**1.4.3 Treatment of established recurrent HCV hepatitis**

Treating significant HCV recurrence that has been confirmed in liver biopsy is currently the best option to manage post-LT HCV infection. With the exception of fibrosing cholestatic hepatitis (FCH) antiviral treatment should be initiated after the first year of transplantation. Decrease in the doses of immunosuppressive drugs result in the lower HCV-RNA levels and better tolerance. Patients become clinically stable and have fewer contraindications for IFN and RBV. This strategy requires ease in performing protocol or clinically driven liver biopsies with repeated frequency, or implementation of reliable non-invasive methods to detect liver fibrosis. Current policy is to treat well established HCV recurrence defined by grade 3 or 4 of inflammation or by at least grade 2 of fibrosis. In such way patients with mild and non-progressing disease avoid unnecessary treatment, related drug toxicities and possible serious complications. Despite these issues, study results show that the efficacy of anti-HCV therapy in transplant setting is poor and SVR can be achieved in around 20% of treated patients (Samuel et al., 2003). In randomized controlled trials and in trials with pegylated interferon SVR seems to be higher and reaches rates of 38-50% (Berenguer et al. 2006b). The target dose of peg-IFN is 1.5 µg/kg/week for α-2b and 180µg/week for α-2a in 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 % of treated patients (Selzner et al., 2011).

#### **1.5 Retransplantation in HCV recurrence**

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

added to that list (Zimmerman & Ghobrial, 2005). With use of these prognostic measurements as screening tools survival in HCV-infected patients after reLT reached similar rates as survival in non-HCV patients.
