Hepatitis C Virus Donor Positive Kidney Transplantation for Hepatitis C Virus Negative Recipients

Study Overview
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Brief Summary
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The development of direct acting anti-virals (DAAs) for the treatment of Hepatitis C virus (HCV) has changed the landscape of HCV therapy dramatically in the last several years with reported sustained virologic response (SVR) rates in excess of 95% for treatment-naïve HCV positive patients including those who have received liver or kidney transplants. Since these new regimens do not include interferon and have already been studied in the post-liver and kidney transplant setting, they now offer a unique opportunity to expand the donor pool and improve the lives of those awaiting renal transplant. The address this gap in knowledge, the investigators hypothesize that pre-emptive treatment with a direct acting anti-viral HCV medication to cure HCV soon after transplant would allow for safe transplantation of HCV positive kidneys in disadvantaged and needy HCV negative kidney recipients with acceptable risks and improved survivals compared with historical cohorts.

Detailed Description
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Traditionally, HCV+ kidneys are not offered to HCV- patients on the waiting list. The primary concern with offering HCV+ kidneys to HCV- recipients is a risk of viral transmission. Although data about the long-term impact of HCV+ kidney transplantation in to HCV- recipients is unclear, there was a clear suggestion of an increased risk of liver disease in these patients based upon studies performed in the 1990s. Traditional therapy with Interferon could not be offered to these patients as it can lead of rejection if kidney transplant. It was recently reported that nearly 65% (out of a total 6546) of all HCV+ kidneys were discarded between the years 2005-2014. These kidneys were otherwise of excellent quality and could have benefitted more than 4000 patients with 12,000 plus years of graft life. Since the recent FDA approval of Direct Acting Anti-virals (DAA), these drugs have now been shown to be safe and efficacious even in the setting of kidney transplant. They could offer a unique opportunity to expand the kidney donor pool. For this study, the investigators hypothesize that pre-emptive treatment with a direct acting anti-viral HCV medication to cure HCV soon after transplant would allow for safe transplantation of HCV+ kidneys in disadvantaged and needy HCV- kidney recipients with acceptable risks and improved survivals compared with historical cohorts. This novel study will develop pilot data on the safety and efficacy of utilizing HCV+ kidneys in high-risk HCV- recipients in order to expand the donor pool and reduce the morbidity and mortality of hemodialysis.

Official Title
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Hepatitis C Virus Donor Positive Kidney Transplantation for Hepatitis C Virus Negative Recipients: A Trial of Ultra-short Duration Direct Acting Anti-viral Prophylaxis To Prevent Virus Transmission From Hepatitis C Viremic Donors To Hepatitis C Negative Kidney Transplant Recipients (DAPPER)

Conditions
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Kidney Transplant, Hepatitis C

Intervention / Treatment
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* Drug: Direct acting Anti-Viral Therapy using Epclusa or Zepatier


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: No evidence of HCV infection by HCV PCR (done at the time of the initial consent) Age>60 yrs with an expected waiting time>2 years; or Age<60 yrs with any one of the following risk factors: Diabetes, coronary artery disease, peripheral artery disease and/or cerebrovascular disease Willingness to provide informed consent Absence of a living donor. Exclusion Criteria: Estimated life expectancy of less than one year based on clinical judgment of the investigator Prior liver or renal transplantation Pregnant women Incarcerated patients Medical or social condition which in the opinion of the investigator will interfere with or prevent follow-up per protocol Unable or unwilling to return for follow-up visits Donor Exclusion Criteria: HBV sAg positive HIV PCR or antibody positive HCV RNA negative

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: HCV+ Donor Kidney Recipient<br>All HCV- participants who receive an HCV+ donor kidney transplant will receive a first 'on-call' dose of Epclusa (sofosbuvir/velpatasvir; Gilead) and then three more doses on post-operative Day 1, 2 and 3. Donor HCV Genotype data will be available by Day 7 of transplant. Patients will then be followed by serial HCV PCRs. Patients who are HCV PCR positive by Day 14 will be treated with Epclusa once daily x 12 weeks. | Drug: Direct acting Anti-Viral Therapy using Epclusa or Zepatier<br>* All patients will receive one 'on-call' dose of SOFOSBUVIR/VELPATASVIR (Epclusa, Gilead) immediately prior to transplant and one dose on post-operative Day 1 post-transplant. Patients who develop detectable HCV viremia will be initiated on Direct Acting Anti-viral (DAA) therapy between 2-4 weeks post-transplant. Patients with GT1 will be treated with ELBASVIR/GRAZOPREVIR (Zepatier, Merck) and those with GT2 or 3 will be treated with SOFOSBUVIR/VELPATASVIR (Epclusa, Gilead) based upon donor genotyping results<br>* Other names: Epclusa, Zepatier;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sustained Virologic Response (SVR) | Among the patients who develop HCV viremia SVR rates with DAA will be measured | 12 weeks | 
| Graft and Patient Survival | Age and co-morbidity will matched historical HCV- recipients as controls. Patient survival will also be compared to a contemporary cohort of wait listed patients who declined enrollment due to personal choice | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sustained Virologic Response (SVR) Follow Up 1 | Among the patients who develop HCV viremia SVR rates with DAA will be measured | 24 weeks | 
| Sustained Virologic Response (SVR) Follow Up 2 | Among the patients who develop HCV viremia SVR rates with DAA will be measured | 48 weeks | 
| Liver Disease | Among patients who develop HCV viremia liver disease progression will be measured using non-invasive panels like fibroscan | 1 year |