NATURAL COURSE AND TREATMENT OUTCOME IN HEPATITIS C RECURRENCE AFTER LIVER TRANSPLANTATION

Hepatitis C virus (HCV) infection post-liver transplantation (post-LT) is associated with an increased rate of fibrosis progression compared to non-transplanted patients. Thus, 25% of the recipients will progress to cirrhosis within 5 years after LT. Antiviral treatment after LT with peg-INF and ribavirin (RBV) yields lower sustained viral response (SVR) than in nontransplanted patients. In many LT-recipients non-response to treatment will eventually lead to progression to cirrhosis. The aim of this thesis was to study the natural course and treatment outcome in liver transplant patients with hepatitis C recurrence, and the influence of baseline factors on the course of the HCV recurrence and antiviral treatment, with particular emphasis on HCV genotype and IL28B gene polymorphism. In paper I we conducted a pilot-study on 21 hepatitis C LT recipients with the aim to increase adherence and tolerance to antiviral treatment. All recipients were pre-treated with Darbepoetin (EPO) starting 2 weeks before the initiation of Peg-IFN and RBV. RBV was dosed taking weight and kidney function into account, with a target serum concentration set to10 μM/L by using a formula to calculate the dose. A majority of patients achieved the target concentration, and 90% could stay adherent to a full treatment course. SVR was reached in 18% recipients with genotype 1 and 60% with genotype non-1. Recipients with mild fibrosis achieved SVR in 67%. In paper II we studied the influence of IL28B gene polymorphism on fibrosis progression and treatment outcome in 54 LT recipients, who had received antiviral treatment, and in 45 of their donors. The most favorable IL28B genotype CC was associated with slower fibrosis progression and better treatment outcome. Patients with HCV genotype non-1 and the IL28B CC gene achieved SVR in 71%, whereas patients with genotype 1 and IL28B non-CC did so in only 23%, p < 0,016. Patients with mild fibrosis (F1-2) had better treatment outcome than patients with advanced fibrosis. In paper III we treated 46 Swedish and 8 Norwegian patients with the treatment regimen evaluated in paper I. 94% stayed adherent to the treatment course. SVR was achieved in 82% of recipients with HCV genotype 2/3 versus in only 22% with genotype 1, p < 0.002. Patients with IL28B CC achieved SVR in 73% and patients with non-CC in 33%, p < 0.001. Patients with mild fibrosis achieved SVR in 56% and patients with advanced fibrosis in 26% p < 0.01. Thus, with favorable HCV genotype and IL28B genotype, LT recipients have a good chance to achieve SVR, when treated before advanced fibrosis has developed. In paper IV we evaluated the utility of an early liver biopsy post-LT to detect and predict fibrosis progression of recurrent HCV infection post-LT. 35 HCV RNA positive, and 11 HCV RNA negative LT recipients, who underwent protocolled liver biopsies 6 and 12 months post-LT, were studied. Histological recurrence with fibrosis stage ≥ F1was noted in 56% of the HCV positive LT recipients at 6 months, and in 82% 12 months post-LT. Acute cellular rejection (ACR) and IL28B genotype CC were associated with a more pronounced fibrosis progression 12 months post-LT. Fibrosis was absent in all eleven recipients who were HCV RNA negative directly after LT. Thus, a 6 months biopsy post-LT is a valuable tool for detection of an early HCV recurrence, which makes an early treatment intervention for HCV possible. LIST OF SCIENTIFIC PAPERS I. Ackefors M, Gjertsen H, Wernerson A, Weiland O. Concentration-guided ribavirin dosing with darbepoetin support and peg-IFN alfa-2a for treatment of hepatitis C recurrence after liver transplantation. J Viral Hepat. 2012 Sep;19(9):635-9. II. Ackefors M, Nystrom J, Wernerson A, Gjertsen H, Sonnerborg A, Weiland O. Evolution of fibrosis during HCV recurrence after liver transplantation influence of IL-28B SNP and response to peg-IFN and ribavirin treatment. J Viral Hepat. 2013 Nov;20(11):770-8 III. Ackefors M, Castedal M, Dahlgard O, Verbaan H, Gjertsen H, Wernerson A, Weiland O. Cost-effective treatment for genotype 2 and 3 Hepatitis C Recurrence after Liver Transplantation. Submitted manuscript IV. Ackefors M, Wernerson A, Gjertsen H, Weiland O. The utility of an early liver biopsy to predict fibrosis progression of recurrent hepatitis C after liver transplantation. Submitted manuscript