**4. Antiviral therapy**

214 Liver Transplantation – Basic Issues

64, 65]. IL-28B-gene encodes an antiviral protein - IFN-λ with antiviral properties in response to IFN-α, and is upregulated by peripheral blood mononuclear cells and hepatocytes during HCV-infection [40, 66-68]. Recently, a significant association of IL-28Bgenotype distribution was observed with the median grade of inflammation (p<0.001), mean levels of aminotransferases (ALT: p=0.001, AST: p=0.003; fig.5), median pre-treatment viremia level within 1 year after LT (p=0.046) and interferon-based antiviral therapy failure (p<0.001). IL-28B polymorphism (rs8099917) seems to influence the degree of graft

inflammation at biochemical and histological levels [64].

Fig. 5. Levels of aminotransferases according to IL-28B-genotypes

population [60, 64].

indication for antiviral treatment.

**3.7 Organ allocation system** 

Among successfully treated patients G-allele was significantly less frequent and GGgenotype was not present at all [64]. G-allele might serve as a marker for graft inflammation and as predictor for unfavorable antiviral therapy outcome in HCV-re-infected LT-

The identification of non-invasive inflammation and fibrosis markers might help to differentiate re-infected patients with stable graft function without significant inflammation or fibrosis progression from patients at risk for short-term graft damage and define the

Methodological changes in the principals of graft allocation may affect the course of HCVassociated graft disease. Since December 2006 liver graft allocation has been carried out according to MELD-score, which primarily assesses the impairment of liver function and secondarily reflects the extent of kidney damage. Some evidence arises about the negative impact of the current allocation system regarding survival, rate of re-transplantation, fibrosis progression and success of antiviral treatment. Therefore, the MELD-score, as an The indication for HCV-treatment after LT depends on the individual clinical and biochemical condition after a definitive stabilization of the graft function, which is usually achieved within six post-operative months [69]. Analogously to the natural setting, therapy regimen is based on the administration of pegylated interferon-α2a (Peg-IFN-α2a) and ribavirin (RBV) for 12-18 months. Interferons are natural proteins with antiviral, antiproliferative and immunomodulatory features. They are responsible for the intracellular RNA-degradation and the inhibition of RNA-translation. Among all known interferons (IFN-α, IFN-β, Peg-IFN-α2b), pegylated IFN-α2a seems to have the highest antiviral potency, though similar to Peg-IFN-α2b, demonstrating superior treatment results in patients with HCV-re-infection [19, 70-75]. Attenuation of renal clearance and improved biochemical stability may explain prolonged half-time and therapeutical advantages observed. Ribavirin inhibits inosinmonophosphate-dehydrogenase and reduces the intracellular concentration of guanosin. RBV-monotherapy may significantly decrease the HCV-load (1 log step).

For a better comparability of results, the treatment outcome has been divided into widely accepted terms: end of treatment response (ETR: HCV-negativity at the end of treatment), sustained virologic response (SVR: HCV-RNA-negativity 6 months after therapy completion), relapse (detectable HCV-RNA after therapy completion), breakthrough (detectable HCV-RNA during treatment after initial therapy response) and non-response (persistent HCV-load under treatment). SVR before transplantation is observed in 50% of all treated cases with HCV-genotype-1 and in 80% with genotypes 2-3 [74]. As long as IFNα remains the backbone of antiviral therapy, the identification of predictors for the therapy outcome is crucial. 50% of graft recipients survive 10 years without any significant fibrosis progression and in some cases even without antiviral treatment (own data, Charité, Berlin, Berlin). Therefore, unnecessary exposition to adverse therapy events in non-responders could be avoided by improved predictability. HCV-genotype and early viral kinetics are predominantly considered to be important for therapy performance and its potential modification [69, 76]. Apart from the identified factors (high levels of immunosuppression, corticosteroid-based ACR-treatment and HCV-genotype-1b), unfavorable host- and donorrelated genetic confounders are suspected to exert a negative influence on the course and success of antiviral treatment [22, 69, 77]. According to several studies, genetic variants of IL-28B are strongly considered to affect the antiviral therapy results [64, 78, 79]. Along with other accepted predictive parameters, IL-28B-genotyping may be a useful diagnostic instrument for the indication and performance of antiviral therapy before and after LT [52, 60, 78, 80].
