**3. HCV antiviral treatment**

196 Liver Transplantation – Basic Issues

Recent studies appear to show that polymorphisms in the interleukin 28 B gene (*IL-28B*), in both the donor and the recipient, may influence not only the response to antiviral therapy but also the evolution of hepatitis C due to post-transplant HCV reinfection, with a worse evolution in those with the genotypes CT and TT (of the polymorphism rs12979860) as

Agreement exists that immunosuppression is significantly associated with the natural history of recurrent hepatitis C (Samuel et al, 2006). However, controversy still surrounds the role of each immunosuppressive agent on HCV replication and the evolution of hepatitis

Immunosuppression contributes greatly to the increased viral load that takes place in these patients during the immediate post-transplant months. The recipient's cellular immune response against the infected hepatocyte, and thus against the virus, is altered. It is almost absent in patients with fibrosing cholestatic hepatitis and severe disease recurrence

The role of the type of immunosuppressive regimen and its influence on the progression of recurrence are still unclear and there is no established ideal immunosuppression protocol. The use of high-dose steroid boluses to treat episodes of acute rejection, , has been shown to be clearly prejudicial, as they condition an increase in viral replication, a more aggressive relapse and increased early post-transplant mortality (Samuel et al 2006, Berenguer et al,

Some studies suggest the possible benefit of maintaining low-dose steroid regimens with progressive withdrawal during the first 6-12 months (Berenguer et al, 2006a). However, two recent meta-analyses found that steroid-free immunosuppression protocols are significantly better and provide benefits related with such factors as the acute graft hepatitis, HCV recurrence, cholesterol levels and the development of de novo diabetes mellitus (Sgourakis et al, 2009, Segev et al, 2008). Thus, the use of steroid-free immunosuppression protocols

Regarding the use of calcineurin inhibitors, numerous studies have compared the recurrence of HCV with the two drugs, cyclosporine and tracrolimus. However, the results are not completely conclusive, with most studies failing to find differences. Thus, it is not possible to recommend the use of a specific calcineurin inhibitor. There seems to be evidence that the use of cyclosporine during interferon treatment may be beneficial, and that tacrolimus seems to reduce episodes of acute rejection and the need for steroid boluses. A possible beneficial immunosuppressive regimen could be to start with tacrolimus and later substitute it with cyclosporine if antiviral treatment is considered necessary for HCV recurrence (Berenguer et al, 2007, Levy et al, 2006, O´Grady et al, 2007). For other immunosuppressive agents, such as mycophenolate, azathioprine, mTor inhibitors or anti-IL-2 receptor antibodies, no solid studies have yet been done from which to obtain conclusions. In summary, therefore, the only firm recommendation would be to avoid a state of overimmunosuppression, avoiding steroid boluses and full-dose triple or quadruple regimens.

This could lead to improved results in these patients (Berenguer et al, 2006a).

compared with the genotype CC (Charlton et al, 2011, Brocato et al, 2010).

**2.3.1 Role of immunosuppression in recurrence of hepatitis C** 

C on the graft.

2006a).

(McCaughan 2004, Samonakis et al, 2005).

improves the management of metabolic complications.

Although treatment is based on the administration of pegylated interferon and ribavirin, as is done in immunocompetent patients, no standardized consensus criteria exist about the ideal time to initiate such therapy, which patients should be treated or the most suitable dose or duration of the regimen. The 2010 Expert Opinion Meeting of the Italian Association for the Study of the Liver (AISF, 2010) established the following criteria for starting antiviral therapy in patients with post-transplant HCV reinfection: the presence of positive HCV-RNA serology, compatible liver histology (HCV recurrence and fibrosis stage ≥F2 (Scheuer)) and the exclusion of rejection, vascular disease or biliary obstruction, with level III evidence and grade B recommendation.

As HCV recurrence is one of the most usual causes of graft loss, it can be assumed that those patients who respond to treatment will have a better prognosis, and consequently, an improved survival. One of the main problems of antiviral therapy concerns its frequent, and sometimes severe, secondary effects, which reduce tolerability and thus efficacy. Thus, given the lack of universal methods to prevent graft reinfection, the only alternative is antiviral therapy, to be used at varying times around the transplantation.

#### **3.1 Pre-transplant antiviral therapy**

Pre-transplant therapy consists of treating patients with chronic HCV liver disease who are candidates for a liver transplant before the transplantation, in order to reduce the viral load or even make it negative, thereby avoiding later reinfection in the graft.

Studies indicate that using interferon and ribavirin up to 30% of patients manage to reach the time of transplant with negative viraemia, though a negative HCV-RNA prior to transplant does not guarantee the absence of post-transplant recurrence of infection (Charlton et alt, 1998). The main inconvenience of this regimen concerns the poor tolerance to treatment in patients with advanced cirrhosis, and the presence of more and worse side effects in relation to the evolution of the liver disease, so that it can only be used in fewer than 50% of patients. In 60% of those patients who do receive this regimen, the doses of pegylated interferon and ribavirin have to be reduced due to the high rate of undesired effects, and even occasionally stopped prematurely, which leads to the poor virological results seen. This therapeutic strategy, therefore, should be given prudently, and can be recommended for those patients on the transplant waiting list who have compensated liver disease (Child Pugh A plus hepatocarcinoma, for example), independently of the genotype and viral load, and in those patients in Child Pugh stage A-B and MELD ≤18 with a good virological response profile who have no contraindication to starting the treatment (Everson et al, 2005, Crippin et al, 2002).

#### **3.2 Post-transplant antiviral therapy**

Post liver transplant therapy can be given either shortly after the operation or some time later, when the recurrence of the hepatitis C is established.

### **3.2.1 Early post-transplant antiviral therapy (Pre-emptive therapy)**

Early treatment is given during the first weeks after the transplant (mainly between the second and sixth weeks). The idea behind this strategy is to anticipate the infection and eliminate the HCV before the hepatic lesion appears. Nevertheless, this early antiviral therapy has numerous limitations, such as the degree of post-transplant immunosuppression present in these patients; their clinical situation after the transplant, which affects their tolerance to treatment; their high viral load, partly related with the degree of immunosuppression, and the corresponding reduction in therapeutic success plus the high risk of episodes of rejection, which advise delaying treatment until a more suitable time from the immunological standpoint (Sheiner et al, 1998, Chalasani et al, 2005, Sugawara et al, 2004, Shergill et al, 2005).

This strategy is, however, applicable to all patients who receive a transplant due to HCV infection, including those who have no aggressive rejection episode and remain stable, with minimum hepatic lesions for whom antiviral therapy would perhaps not otherwise be indicated.

The viral response experienced, according to the various studies published, ranges from 1% to 13%. However, treatment had to be withdrawn early in 35% of the patients treated, due to adverse effects (Shergill et al, 2005). The application of this treatment regimen could perhaps be considered in those patients who receive a further transplant due to aggressive HCV infection or in coinfected (HIV) patients.
