**2. Hepatitis B**

234 Liver Transplantation – Basic Issues

combination with ribavirin in a standard dose of 800–1200 mg/kg daily (or at least 10.6mg/kg/day). Duration of treatment is 48 weeks, but in previous relapsers or nonresponders can be extended to 72 weeks or longer provided that there is an early viral response (EVR) at the end of the third month. Only a small proportion of patients are able to continue therapy without initial dose reductions and/or discontinuation mostly due to severe anemia or another cytopenia. The best predictors of SVR are non-1 genotype, achievement of viral clearance after 3 months of therapy, good compliance (>80% of IFN and >80% of RBV received) and less advanced fibrosis. EVR seems to have the strongest impact on treatment outcome. The most important concern regarding antiviral treatment in transplant setting is an increased risk of either acute or chronic rejection. Treatment of ACR episode requires otherwise unwanted high doses of steroids, and chronic rejection may lead to retransplantation. Recent studies suggest that ACR develops due to decreasing levels of immunosuppressive drugs after viral clearance and subsequent improvement of hepatic microsomal function. Reported rejection rates vary in respect to the study design, being lower in randomized controlled trials (0-5%) [Chalasani et al., 2005; Samuel et al., 2003) and as high as 35% in uncontrolled trials (Dumortier et al., 2004; Sharma et al., 2007; Stravitz et al., 2004). Berenguer M et al. reported trend towards higher rejection rate on pegylated IFN in comparison with standard treatment (Berenguer et al., 2006b). Also *de novo* autoimmune hepatitis due to immunomodulatory properties of IFN and RBV may develop in 0.4 to 3.4 %

It is estimated that approximately 10% of HCV-positive transplant patients will require retransplantation (reLT) due to graft decompensation (Carrion et al., 2010). Similarly to the indications for the primary LT, hepatitis C may soon become the major indication for reLT. Many patients will not be able to survive until reLT is feasible as the mortality on the waiting list varies between 50 and 80%, and many transplant centers hesitate to retransplant patients with recurrent HCV disease due to inferior results of reLT in comparison with non-HCV candidates (Pelletier et al., 2005). However, there is no firm evidence that the unfavorable scenario after primary LT is going to repeat after reLT in every HCV-positive recipient. Moreover, other recent studies do not identify HCV recurrence as a predictor of increased mortality in comparison with other etiologies with the exception of reLT performed during the first year after primary LT (Ghobrial et al., 2002). Based on multivariate analysis it was shown that early reLT performed in HCV-positive patients is an independent predictor of morality after reLT, indicating that severe hepatitis C recurrence (such as FCH or another reason for early graft dysfunction) should be a contraindication for retransplantation (Ghabril et al., 2008). Multiple prognostic scores were implemented to facilitate decisions which reLT would be unreasonable due to compromised graft and patient survival. Many of them are routinely used for urgent LT, and therefore are not appropriate for candidates with recurrent HCV disease who need an elective retransplantation. Prognostic criteria, traditionally used in patients with cirrhosis, such as MELD and Child-Pugh scores, turned out to be more accurate in the exclusion of high risk candidates. The ILTS expert panel concluded that bilirubin > 10mg/dL, creatinine > 2mg/dl (or EGFR < 40 ml/min), recipient age > 60 years, donor age > 40 years and early HCVrelated cirrhosis (< 1 year post-LT) were the variables significantly associated with poorer outcome and with increased mortality (Wiesner et al., 2003). Lately, a MELD score >28 was

of treated patients (Selzner et al., 2011).

**1.5 Retransplantation in HCV recurrence** 

Liver transplantation for hepatitis B is a true success story. In the early 1990s HBV infection was a relative contraindication for LT as the risk of recurrence was greater than 80% (depending on pre-transplant viral load) and the mortality rate was approximately 50% at 2 years. That was comparable with results of LT in malignancies (O'Grady et al., 1992). Introduction of effective immunoprophylaxis and very potent oral antivirals revolutionized this area in the last two decades and made HBV the best etiology for LT in terms of patient and graft survival (Lake et al., 2005). The number of LTs performed for this indication steadily declines in the Western countries due to effective vaccination program and good results of anti-HBV treatment, but in Asia the majority of patients undergoing LT still has HBV related end-stage liver disease or fulminant hepatitis. Overall, 5 to 10% of LTs worldwide are performed in HBsAg-positive patients (Terrault et al., 2005). By dint of long-term use of hepatitis B immune globulin (HBIG) combined with highly effective and well-tolerated nucleoside/nucleotide analogues (NUCs) HBV reinfection rate decreased below 10% (Angus et al., 2000; Marzano et al., 2001). Together with these favorable results there are, however, some concerns. According to current understanding of HBV pathogenesis complete withdrawal of reinfection prophylaxis is not feasible. Life-long prophylaxis makes LT for hepatitis B a very expensive procedure. Economical pressure stimulates studies on various alternatives which are cheaper and more convenient for the patient. Moreover, long-term use of HBIG is associated with some side-effects and the development of escape mutants in HBsAg region. Indefinite use of NUCs plus surface antigen mutations during long-term HBIG administration pose a great risk of multidrug resistance. Novel strategies need to be developed to optimize outcomes in this setting.
