**1.4.1 Pre-transplant antiviral therapy**

Treating patients on the waiting list is an attractive option, because there is a body of evidence that viral clearance at the time of transplantation can minimize the risk of recurrent HCV infection post-LT and improve outcomes. However, only few candidates are suitable for the treatment. In a vast majority signs and symptoms of liver decompensation (jaundice, variceal bleeding, encephalopathy, tense ascites) and cytopenias (platelet count below 50 000/µL, absolute neutrophil count < 1500/µL) are the most common exclusion criteria. Those who are eligible, constitute a difficult-to-treat group of patients usually requiring

There are several reasons for worse results in transplant patients in comparison with the non-transplant setting: history of unsuccessful antiviral treatment pre-LT, predominance of genotype 1 patients, significant increase in viral load following transplantation, concomitant immunosuppressive treatment, frequent dose reductions due to numerous side effects, mostly cytopenias and infections, frequent peritransplant renal impairment, limiting

Firm conclusions on the role of interferon and ribavirin in the transplant setting are hard to be driven from clinical studies due to many methodological limitations such as a small number of patients, mostly retrospective character of the trials, lack of randomization and control, differences in immunosuppressive protocols, variability in patient selection, different doses, schedules and types of anti-viral therapy, different study end-points and scarce number of control liver biopsies. Nevertheless, in a limited and carefully selected number of patients anti-viral treatment can be strongly considered and is currently

• Poor tolerance

• Risk of life-threatening decompensation • Very low SVR rate

• Very low SVR rate • Poor tolerance

infection • Maximal

liver biopsy • High viral load • Low SVR rate

• Higher risk of ACR and

immunosuppression

• More advanced disease in

ribavirin dosing, and ocassionally poor general status of the patient.

**Timing of treatment Advantage Disadvantage** 

general clinical status of

• Minimal or no disease in

• Stable clinical status of the

immunosuppression • Lower risk of ACR

Table 2. Advantages and disadvantages of anti-HCV treatment in the transplant setting

Treating patients on the waiting list is an attractive option, because there is a body of evidence that viral clearance at the time of transplantation can minimize the risk of recurrent HCV infection post-LT and improve outcomes. However, only few candidates are suitable for the treatment. In a vast majority signs and symptoms of liver decompensation (jaundice, variceal bleeding, encephalopathy, tense ascites) and cytopenias (platelet count below 50 000/µL, absolute neutrophil count < 1500/µL) are the most common exclusion criteria. Those who are eligible, constitute a difficult-to-treat group of patients usually requiring

recurrence • Stopping of disease progression • Stabilization of the

the recipient

RNA level

liver biopsy

recipient • Lower doses of

recommended (Wiesner et al., 2003).

**1.4.1 Pre-transplant antiviral therapy** 

**Established recurrent HCV** 

**disease** 

**Pre-transplant** • Elimination of HCV

**Preemptive** • Treatment at the low HCV

frequent administration of hematopoietic growth factors or decompensating on the treatment with the necessity for urgent transplantation. Expert panel recommends that antiviral treatment is worth considering in clinically stable patients with MELD score < 18 or Child-Pugh score < 7 points (Wiesner et al., 2003). Careful monitoring by the experienced team and local donor availability are mandatory. A special group of HCV-positive patients listed for LT are transplant candidates with HCC. They are often upgraded on the waiting list not due to the impaired hepatic synthetic function, but the risk of cancer growth. As having a well-compensated cirrhosis they should be strongly considered for antiviral treatment.

Duration of the treatment is not clearly defined, because cirrhotic patients can become HCV-RNA negative with a delay (if at all) and LT is not a scheduled procedure (with the exception of living donor LT). Some authors suggest keeping patients on treatment until viral clearance is achieved and continue at least for three months before LT. To avoid serious side effects, a low maintenance dose or a low accelerating dose regimen (LADR) was proposed (Everson, 2000; Everson et al., 2005). LADR was initially based on the recombinant interferon which is no more used as a standard of care (SOC). Encouraging results have been achieved by Everson (overall sustained viral response in 24% of patients and no recurrence after LT in most cases), but other trials were far less enthusiastic (Forns et al., 2003; Martinez-Bauer et al., 2006). In a low maintenance dose regimen 1 MU of standard interferon and 400 mg of ribavirin daily have been used; in LADR interferon was given 3 times a week with a starting dose of 1 MU and ribavirin was administered daily with a starting dose of 200mg, both drugs being subsequently increased fortnightly to a standard dose of 3 x 3 MU of IFN weekly and 800 mg of RBV daily.

Although combination therapy with pegylated interferons (peg-IFN) and ribavirin has limited efficacy in patients with advanced fibrosis and cirrhosis, especially if decompensated, results with peg-IFN can be better in comparison with the standard formula. Based on the current literature patients with compensated cirrhosis receive SOC therapy with peg-IFN α in a routine dose of 1.5µg/kg weekly with RBV in a routine dose of 1000-1200 mg daily for genotype 1 and 4, and in a dose of 800-1000 mg for another genotypes. In decompensated cirrhosis patients are more likely to develop various side effects and they cannot tolerate SOC easily. The suggested dose in this setting appears to be 1µg/kg/week of peg-IFN and 10.6 mg/kg/daily of RBV. In case of cytopenias, dose reductions are recommended in the first instance. If this strategy fails, hematopoetic growth factors can be used. For neutropenia G-CSF may be considered in a starting dose of 480 µg weekly, then adjusted according to the response rate to a maximum dose of 480 µg 3 times a week. Once adequate neutrophil count is attained, IFN dose can be increased to the optimum level. EPO may be considered if hemoglobin falls below 8 g/dL or by 4 g/dL. The starting dose is 20.000 IU weekly to a maximum dose of 60.000 IU weekly or, according to another study suggesting lower dosing, 4.000 IU thrice weekly with increase upon the response.

Although decompensated cirrhosis is no more an absolute contraindication to antiviral treatment, it must be used with caution. A chance to achieve sustained viral response (SVR) is rather low and patients experience numerous side effects, including life-threatening complications such as sepsis and liver function deterioration. Patients must be closely monitored and treated in experienced transplant centers. Treatment indications should be 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 be more beneficial in decompensated HCV-related cirrhosis.
