**HCV-Recurrence After Liver Transplantation**

Dennis Eurich, Marcus Bahra and Peter Neuhaus

 *Charité Campus Virchow / General, Visceral and Transplant Surgery / Berlin, Germany* 

#### **1. Introduction**

204 Liver Transplantation – Basic Issues

Sugawara Y, Makuuchi M, Matsui Y et al. Preemptive therapy for hepatitis C virus after

Hepatology 1999; 29:365-370.

living-donor liver transplantation. Transplantation 2004; 78: 1308-1311.-Rosen HR, Madden JP, Martin P. A model to predict survival following liver retransplantation.

> Hepatitis-C-virus (HCV) represents one of the most serious threats for human liver and chronic HCV-infection results in the development of liver cirrhosis and hepatocellular carcinoma (HCC). HCV is an enveloped RNA-virus belonging to the flaviviridae family. Currently six identified HCV-genotypes, different in their geographic distribution define the severity of pathogenic effect, disease course and treatment results. About 1.5% of the European population are HCV-positive. Although the natural history of HCV-infection is rather slow, highly variable disease progression may lead to a rapid loss of liver function [1, 2]. An estimated annual incidence of new infections (3-4 millions) explains 170 million HCV-positive people worldwide. 80% of all HCV-infections become chronic and fewer than 25% of HCV-positive individuals are clinically apparent presenting either in a clinically stable state with few only symptoms or with fully decompensated liver disease with a dire prognosis [1, 3, 4]. Once chronic HCV-infection is established, the rates of spontaneous viral clearance remain discouraging.

> The development of liver fibrosis is the main determinant of morbidity and mortality of HCV-positive patients [1]. Fibrosis results from excessive formation of extracellular matrix (ECM). The established imbalance of fibrogenesis and fibrolysis during chronic liver damage, which leads to scarring of the liver, is accompanied by a progressive loss of liver function despite the use of antiviral or anti-inflammatory agents [1, 5]. HCV-re-infection can trigger the excess synthesis and deposition of ECM usually by activation of cytokine release [1, 5]. Activated macrophages, lymphocytes, bile duct epithelia but also endothelia and myofibroblasts are sources of fibrogenic cytokines and growth factors that can stimulate hepatic stellate cells HSCs to produce ECM-molecules leading to fibrosis during chronic liver injury [1, 5]. The most prominent fibrogenic cytokine seems to be the transforming growth factor-β1 (TGF-β1), which is released during inflammation, tissue regeneration and fibrogenesis. TGF-β1 is considered to play a pivotal role in the hepatic fibrogenesis strongly increasing the production and deposition of ECM-components [1, 6]. Fibrosis progression is influenced by a whole range of virus, host and environmental factors. Advanced age, male gender, race (black), viral co-infection (HBV), alcohol intake and genetic background seem to influence the course of the disease [7-10]. For patients with HCV-induced end-stage liver disease (ESLD) liver transplantation (LT) remains the treatment of choice according to functional (cirrhosis CHILD B-C) or neoplastic (HCC) severity of hepatic injury [11]. 30-50% of all LTs are performed due to HCV-associated ESLD thus representing one of the leading LT-indications.

Regarding the recurrence of pre-transplant diseases after LT, HCV-re-infection may represent one of the most important threats to graft and patient survival after primarily successful transplantation. Although remarkable differences in the course of HCV-infection exist between pre- and post-transplant settings, the uniform picture of liver or graft cirrhosis is similar and comparable to a certain extent.

#### **2. HCV-recurrence after liver transplantation**

HCV-recurrence after LT is one of the most important issues regarding the spectrum of current graft diseases. Despite comparable pathophysiological processes, the course of graft hepatitis is usually more progressive compared to the natural setting of HCV-infection [11-15].

#### **2.1 Epidemiological and etiological aspects**

Most of the patients either show biochemical or histological signs of inflammation, whereas 30% of all graft recipients develop graft cirrhosis within 5 years after LT, leading to an impaired patient survival and a dubious transplant success. Progressive loss of graft function may even require re-transplantation despite of consistent antiviral treatment [16].

Arbitrary in use and manifold in extent, the term "HCV-recurrence" implies the whole spectrum of graft disease such as asymptomatic infection, graft-hepatitis, fibrosis and eventually transplant cirrhosis. The uniform picture of end stage graft disease comprises scar formation and replacement of liver parenchyma by connective tissue as a result of accelerated fibrogenesis [1, 17, 18]. Clinical presentation of graft function loss is very similar to the natural setting though more rapid and progressive. Ascites, variceal bleeding, encephalopathy and jaundice are common results of graft decompensation.

Patient survival with HCV-recurrence is dramatically compromised compared to non-HCVrelated transplants [15]. Several studies pointed out significantly lower survival rates in HCV-positive recipients due to accelerated fibrosis development. Survival analysis performed in a cohort of 2294 patients (Charité, Berlin, Germany since 1988) demonstrated highly significant differences (unpublished data) comparing 455 HCV-positive to 1839 HCVunrelated transplants (p<0.001; fig.1).

Fig. 1. Disease-related post-transplant survival

Persisting in the extrahepatic reservoir, HCV reappears as a universal post-transplant phenomenon, leading to the development of graft disease in a highly variable manner. At the moment of hepatectomy HCV-load may become even undetectable indicating the importance of the liver as major HCV-reservoir. After transplantation, HCV-redistribution arises from extrahepatic sources (lymphatic tissue) and HCV-viremia reappears within first post-transplant days [19, 20]. Molecular analysis has shown that postoperative viral strains are identical to those detected before transplantation. HCV-load literally explodes after one week achieving values of one logarithmic step higher compared to pre-transplant condition basically due to indispensable immunosuppressive medication [21]. Among currently known genetic HCV-variants (1-5), genotype-1b predominates in the post-transplant setting due to selection as the most stubborn [22].
