**1.4.2 Early post-transplant antiviral treatment**

#### **1.4.2.1 Pros and cons of preemptive therapy**

Similarly to the idea of treating decompensated cirrhosis, early post-LT anti-HCV treatment has a theoretical rationale. It is well documented that the lower the HCV viremia, the more effective the antiviral therapy. Also treatment of acute hepatitis C gives extremely favorable results with almost 90% chance for viral clearance. However, transition of experience from immunocompetent patients onto the post-transplant setting is not possible due to several reasons. Indeed, HCV-RNA level rapidly decreases after reperfusion, but within one-two weeks reaches pretransplant load and tends to increase by 1 to 2 logs thereafter. Hence, time for antiviral intervention, optimal at the lowest viremia, is very narrow and falls to the moment of greatest clinical instability of the recipient (renal impairment, risk of rejection, risk of bacterial infection related to the surgical procedure, deep cytopenias, etc.). During early post-LT period patients are under the strongest immunosuppression and cannot spontaneously clear the virus as it happens in a significant proportion of immunocompetent patients with the acute C hepatitis. Moreover, immunological responses to HCV that were unable to clear the virus in the past, remain the same. These factors make early posttransplant anti-viral treatment a mission almost impossible. No more than two third of liver recipients are eligible for early treatment, but even if they start therapy, dose reductions as well as rate of discontinuation are very high (Sheiner et al., 1998; Verna & Brown, 2008).

#### **1.4.2.2 Treatment regimes**

Experience with interferon monotherapy, either standard or pegylated, is scarce and disappointing. Patients were started on therapy at a mean time of 2–3 weeks post LT. Results obtained with standard interferon did not show any SVR cases (Sheiner et al., 1998; Singh et al.,1998). According to Singh et al. prophylactic treatment with IFN did not have any influence on the severity of recurrent C hepatitis, whereas in the study of Sheiner et al. treated patients less frequently developed recurrent hepatitis on liver biopsy or had abnormal liver tests. In both studies discontinuation rate was high and IFN did not influence patient and graft survival. There was the only one well designed trial published to date with peg-IFN alone given prophylactically. According to Chalasani et al., SVR was a rare event (8% of treated patients vs. no treatment), but discontinuation from the study, rejection episodes, adverse events and life threatening complications were similar in both groups. One third of treated patients were withdrawn from the study (Chalasani et al., 2005).

Slightly better results were obtained using combined non-pegylated or pegylated IFN with ribavirin. In a study of Mazzaferro et al., SVR was achieved in 33.3% of patients treated with IFN and RBV in comparison with 13% of SVR in patients on IFN alone (Mazzaferro et al., 2003). Interestingly, those who cleared the virus, did not show recurrent hepatitis C. Less encouraging effects were shown by Terrault. Only 11% obtained SVR and there was no difference in the frequency of recurrent hepatitis between responders and non-responders (Terrault, 2003). In the latter trial therapy was initiated a bit later – within 6 weeks post LT – and almost 50% of recipients did not meet inclusion criteria. Only minority (23%) received a full-dose RBV, haemolytic anemia being the main reason for significant dose reduction or discontinuation, what may explain worse results. Experience with pegylated IFN in combination with RBV in preemptive anti-HCV treatment is very limited and further studies are necessary to draw conclusions.

Given that early post-LT antiviral treatment in not efficacious and requires further studying, the expert panel consensus conference recommends that it should be limited to rapidly progressing recurrent C hepatitis and *de novo* acute C hepatitis in recipients who received grafts from HCV-positive donors (Wiesner et al., 2003).

#### **1.4.2.3 Immunoprophylaxis**

232 Liver Transplantation – Basic Issues

individualized and very sick patients should be ruled out. Still the ideal candidate for pre-LT treatment is a patient in Child-Pugh class A to B, or MELD below 18 points listed because of HCC or history of variceal bleeding. Hopefully, novel therapies with combination of direct antiviral agents (DAA) such as protease or polymerase inhibitors will

Similarly to the idea of treating decompensated cirrhosis, early post-LT anti-HCV treatment has a theoretical rationale. It is well documented that the lower the HCV viremia, the more effective the antiviral therapy. Also treatment of acute hepatitis C gives extremely favorable results with almost 90% chance for viral clearance. However, transition of experience from immunocompetent patients onto the post-transplant setting is not possible due to several reasons. Indeed, HCV-RNA level rapidly decreases after reperfusion, but within one-two weeks reaches pretransplant load and tends to increase by 1 to 2 logs thereafter. Hence, time for antiviral intervention, optimal at the lowest viremia, is very narrow and falls to the moment of greatest clinical instability of the recipient (renal impairment, risk of rejection, risk of bacterial infection related to the surgical procedure, deep cytopenias, etc.). During early post-LT period patients are under the strongest immunosuppression and cannot spontaneously clear the virus as it happens in a significant proportion of immunocompetent patients with the acute C hepatitis. Moreover, immunological responses to HCV that were unable to clear the virus in the past, remain the same. These factors make early posttransplant anti-viral treatment a mission almost impossible. No more than two third of liver recipients are eligible for early treatment, but even if they start therapy, dose reductions as well as rate of discontinuation are very high (Sheiner et al., 1998; Verna & Brown, 2008).

Experience with interferon monotherapy, either standard or pegylated, is scarce and disappointing. Patients were started on therapy at a mean time of 2–3 weeks post LT. Results obtained with standard interferon did not show any SVR cases (Sheiner et al., 1998; Singh et al.,1998). According to Singh et al. prophylactic treatment with IFN did not have any influence on the severity of recurrent C hepatitis, whereas in the study of Sheiner et al. treated patients less frequently developed recurrent hepatitis on liver biopsy or had abnormal liver tests. In both studies discontinuation rate was high and IFN did not influence patient and graft survival. There was the only one well designed trial published to date with peg-IFN alone given prophylactically. According to Chalasani et al., SVR was a rare event (8% of treated patients vs. no treatment), but discontinuation from the study, rejection episodes, adverse events and life threatening complications were similar in both groups. One third of treated patients were withdrawn from the study (Chalasani et al.,

Slightly better results were obtained using combined non-pegylated or pegylated IFN with ribavirin. In a study of Mazzaferro et al., SVR was achieved in 33.3% of patients treated with IFN and RBV in comparison with 13% of SVR in patients on IFN alone (Mazzaferro et al., 2003). Interestingly, those who cleared the virus, did not show recurrent hepatitis C. Less encouraging effects were shown by Terrault. Only 11% obtained SVR and there was no

be more beneficial in decompensated HCV-related cirrhosis.

**1.4.2 Early post-transplant antiviral treatment 1.4.2.1 Pros and cons of preemptive therapy** 

**1.4.2.2 Treatment regimes** 

2005).

Another strategy that theoretically could be implemented in the early post-transplant period is immune globulin prophylaxis to prevent HCV recurrence similarly to highly successful use of hyperimmune anti-HBV globulin (HBIG). Farci et al., demonstrated the existence of neutralizing anti-HCV antibodies, at least in the animal model (Farci et al., 1996), and Krawczynski K. showed that hyperactive anti-HCV globulin can delay hepatitis C onset in chimpanzees (Krawczynski, 1999). It was also shown that HBIG used in liver recipients before 1990, hence before HCV discovery, also reduced graft reinfection with HCV and recurrent C hepatitis in patients coinfected with HBV and HCV (Feray et al., 1998). These results suggested that at that time HBIG possibly contained antibodies with the anti-HCV properties. Unfortunately, clinical trials with high doses of human hepatitis C antibody enriched immune globulin product (Civacir) failed to prove any beneficial effects in HCVpositive recipients in terms of HCV suppression (Davis et al., 2005) and this strategy has been abandoned. There are several reasons for failure including unclear neutralizing properties of HCV antibodies, high genetic variability of HCV allowing easy escape from immune control and lack of small animal models to test various antibody preparations.
