A Prospective Cohort Study to Improve HCV Care in Dialysis Patients
A Prospective Cohort Study to Improve HCV Care in Dialysis Patients
Hepatitis C virus (HCV) infects an estimated 185 million individuals worldwide and 3.4
 million to 4.4 million people in the United States. Approximately 80% of acutely infected HCV
 patients progress to chronic infection, 20% of whom develop cirrhosis within 25 years, with
 25% of patients with cirrhosis developing hepatocellular carcinoma and/or decompensated liver
 disease. Hepatitis C virus is the primary cause of liver transplantation in the United
 States.

 There are 6 known genotypes of HCV. The most common genotypes in the United States are
 genotype 1 (subtypes 1a and 1b), 2, and 3, which together comprise 97% of all infections.

 In chronic kidney disease (CKD) patients, the prevalence of HCV infection is higher than in
 the general population. Patients with impaired kidney function have limited therapeutic
 options. The US Food and Drug Administration (FDA) recently approved Elbasvir/Grazopevir for
 treatment of genotype 1 and 4 infection in CKD patients including those on hemodialysis.

 At our institution, the Multidisciplinary Approach to the Treatment of Chronic Hepatitis C
 (MATCH) Initiative is a program which was first implemented to increase screening, diagnosis
 and treatment of HCV by actively incorporating primary care providers (PCP) at every step of
 the HCV care process. Following implementation of MATCH, early data indicates, marked
 increase in screening high risk and baby-boomer cohorts, as well as safe and effective
 treatment of HCV cases at the primary provider setting. The initiative proved that active
 participation of PCPs in the care of HCV reduced the treatment lag by 71% compared to
 traditional care of referring HCV cases to specialized care (Gastroenterology or Hepatology)
 while keeping similar SVR. We intend to expand the program to improve quality of care for HCV
 patients in dialysis center. We propose active involvement of dialysis clinical staff
 including nephrologist, to increase HCV screening rate, promote timely diagnosis and
 treatment of CHC in patient with end-stage renal disease.

 This study is being conducted to evaluate real-world effectiveness of HCV DAA therapy in CHC
 hemodialysis patients when the DAA-treatment is managed and monitored by the clinical staff
 of hemodialysis center.

 Primary objective: To determine sustained virologic response (SVR) rates attained with
 open-label Zepatier administered through hemodialysis center under the supervision of a
 nephrologist in chronic hepatitis C infected (CHC) patient currently on hemodialysis.

 Secondary objective:

 1. To estimate prevalence of HCV infection, severity of fibrosis (using non-invasive
 measures), and HCV detection rate in patients with End stage renal disease on
 hemodialysis.

 2. To calculate the average treatment-lag time (time from HCV diagnosis to submission of
 treatment approval).
This study is being conducted to evaluate real-world effectiveness of HCV DAA therapy in CHC
 hemodialysis patients when the DAA-treatment is managed and monitored by the nephrologist of
 hemodialysis center.

 Hepatitis C virus (HCV) infects an estimated 185 million individuals worldwide (1) and 3.4
 million to 4.4 million people in the United States.(2) Approximately 80% of acutely infected
 HCV patients progress to chronic infection, 20% of whom develop cirrhosis within 25 years,
 with 25% of patients with cirrhosis developing hepatocellular carcinoma and/or decompensated
 liver disease.(3) Hepatitis C virus is the primary cause of liver transplantation in the
 United States.(4) There are 6 known genotypes of HCV. The most common genotypes in the United
 States are genotype 1 (subtypes 1a and 1b), 2, and 3, which together comprise 97% of all
 infections.(5) Since the discovery of HCV in 1989 (6) strategies to cure the infection have
 evolved dramatically. A cure is defined as a sustained virologic response (SVR) and consists
 of undetectable levels of plasma HCV RNA 12 or 24 weeks after therapy completion.(7)
 Treatment of HCV has evolved rapidly and has led to improved rates of SVR.

 Although these highly effective therapies for hepatitis C virus (HCV) infection have
 revolutionized treatment, only a few patients are able to receive treatment.(8) Barriers
 arising at multiple levels, from diagnosis to specialist referral, that still need to be
 overcome to move toward disease eradication.(9) In chronic kidney disease (CKD) patients, the
 prevalence of HCV infection is higher than in the general population. Testing for HCV in
 hemodialysis patients should be repeated every 6 months.(10) The national study on
 dialysis-associated diseases was published in 2002 and represents the infection statistics
 from dialysis center nationwide.(11) The overall estimated prevalence of HCV antibody in this
 study was 7.8%.

 In addition, patients with impaired kidney function have limited therapeutic options. The US
 Food and Drug Administration (FDA) recently approved Elbasvir/Grazopevir for treatment of
 genotype 1 and 4 infection in CKD patients including those on hemodialysis.

 At our institution, the Multidisciplinary Approach to the Treatment of Chronic Hepatitis C
 (MATCH) Initiative is a program which was first implemented to increase screening, diagnosis
 and treatment of HCV by actively incorporating primary care providers (PCP) at every step of
 the HCV care process. Following implementation of MATCH, early data indicates, marked
 increase in screening high risk and baby-boomer cohorts, as well as safe and effective
 treatment of HCV cases at the primary provider setting. The initiative proved that active
 participation of PCPs in the care of HCV reduced the treatment lag by 71% compared to
 traditional care of referring HCV cases to specialized care (Gastroenterology or Hepatology)
 while keeping similar SVR. (13) We intend to expand the program to improve quality of care
 for HCV patients in dialysis center. We propose active involvement of dialysis clinical staff
 including nephrologist, to increase HCV screening rate, promote timely diagnosis and
 treatment of CHC in patient with end-stage renal disease.

 Rationale of the study- We will perform a phase IV study to prove real world effectiveness of
 Zepatier in successful treatment of CHC in patients on chronic hemodialysis at hemodialysis
 centers, when administered under the supervision of a nephrologist. The study will be
 conducted in the selected collaborative hemodialysis centers.

 Zepatier Open-label Zepatier (grazoprevir 100 mg and elbasvir 50 mg) will be administered in
 this study.(14, 15) Zepatier is a fixed-dose combination tablet without ribavirin. GZR is an
 HCV NS3/4a inhibitor while EBR is an HCV NS5A inhibitor. Both grazoprevir and elbasvir are
 direct-acting antivirals, which together form an effective therapy for HCV and reduce the
 likelihood and effects of long-term liver-related HCV complications.

 Zepatier has been evaluated globally in multiple phase I, II, and III trials to treat HCV.
 (14, 15) Randomized, placebo-controlled trials have been carried out, which led to FDA
 approval for Zepatier as a treatment for genotype 1 and 4 HCV.

 As of July 1, 2015, a diverse population of over 1000 HCV patients has been exposed to
 Zepatier either as a single agent or in combination with ribavirin or sofosbuvir in phase
 I/II/III studies. Zepatier has been generally well tolerated at doses of 50-100 mg GZR and 50
 mg EBR orally once daily. It has been comparably effective across all subgroups it has been
 tested in, including non-cirrhotic and/or treatment-naïve subjects. (14, 15) Headaches,
 fatigue, and nausea represent the most common adverse drug reactions with Zepatier.3,4 Other
 drug-related adverse events have included arthralgia, insomnia, diarrhea, dizziness, pyrexia,
 and asthenia. (14, 15) Drug-related serious adverse events are uncommon, but include allergic
 reactions, possible adverse interactions with other medications, or elevated liver enzymes.
 In past Zepatier trials, the majority of the adverse events were reversible. These adverse
 events are usually mild or moderate events.

 The dosage in our study (100/50 mg daily) is a commonly attainable dose in clinical practice.
 Zepatier has shown to be safe for subjects with chronic kidney disease or who are on
 hemodialysis. Less than 1% of Zepatier is excreted renally. In Merck's C-SURFER, a phase 1
 randomized, controlled Zepatier trial, subjects with advanced kidney disease tolerated the
 drug well for the required 12 weeks without dose adjustments. (16) Zepatier trials have
 demonstrated a 94-100% success rate achieving HCV RNA levels of <15 IU/ml after 12 weeks of
 treatment (SVR-12) among genotype 1 HCV patients. (14, 15) This is a prospective cohort phase
 IV study using multidisciplinary approach for the treatment of hepatitis C in hemodialysis
 patients. Hemodialysis centers will be used to deliver all HCV related care.

 The study will be conducted in the selected collaborative hemodialysis centers in
 Philadelphia. In addition to the standard of care (SOC), all subjects with CHC will be
 evaluated for HCV DAA therapy: review of clinical records, assessment of the degree of liver
 fibrosis using FibroScan, baseline HCV virological tests, HIV and HBV screening, etc.
 Baseline and follow-up laboratory tests and FibroScan imaging will be performed at the
 Einstein lab or an alternative laboratory if requested by the patient. Baseline clinical
 evaluation and follow up focused H/P will be done by the nephrologist at the dialysis unit..
 The study coordinator is a MATCH-D navigator and is responsible for compiling supporting
 documents for HCV DAA treatment request and fax it to a designated fax number (to mimic
 faxing to the payers in real world scenario). Local specialty pharmacy pharmacist (also a
 part of the MATCH-D group) will be responsible for providing hepatitis C treatment education
 to approved patients, ensure delivery of DAA therapy and monitoring for any drug related
 adverse events.

 MATCH-D group will comprise of a study coordinator, study investigators, nephrologist,
 specialty pharmacy pharmacist, and dialysis unit . The group will meet weekly to review cases
 and provide recommendations on diagnosis, DAA selection and assist with HCV treatment This
 study will be divided to 3 phases.

 1. Training study team, dialysis center clinical staff (Quarterly refresher)

 2. Identifying hepatitis C patient and evaluation for treatment

 3. Treatment and follow up Phase 1: Training study team and dialysis center clinical staff
 education All collaborative hemodialysis centers coordinator and the study team will be
 educated for HCV screening, work-up, treatment and study protocol in the first month of
 study. There will be refresher course every 3 months.

 Phase 2: Identifying hepatitis C patient and evaluation for treatment

 1. Patient Screening a. Every dialysis patient will be offered HCV screening every 6 months
 as standard of care.

 b. HCV Ab with reflex HCV viral load will be ordered.

 2. Patient Identification

 1. Patients will be assessed for positive HCV Ab and detectable viral load.

 2. Nephrologist will notifythe patient with the results.

 3. Nephrologist will have the patient complete and sign HIPAA form.

 4. Nephrologist will email patient information to the study coordinator.

 5. Study coordinator is expected to keep composite record (including the above
 results) of all identified patients until enrollment. This record will be utilized
 at the Multidisciplinary Meeting.

 6. Informed consent will be obtained by the study coordinator.

 7. Basic demographic information will be collected.

 3. Patient evaluation for treatment

 1. Complete blood work and FibroScan imaging will be conducted at Einstein lab or an
 alternative laboratory if requested by the patient.

 2. Study coordinator is expected to ensure patients have all testing completed.

 3. Study coordinator will ensure all patients are tested for FibroScan imaging using
 the portable FibroScan® 530 Compact system. .

 This trial will enroll approximately 71 compensated cirrhotic and non-cirrhotic, Genotype 1
 and 4, HCV patients who are currently on hemodialysis. Non-invasive test will be used to
 determine the presence or absence of cirrhosis. All excluded CHC patients will receive
 standard of care. Patients who have decompensated cirrhosis or hepatoma will be referred to
 the hepatology clinic and receive care by the hepatologist.

 Study visits There will be 4 study visits in our study. Subjects may be asked to come early
 before dialysis session to have physical examination or Fibroscan.

 Screening and Informed consent

 During screening period, the following procedures and activities will be performed at
 hemodialysis center after the informed consent is signed:

 -  Review medical history and physical examination

 -  Review medication list

 -  Review laboratory data Baseline study • First laboratory tests will be performed at the
 Einstein lab or an alternative laboratory if requested by the patientand include: • CBC,
 CMP, PT/INR • HCV PCR Viral load

 -  HCV PCR genotype

 -  HCV NS5A RAV testing

 -  HBV screening: HBsAg, HBcAb

 -  HIV 1 / 2 Ab screening

 -  FibroScan

 -  Women of childbearing potential will have a pregnancy test at screening visit.
 Phase 3: Treatment and follow up 1. Treatment a. MATCH-D group will review and
 discuss identified CHC patients and determine those appropriate for DAA therapy
 through the dialysis center, and those who require referral to Liver Center based
 on work-up (e.g. decompensated cirrhosis).

 i. Patients appropriate for dialysis center treatment and agreeable to treatment
 will be enrolled in study.

 b. Meeting to occur weekly c. Study coordinator will notify the nephrologist, who
 saw patient, by email of the meeting decision. Subsequently, the nephrologist
 should notify patient of the decision and a) refer to hepatology if needed or b)
 explain need for treatment.

 d. Prescription along with pertinent information (e.g. lab results, fibrosis stage,
 etc.) will be compiled and sent to local specialty pharmacy by the study
 coordinator for all enrolled patients.

 e. Specialty pharmacy will:

 1. Provide education to patients about prescribed treatment.

 2. Identify potential drug interactions and notify team.

 3. Oversee delivery of medications. Provide refill reminders to patients or
 dialysis center staff.

 4. Monitor medication adherence.

 5. Keep "database" that is accessible to study coordinator and MATCH-D study
 group Specialty pharmacy will be the investigational pharmacy who is
 expertised in HCV care.

 Initiation treatment with Zepatier All subjects will be provided with a 28-day supply of the
 study drug and instructed to begin treatment once all tests are done. The study coordinator
 will call the patient to ensure treatment has begun for HCV with Zepatier.

 As with any scientific protocol, safety will be considered before treating the patients. The
 MATCH-D team will evaluate the patient's overall condition and make a judgment on whether
 initiating treatment is safe.

 Zepatier for 12 weeks or 16 weeks ± Ribavirin will be used to treat HCV genotype 1, 4 in our
 patients and will be supplied by Merck & Co.Inc.

 Statistical Methods The data will be collected using an Excel spreadsheet and analyzed with
 Stata 14.0 (Statacorp., College Town, TX). Descriptive statistics will be used to summarize
 the demographic characteristics. Screening rates, treatment rates, and treatment lag (time
 from detection to treatment submission) will be calculated. Categorical variables will be
 compared using chi square or fischer's exact test whereas continuous variables will be
 compared using student's t-test. SVR rates will also be compared with historical controls. P
 value of less than 0.05 will be considered statistically significant.

 Power/Sample Size:

 Power of 0.8 with a p-value of 0.05 were used a priori for sample size calculation. As was
 shown in C-SURFER trial recently, SVR of 99% was attained in chronic kidney disease patients
 including those on dialysis. Accepting a non-inferiority margin of 5% and similar expected
 SVR in our cohort, the sample size was calculated to be 71 patients.

 Potential Benefits The subjects will get clinical benefits as the HCV treatment can prevent
 cirrhosis and hepatocellular carcinoma in the future. This study also has a potential to
 speed up treatment evaluation and the subjects may get the treatment faster.
Inclusion Criteria:

 -  Be 18 years of age or older on day of signing the informed consent form.

 -  Be on long term hemodialysis at any of the selected 4 collaborative hemodialysis
 centers

 -  Have positive anti-HCV antibody titers and detectable HCV RNA level before or after
 the initiation of MATCH-D.

 -  HCV genotype 1 and 4

 -  Have an HCV treatment status that is one of the following:

 1. Treatment naïve: Naive to all anti-HCV treatment

 2. Prior IFN or PEG-IFN + Ribavirin Treatment failures: Null responders, Partial
 responders, Relapsers

 3. P/R Intolerant: Subjects were intolerant to a prior IFN or PEG-IFN

 -  Ribavirin regimen, Subjects discontinued treatment prematurely and were
 therefore unable to complete a full course of therapy because of
 drug-related toxicity.

 Exclusion Criteria:

 -  Has evidence of decompensated chronic liver disease such as presence of or history of
 - ascites, gastric or variceal bleeding, hepatic encephalopathy or other signs or
 symptoms of advanced liver disease

 -  Have Child-Pugh B or C cirrhosis (these patients will need to be referred to a
 hepatologist for HCV therapy)

 -  Have a likelihood of receiving a renal transplant or liver transplant during the study
 treatment period.

 -  Have hepatocellular carcinoma

 -  Have other liver disease (which require HCV therapy to be delivered under the
 supervision of a hepatologist)

 -  A patient with a life expectancy less than 12 months

 -  Current untreated chronic hepatitis B infection HBsAg+ patients are excluded. Note:
 Patients with HBcAb+ will not be excluded, but will have HBV DNA levels checked and
 will be monitored while on DAA therapy and medically managed as considered appropriate
 by the PI.

 -  Have HIV and currently not under Antiretroviral Therapy (ART)

 -  Pregnant or nursing (lactating) women

 -  Albumin below 3g/dL

 -  Platelet count below 75,000

 -  Unable to comply with research study visits

 -  Poor venous access not allowing screening laboratory collection

 -  Have any condition that the investigator considers a contraindication to study
 participation