine rates of reversal of decompensation, reversal of cirrhosis and improvements in graft survival post treatment, and for future contact by the NIH Clinical Center to assess longer term outcomes when this study ends.

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

Prospective Subjects: from participants first dose until 6 months post treatment discontinuation, through study completion, up to twelve months, plus deaths at any-time. Retrospective Subjects: from participants first dose to end of treatment, through study completion, up to six months, plus deaths at any-time.

All serious adverse events were recorded from time of HCV treatment initiation until last followup for subjects enrolled prospectively (7). For subjects enrolled retrospectively (61), only serious adverse events related to hospitalizations during treatment with sofosbuvir based DAA therapy, anemia require transfusion or EPO during treatment with DAA therapy, or death were recorded.

This study was limited by the necessity to change the design from a prospective to a retrospective/prospective analysis. This change in study design resulted from the urgency in treating the HIV/HCV coinfected liver transplant candidate with DAAs, based on the dismal survival outcome in this cohort. By the time this trial was approved, many of the DAAs for HCV were approved, and centers immediately treated their decompensated HIV/HCV recipients.