The suppression of HCV viraemia in LT candidates may reduce or eliminate the risk of recurrent infection. However, this approach has been shown to be limited in HCV patients with decompensated cirrhosis: antiviral therapy is significantly less effective in patients with cirrhosis than in patients with mild disease . Moreover, there is a high prevalence of genotype 1 in these patients, there have been problems in administering full doses of IFN and RBV because of side effects and a risk of complications, such as life-threatening infection and the possible acceleration of hepatic decompensation exist . As a result of severe cytopenia, 26–75% of screened patients are excluded for antiviral therapy. Growth factors can be used for treatment-associated anaemia, leukopaenia or thrombopaenia and may limit the need for antiviral dose reductions.
Interferon and ribavirin treatment
A few published studies have investigated the role of standard or PEG-IFN with or without RBV in patients with decompensated HCV cirrhosis. All these studies were performed in a single centre, were frequently uncontrolled and varied significantly in their aims (effect on the natural history of disease, prevention of recurrence after transplantation) and modalities (doses, duration, delay before LT) [4, 5, 7, 15, 16]. Unlike in patients with HBV and cirrhosis, the aim of pretransplantation hepatitis C antiviral therapy is not to reduce the viral load at transplantation because this has not been shown to decrease the rate and severity of recurrence. The aim is either to achieve an SVR at transplantation or on-treatment negative serum HCV RNA at transplantation (Fig 1). At least 24 weeks after the end of treatment is required for the former, which may be too long and deleterious to patients awaiting LT.
Figure 1. Antiviral treatment modalities before liver transplantation. SVR: sustained virological response. (A) standard antiviral therapy (B) short pre-transplant antiviral therapy..
Download figure to PowerPoint
Forns et al. assessed the efficacy of an ‘on-treatment virological response’ in 30 patients awaiting OLT (Table 1) . Treatment with IFN α-2b/RBV lasted a median of 12 weeks. A virological response was observed in nine patients (30%). After LT, six of them (20%) remained free of re-infection after a median follow-up of 46 weeks. None of the patients who achieved an SVR before transplantation had recurrence of HCV. Everson et al. performed a study in 124 HCV patients with cirrhosis treated with IFN/RBV for 1 year with a low accelerating dose regimen . The virological response at the end of treatment was 46% and SVR was 24%. The SVR was significantly lower in patients with genotype 1 (13%) than in those with non-1 genotypes (50%; P < 0.0001). Recurrent HCV infection was prevented in all patients achieving an SVR.
Table 1. Treatment of HCV infection before liver transplantation
|First author (ref)||Patients genotype||Child–Pugh, mean||Treatment regimen||Treatment duration (Months)||Virological response||Transplanted||SVR after LT n (%)||Tolerability|
|End of treatment n (%)||SVR n (%)|
|Crippin (15)||15 G1: 73%||11.9 ± 1.2||IFN 1 MU/day or 3 MU tiw, IFN 1 MU/day plus RBV 400 mg/day Until LT||2||5 (33)||/||2 (HCV RNA positive)||0||20 SAE, 2 sepsis (1 death) Study stopped|
|Thomas (16)||20 G1: 67%||10||IFN 5 MU/day ||14||12 (60)||/||20||4 (20)||GCSF used in all patients Discontinuation 15%|
|Everson (5)||124 G1: 70%||7.4 ± 2.3||Low accelerating dose regimen (IFN plus RBV according to tolerance)||6–12||57 (46)||30 (24) G1:13% G non-1:50%||47 (15 HCV RNA negative)||12 (26)||Dose reduction 71%, Discontinuation 13% 5 sepsis 11 liver decompensatons 2 deaths|
|Forns (4)||30 G1: 70%||A 50%, B 43%, C 7%||IFN 3 MU/day plus RBV 800 mg/day until LT||3||9 (30)||/||30||6 (20)||Dose reduction 60%, Discontinuation 20% 2 sepsis 4 liver decompensations|
|Carrion (7)||51 G1: 80%||A 45%, B 43%, C 12%||Peg IFN 180 μg/w + RBV 0.8–1.2 g/day until LT||3||15 (29)||/||51||10 (20)||Dose reduction 49%, Discontinuation 43% Incidence of decompensation and death similar in the 2 groups (15 vs 9 and 4 vs 1) Incidence of sepsis higher in treated group vs controls (19 vs 3)|
|51 G1: 82%||A 43%, B 43%, C 14%||Control group||/||0||0||51||0|
The study by Carrion et al. is the first to have used PEG-IFN/RBV therapy in 51 patients with HCV and cirrhosis awaiting LT (median duration of therapy: 15 weeks) matched with 51 untreated controls . The aim of this study was to evaluate both the prevention of post-transplantation recurrent HCV and the risk of bacterial infections during therapy. The virological response rate was high, as 24 treated patients (47%) became HCV RNA negative during treatment, but only 15 (29%) were HCV RNA-negative at transplantation (dropouts n = 3, deaths n = 4, viral relapse n = 2) and 10 (20%) achieved an SVR after transplantation. The rate of SVR with PEG-IFN/RBV was similar to that reported previously with a daily standard IFN regimen by the same investigators . One explanation could be the large number of HCV RNA-negative patients who were not transplanted because of death (n = 4) or dropout (n = 3). Although the results of short-term pretransplant treatment with standard or PEG-IFN (SVR after LT: 20%) [4, 7] were very similar to those achieved with standard duration therapy (SVR after LT: 26%) , a longer duration of therapy should be studied further to reduce the relapse rate. No recurrent HCV developed in the grafts of any of the patients who achieved an SVR before LT . Post-transplant HCV recurrence in patients who achieved an on-treatment response without an SVR may have been because of the short duration of therapy and HCV persistence in a second compartment . As reported by other studies, an early (or rapid) virological response (EVR/RVR) and non-1 genotype were the strongest predictors of viral clearance during therapy. The absence of a ≥ 2 log10 reduction in HCV RNA between baseline and week 4 had a strong negative predictive value. This finding is highly relevant, as treatment can be stopped in patients with a low probability of response, thus reducing the risk of complications. The other predictors of an SVR are pretreatment viral load , Child-Pugh score class A (genotype 1 only) and completion of treatment . Recently, several authors have reported the results of separate genome-wide association studies (GWAS) supporting the association of SVR in genotype 1 patients with single nucleotide polymorphisms (SNP) within the gene region IL28B encoding interleukin (IL)-28B or interferon lambda . In the study by Ge et al., the presence of the C/C genotype was associated with a more than two-fold higher chance of achieving an SVR: around 80% for the C/C genotype, around 40% for the T/C genotype and around 30% for the T/T genotype . In the same study, IL28B variations were shown to be the strongest pretreatment predictor of virological response and were associated with very early on-treatment viral kinetics. Also, in genotype 4 infected patients from different ethnic groups (Egyptian, European and Sub-Saharan African), IL28Brs12979860 CC genotype was associated with a higher sustained virological response .
The safety of PEG-IFN therapy is a major concern in patients with decompensated cirrhosis. The reported rates of neutropaenia, thrombocytopaenia, anaemia, and episodes of infection or liver decompensation during therapy are 50–60%, 30–50%, 30–60%, 4–13% and 11–20% respectively [4, 5]. In the study by Carrion et al., the incidence of episodes of bacterial infection (mostly spontaneous bacterial peritonitis and spontaneous bacteraemia because of Gram-negative bacilli) was higher in treated patients (25%) than in controls (6%) (P = 0.01) . Variables independently associated with the occurrence of bacterial infections were antiviral treatment and a Child-Pugh score of B–C. In summary, these studies suggests that antiviral therapy using standard or PEG-IFN regimens in decompensated HCV patients with cirrhosis is possible with a relatively high rate of virological response, especially in patients with a non-1 genotype and an early (or rapid) virological response. Because of the potential for serious adverse events, patients should be closely monitored during antiviral treatment and followed by centres with considerable experience in managing decompensated cirrhosis.
The best candidates for therapy remain Child-Pugh class A patients whose virological response rate is high and in whom the risk of side effects is almost identical to that of controls. Antiviral therapy is currently not indicated in Child-Pugh class C patients (or MELD > 18) because of the high risk of septic complications during treatment and a low SVR rate. In Child-Pugh class B patients, treatment should be discussed on a case-by-case basis according to baseline factors for a potential response: genotype non-1, low viral load, good-response IL28B genotype, treatment naïve or patients who have relapsed from previous antiviral therapy. Antiviral therapy can be discontinued after 4 or 12 weeks if there is no virological response. Antibiotic prophylaxis and the use of growth factors may facilitate antiviral therapy in patients with poor liver function.
Data on therapy using HCV NS3/4 protease inhibitors (PI) are limited in patients with cirrhosis. Only a few patients with advanced fibrosis or compensated cirrhosis have been included in phase III trials with either telaprevir or boceprevir. However, this is the group of patients who will probably benefit the most from this treatment. In phase III trials, in treatment of naïve patients with cirrhosis (around 6% of the total population), an SVR was obtained in 62% of patients treated with telaprevir (12 weeks) compared with 33% with the standard treatment regimen . An SVR was obtained in 52% of patients with baseline Metavir fibrosis score 3 or 4 (around 10% of the total population) treated with boceprevir (44 weeks) compared with 38% with the standard regimen . In patients with cirrhosis who had been previously treated (around 25% of the total population), an SVR was obtained in 84% of those who had relapsed and were treated with telaprevir, compared with 13% with the standard regimen, in 34% of those with a previous partial response (defined as a reduction in HCV RNA of 2 log10 or more after 12 weeks of therapy, but still detectable) treated with telaprevir compared with 20% with the standard regimen, and in 14% of those with a previous non-response (defined as a reduction of less than 2 log10 in HCV RNA after 12 weeks of therapy) treated with telaprevir compared with 10% with the standard regimen . In previously treated patients with a baseline Metavir fibrosis score of 3 or 4 (approximately 49% of the total population), an SVR was obtained in 83% of those who had relapsed and were treated with boceprevir (44 weeks) compared with 20% with the standard regimen and in 46% of those with a previous non-response (defined as a reduction of 2 log10 or more in HCV RNA after 12 weeks of therapy, but still detectable) treated with boceprevir (44 weeks) compared with 0% with standard regimen . Cure rates in patients with advanced fibrosis were significantly lower than in patients with mild to moderate fibrosis, although results were still encouraging. However, there is no experience on the efficacy and safety of telaprevir or boceprevir in patients with decompensated cirrhosis. Therefore, these drugs should not be used in these patients outside of carefully designed clinical trials.