Transplant-Related Accelerated Progression of Hepatitis C
Transplant-Related Accelerated Progression of Hepatitis C
This study will explore why severe scarring of the liver (cirrhosis) develops so rapidly in
 hepatitis C-infected patients who have had a liver transplant and possibly in kidney
 transplant patients as well. The hepatitis C virus (HCV) can cause cirrhosis in about 20
 percent of infected persons. Generally, it takes 20 years or more for cirrhosis to develop.
 After liver transplantation, however, patients may develop cirrhosis in as little as 5 years.
 Cirrhosis does not develop as rapidly in kidney transplant patients, but it may develop
 faster than in people who do not undergo transplantation. The study will look at the possible
 role of immune-suppressing medications given to liver and kidney transplant patients in
 increasing the severity of hepatitis C infection and in speeding the cirrhotic process.

 Patients 18 years of age and older with chronic HCV infection who require a liver transplant
 for end-stage liver disease or a kidney transplant for kidney failure may be eligible for
 this study. Liver transplant patients are recruited from the Inova Fairfax Liver Transplant
 Center in Fairfax, Virginia, and from the Georgetown University Medical Center Liver
 Transplant Institute in Washington, D.C. Kidney transplant patients are recruited from the
 Transplantation Branch of the National Institute of Diabetes and Digestive and Kidney
 Diseases.

 Participants undergo the following procedures:

 -  Regular care: As part of their regular transplant-related treatment, patients have a
 medical history, physical examinations and blood draws before their transplant and on
 regularly scheduled visits after the transplant.

 -  Blood draws for research: Special blood tests are done to measure the immune response to
 HCV. They measure the amount of HCV in the blood, the number of HCV strains present and
 how they change over time and the HCV antibodies in the blood.

 -  Liver biopsies: This procedure is done at 3 months, 1 year, 3 years and 5 years after
 the transplant to determine the extent of scarring of the liver and to study the immune
 responses within the liver, the proportion of liver cells infected with HCV and the
 presence of scar-producing cells. The biopsy is done during a 1- to 2-day inpatient
 hospital stay. The patients are given a sedative medication through a vein before the
 procedure. The skin over the biopsy site is numbed and the biopsy needle is passed
 rapidly into and out of the liver to collect a small sample of liver tissue for study.

 -  Apheresis: This procedure is done to collect a large number of white blood cells needed
 to test the immune response to the HCV. On the day before each liver biopsy, blood is
 drawn through a needle from a vein in one arm and run through a machine that separates
 and collects the white cells. The red cells and plasma are returned to the patient's
 body through the same needle or a second needle in the other arm.
Nearly all patients with hepatitis C virus (HCV) related end-stage liver disease who receive
 an orthotopic liver transplant (OLT) develop hepatitis C reinfection of the graft after
 transplantation. Most of these patients will progress to chronic hepatitis and 20-30% will
 experience a rapid progression to cirrhosis. It is unclear why it generally takes 20 or more
 years for progression to cirrhosis after the initial HCV infection, but as little as five
 years after OLT. Additionally, it is paradoxical that hepatitis C, which is thought to be
 immune-mediated, should advance more rapidly in patients who are immune suppressed. Rapid
 fibrosis progression post-transplantation is likely related to complex interactions between
 viral factors, host immune responses and induction and maintenance of immunosuppression for
 the prevention of graft rejection.

 This study has been designed as an observational, hypothesis-generating pilot study of
 patients with chronic hepatitis C requiring organ transplantation and concomitant
 immunosuppression. Patients who require a liver-transplant for chronic hepatitis C-related
 end-stage liver disease and patients with hepatitis C who require a kidney transplant for
 renal failure will be enrolled and followed for up to five years. Virologic, immunologic and
 intrahepatic parameters will be correlated with the level of immunosuppression, degree of
 fibrosis, progression to cirrhosis and liver-related deaths in study subjects. The objectives
 of this study are to: 1) determine the proportion of patients with hepatitis C that progress
 to bridging fibrosis or cirrhosis at three and five years after liver or kidney
 transplantation (rapid-progressors); 2) compare virologic, host-immune and intrahepatic
 factors in rapid-progressors to non-progressors and slow progressors; 3) characterize the
 relationship between general and HCV-specific immune responses and the extent of liver
 fibrosis; and 4) develop a predictive model that discriminates between rapid-progressors and
 non- or slow-progressors.
-  INCLUSION CRITERIA

 To fulfill criteria for study entry, the patient must:

 -  be 18 years of age or older.

 -  have detectable HCV RNA

 -  require orthotopic liver transplantation for chronic hepatitis C induced cirrhosis or
 require renal transplantation for end-stage kidney disease

 -  have a MELD score greater than 18 (for liver transplant patients) or have an otherwise
 high probability of receiving a liver or kidney transplant within six months of
 enrollment based on assessment by the clinical transplant team at each hospital.

 -  be able/willing to travel to the collaborating center for blood sampling prior to
 liver or kidney transplantation, and at 2, 3, 4, 5, 6, 8, 12, 16, 24 weeks after
 transplantation and then bi-annually until the end of the study at 5 years

 -  be willing to have study-related liver biopsies at 3 months, and then 1, 3 and 5 years
 after transplantation

 -  provide informed consent.

 EXCLUSION CRITERIA:

 To fulfill criteria for study entry, the patient must NOT:

 -  be HIV or Hepatitis B virus (HBsAg) positive

 -  receive a liver graft from an anti-HCV antibody positive or HBV core positive donor

 -  have other forms of liver disease including primary biliary cirrhosis, autoimmune
 hepatitis, hemochromatosis and Wilson's Disease

 -  have hepatocellular carcinoma if any single lesion is 5 cm. or more or if there are 3
 or more lesions exceeding 3 cm.

 -  be on immunomodulatory medications such as corticosteroids within four weeks of
 collection of blood for pre-transplant baseline laboratory testing

 -  have been diagnosed with any hereditary or acquired immunodeficiency state prior to
 liver or kidney transplantation