Clinical trial NCT02533934: Sofosbuvir Based DAA Therapy in HIV/HCV Coinfected Pre or Post Liver Transplant
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: HIV
Hepatitis C
Cirrhosis
Keywords: HIV
Hepatitis C
Liver Disease
HCV Treatment
transplant
Lead sponsor: University of California, San Francisco
Sponsor class: OTHER
Collaborators: name: National Institute of Allergy and Infectious Diseases (NIAID)
name: Icahn School of Medicine at Mount Sinai
name: Columbia University
name: University of Pennsylvania
name: University of Maryland, College Park
name: Georgetown University
name: Johns Hopkins University
name: National Institutes of Health Clinical Center (CC)
First posted: 2015-08-27
Enrollment: 68
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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

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.

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

Primary outcomes:
measure: Number of Participants With Sustained Virologic Response (SVR)
timeFrame: Median time from end of treatment was 38.5 months
Secondary outcomes:
measure: Reversal in Decompensation
timeFrame: Median months from baseline to last MELD measurement is 48 months
measure: Change in Liver Fibrosis
timeFrame: Median months from baseline to last APRI measurement is 41 months Median months from baseline to last FIB-4 measurement is 41 months
measure: HIV Viral Breakthrough or Relapse
timeFrame: Median months from baseline to last HIV follow-up is 38 months
measure: Number of Subjects Treated With Sofosbuvir-based DAA Therapy Who Had Alanine Aminotransferase (ALT) Normalization Post Treatment (Normal Reference Range: 7 - 55 IU/L)
timeFrame: Median months from baseline to last ALT measurement is 41 months
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: University of California, San Francisco
state: California
city: Washington
country: United States
facility: Georgetown University
state: District of Columbia
city: Baltimore
country: United States
facility: University of Maryland
state: Maryland
city: Baltimore
country: United States
facility: Johns Hopkins Medical Center
state: Maryland
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center
state: Maryland
city: New York
country: United States
facility: Mt. Sinai Medical Center
state: New York
city: New York
country: United States
facility: Columbia University
state: New York
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
Study officials:
affiliation: University of California, San Francisco
name: Peter Stock, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: National Institutes of Health Clinical Center (CC)
name: Henry Masur, MD
role: PRINCIPAL_INVESTIGATOR
References: