Sofosbuvir Based DAA Therapy in HIV/HCV Coinfected Pre or Post Liver Transplant (STOP-CO)

A Retrospective/Prospective Cohort Study to Assess Safety, Tolerability, and Efficacy of Sofosbuvir Based Direct Acting Antiviral (DAA) Therapy for Hepatitis C Treatment in HIV/HCV Coinfected Subjects Pre or Post Liver Transplant

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

Study Overview

• Status: Completed
• Conditions: Hepatitis C; HIV; Cirrhosis
• Intervention / Treatment: Drug: Harvoni

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 68
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • California
    • San Francisco, California, United States, 94143
      • University of California, San Francisco
  • District of Columbia
    • Washington, District of Columbia, United States, 20057
      • Georgetown University
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins Medical Center
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health Clinical Center
  • New York
    • New York, New York, United States, 10032
      • Columbia University
    • New York, New York, United States, 10029
      • Mt. Sinai Medical Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment with Sofosbuvir based HCV Therapy; Prospective and retrospective treatment for HCV	Drug: Harvoni; Treatment of Hepatitis C with sofosbuvir based HCC therapy; Other Names: SOF/LDV

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Sustained Virologic Response (SVR)	Sustained virologic response (SVR) defined by hepatitis C virus (HCV) RNA less than the lower level limit of quantification (LLOQ) of <15 IU/ml at a median time of 38.5 months after the end of sofosbuvir-based direct-acting antiviral (DAA) therapy	Median time from end of treatment was 38.5 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Reversal in Decompensation	Number of participants with an improved, worsened or unchanged MELD (Model for End-stage Liver Disease) score. A MELD score ranges from 6 to 40. The higher the number, the worse the liver disease.	Median months from baseline to last MELD measurement is 48 months
Change in Liver Fibrosis	Change in AST to Platelet Ratio Index (APRI) where negative values indicate improvement in liver fibrosis score and positive values indicate worsening of fibrosis score. There is no upper or lower limit for change. Change in Fibrosis-4 (FIB-4) where negative values indicate improvement in liver fibrosis score and positive values indicate worsening of fibrosis score. There is no upper or lower limit for change.	Median months from baseline to last APRI measurement is 41 months Median months from baseline to last FIB-4 measurement is 41 months
HIV Viral Breakthrough or Relapse	Number of participants with a detectable HIV viral load after sofosbuvir-based HCV therapy	Median months from baseline to last HIV follow-up is 38 months
Number of Subjects Treated With Sofosbuvir-based DAA Therapy Who Had Alanine Aminotransferase (ALT) Normalization Post Treatment (Normal Reference Range: 7 - 55 IU/L)	Change in ALT after sofosbuvir based DAA therapy	Median months from baseline to last ALT measurement is 41 months

Collaborators and Investigators

• Sponsor: University of California, San Francisco
• Collaborators: National Institutes of Health Clinical Center (CC); Johns Hopkins University; National Institute of Allergy and Infectious Diseases (NIAID); University of Pennsylvania; Georgetown University; Columbia University; Icahn School of Medicine at Mount Sinai; University of Maryland, College Park
• Investigators: Principal Investigator: Henry Masur, MD, National Institutes of Health Clinical Center (CC)

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2016
• Primary Completion (Actual): December 31, 2019
• Study Completion (Actual): December 31, 2019

Study Registration Dates

• First Submitted: August 25, 2015
• First Submitted That Met QC Criteria: August 25, 2015
• First Posted (Estimate): August 27, 2015

Study Record Updates

• Last Update Posted (Actual): February 2, 2021
• Last Update Submitted That Met QC Criteria: January 12, 2021
• Last Verified: January 1, 2021

More Information

Terms related to this study

• Keywords: transplant; HIV; Hepatitis C; Liver Disease; HCV Treatment
• Additional Relevant MeSH Terms: Digestive System Diseases; RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Liver Diseases; Flaviviridae Infections; Hepatitis, Viral, Human; Enterovirus Infections; Picornaviridae Infections; Hepatitis; Hepatitis A; Hepatitis C; Anti-Infective Agents; Antiviral Agents; Ledipasvir, sofosbuvir drug combination
• Other Study ID Numbers: 12044; 1U01AI115714 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO