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Keywords:

  • hepatitis C virus protease inhibitors;
  • hepatitis C;
  • interferon;
  • liver transplantation;
  • ribavirin

Abstract

  1. Top of page
  2. Abstract
  3. Pre-transplantation antiviral therapy
  4. Post-transplantation prophylactic and pre-emptive therapy
  5. Treatment of established infection
  6. Conclusions
  7. Conflicts of interest
  8. References

Liver disease caused by the hepatitis C virus is the main indication for liver transplantation in Western countries. However, HCV re-infection post-transplantation is constant and recent data confirm that it significantly impairs patient and graft survival. Chronic HCV infection develops in 75–90% of patients, and 5–30% ultimately progress to cirrhosis within 5 years. Because of the impact of HCV recurrence on graft and patient survival, several treatment strategies have been evaluated. Antiviral therapy could be administered before transplantation to suppress viral replication and reduce the risk of recurrence. However, this approach is applicable in around 50% of patients and tolerance is poor, particularly in patients with decompensated cirrhosis. Pre-emptive therapy in the early post-transplant period is limited by the high rate of side effects. Frequently, antiviral therapy is initiated when HCV recurs to obtain viral eradication and/or reduce disease progression. Treatment of established graft lesions with Pegylated Interferon (PEG-IFN) and Ribavirin (RBV) combination therapy results in a sustained virological response (SVR) in around 30% of patients. The new classes of potent and direct antiviral agents (DAA) will certainly improve the results of pre- and post-transplant antiviral therapy. However, at the present time, no data are available on the use of these drugs in patients with decompensated cirrhosis or post-transplant hepatitis.

Abbreviations
CSA

cyclosporin

DAA

direct acting antivirals

GWAS

genome-wide association studies

HCV

hepatitis C virus

IFN

interferon

LT

liver transplantation

RBV

ribavirin

SNP

single nucleotide polymorphism

SVR

sustained virological response

TAC

tacrolimus

Liver disease caused by the hepatitis C virus (HCV) is the main indication for liver transplantation (LT) in Europe and the United States. However, HCV re-infection after LT is constant and accelerated in patients who are HCV polymerase chain reaction-positive at the time of transplantation. Recent data confirm that this significantly impairs patient and graft survival [1]. Multiple factors may influence progression of HCV graft injury [2]. Chronic HCV infection develops in 75–90% of patients, and 5–30% ultimately progress to cirrhosis within 5 years [3]. Because of the impact of HCV recurrence on graft and patient survival, several treatment strategies have been evaluated. Antiviral therapy could be administered before transplantation to suppress viral replication and reduce the risk of recurrence or early post-transplantation as well as to prevent the progression of hepatitis (pre-emptive or prophylactic therapy). However, pretransplantation and prophylactic post-transplantation antiviral treatment is limited by poor tolerance and drugs side effects [4-8]. Frequently, antiviral therapy is initiated when HCV recurs to obtain viral eradication and/or reduce disease progression. Treatment of established graft lesions with Pegylated Interferon (PEG-IFN) and Ribavirin (RBV) combination therapy resulted in a sustained virological response (SVR) in 30–45% of patients [9-13]. Specific targeted antiviral C therapies will certainly improve the results of pre- and post-transplant antiviral therapy. However, at the present time, no data are available on the use of these drugs for patients with decompensated cirrhosis or post-transplant hepatitis. This review focuses on news aspects of HCV therapy before and after liver transplantation.

Pre-transplantation antiviral therapy

  1. Top of page
  2. Abstract
  3. Pre-transplantation antiviral therapy
  4. Post-transplantation prophylactic and pre-emptive therapy
  5. Treatment of established infection
  6. Conclusions
  7. Conflicts of interest
  8. References

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 [14]. 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 [7]. 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.

image

Figure 1. Antiviral treatment modalities before liver transplantation. SVR: sustained virological response. (A) standard antiviral therapy (B) short pre-transplant antiviral therapy..

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Forns et al. assessed the efficacy of an ‘on-treatment virological response’ in 30 patients awaiting OLT (Table 1) [4]. 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 [5]. 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 genotypeChild–Pugh, meanTreatment regimenTreatment duration (Months)Virological responseTransplantedSVR after LT n (%)Tolerability
End of treatment n (%)SVR n (%)
  1. IFN, interferon; LT, liver transplantation; NA, not available; RBV, ribavirin; SAE, serious adverse events; VR, virological response (HCV-RNA negativization while on therapy).

Crippin (15)15 G1: 73%11.9 ± 1.2IFN 1 MU/day or 3 MU tiw, IFN 1 MU/day plus RBV 400 mg/day Until LT25 (33)/2 (HCV RNA positive)020 SAE, 2 sepsis (1 death) Study stopped
Thomas (16)20 G1: 67%10IFN 5 MU/day 1412 (60)/204 (20)GCSF used in all patients Discontinuation 15%
Everson (5)124 G1: 70%7.4 ± 2.3Low accelerating dose regimen (IFN plus RBV according to tolerance)6–1257 (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 LT39 (30)/306 (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 LT315 (29)/5110 (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/00510

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 [7]. 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 [4]. 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%) [5], 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 [5]. 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 [4]. 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 [4], Child-Pugh score class A (genotype 1 only) and completion of treatment [5]. 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 [17]. 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 [17]. 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 [18].

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) [7]. 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.

Protease inhibitors

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 [19]. 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 [20]. 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 [21]. 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 [22]. 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.

Post-transplantation prophylactic and pre-emptive therapy

  1. Top of page
  2. Abstract
  3. Pre-transplantation antiviral therapy
  4. Post-transplantation prophylactic and pre-emptive therapy
  5. Treatment of established infection
  6. Conclusions
  7. Conflicts of interest
  8. References

The term ‘prophylactic therapy’ is used to describe therapy given to prevent reinfection. Preclinical studies of hepatitis C immune globulin (HCIG) in non-human primates and the success of anti hepatitis B immune globulins in preventing HBV recurrence prompted interest in antibody therapy for HCV-infected recipients. Unfortunately, clinical studies of hepatitis C antibody therapy in the form of HCIG or monoclonal antibodies directed against the E2 region have been disappointing with only a transient decrease in liver HCV RNA and serum aminotransferase levels [23, 24].

Pre-emptive, or early post-transplant antiviral therapy should be initiated soon after LT, optimally within 1 month, when the viral load is at its lowest level and fibrosis is absent. However, in the early post-transplantation period, antiviral therapy may be less effective because of the high level of immunosuppression, and tolerance is low because of a high risk of poor haematological tolerance, of rejection and sepsis (Table 2) [6, 8, 25-27]. Patients with high pretransplant Child-Pugh or MELD scores are also more frequently ineligible for pre-emptive antiviral therapy [26].

Table 2. Studies on pre-emptive antiviral therapy after liver transplantation
Author (ref)Patients genotype1 (%)Initiation of therapy Post-LTTreatment regimenSVR (%)Treatment discontinuation (%)Rejection (%)Outcome
  1. G, genotype; HAI, histologic activity index; IFN, interferon; LT, liver transplantation; NA, not available; RBV, ribavirin; RCT, randomized controlled trial; SVR, sustained virological response; UCT, uncontrolled trial.

Mazzafero (24), UCT36 (G1:83%)3 weeks IFN 3 MU tiw plus RBV 10 mg/kg/day, 12 months33% (G1/4 20%, G3/3 100%)0 (adverse events 47%)0Follow-up 52 months, Normal histology in patients with SVR
Sugawara (26), UCT21 (G1:83%)4 weeksIFN 3–6 MU tiw and RBV 400–600 mg/day, 12 months or longer39% (G1/4 33%, G2/3 100%)25%26%Follow-up 26 months, HAI index better in patients with SVR vs no SVR
Chasalani (6), RCT26 (G1:73%)3 weeks PegIFN alfa-2a 180 μg/w, 12 months (vs)8% (G1/4 5%, G2/3 14%)31%12%Increase of HAI and fibrosis scores at week 72 similar in both arms
28 (G1:75%)control032%21% (NS)
Shergill (25), RCT22 (G1:NA)2–6 weeks IFN 3 MU tiw, or pegIFN alfa-2b (induction and maintenance), 12 months (vs) 4.5%41%22.7%NA
22 (G1:NA)IFN 3 MU tiw, or pegIFN alfa-2b (induction and maintenance) and RBV 600–1200 mg/day, 12 months18.2%
Bzowej (8), RCT55 (G1:78%)10–26 weeksPegIFN alfa-2a 135 to 180 μg/w and RBV 400 to 1000–1200 mg/day, 12 months (vs)22%28%5.6%Significant HCV recurrence at week 120, patient and graft survival similar in both arms
60 (G1: 81%)control (14 patients switched to treatment upon HCV recurrence0/6.5%

Chalasani et al. enrolled 54 patients within 3 weeks after LT in a randomized trial on prophylaxis to receive either PEG-IFN alfa-2a (n = 26) or no treatment (n = 24) for 48 weeks [6]. Only two treated patients (8%) achieved an SVR. Shergill et al. treated 44 patients with IFN or PEG-IFN alone or in combination with RBV initiated 2–6 weeks after transplantation for a total of 48 weeks [26]. In the monotherapy and combination therapy groups, the respective end-of-treatment response rates were 4.5% and 22.7% and the SVR rates were 4.5% and 18.2%. Suguwara et al. reported an SVR rate of 39% and a significant improvement in histological activity in responders in 21 HCV-infected living-donor recipients treated with IFN and RBV begun within 1 month after transplantation and continued for 48 weeks [27]. Bzowel et al. reports the results of a prospective, multicenter, randomized study (PHOENIX study) designed to compare the efficacy, tolerability, and safety of an escalating-dose regimen of PEG-IFN alfa-2a/RBV for 48 weeks for post-LT prophylaxis vs. no treatment [8]. One hundred fifteen (48.7%) of 236 patients who underwent pre-LT screening were randomized in the study: 55 received prophylaxis and 60 observations. The primary endpoint was the proportion of patients with significant histological recurrence, defined as having either a histological activity index (HAI) inflammation grade ≥ 3, fibrosis stage score ≥ 2, or both using the Batts–Ludwig system 120 weeks post-randomization. Enrolment in the study ended early because of slow inclusion of patients, illustrating the difficulties of initiating antiviral treatment in the early post-transplantation period. The median delay from transplantation to initiation of therapy was 111 and 121 days in the prophylaxis and observation arms respectively, which is significantly higher than in other pre-emptive antiviral studies (Table 2). An SVR was achieved in 12/54 (22%) of the prophylaxis patients. The rate of marked HCV recurrence at week 120 (61.8% of prophylaxis patients vs. 65% of observation patients), the time until the first recurrence of HCV, HAI grades and the progression of fibrosis at week 120 as well as patient and graft survival were similar in both study arms in the intention-to-treat analysis. However, most of the patients who were classified as having HCV recurrence were so because the results of the week 120 biopsy were missing.

These published studies show that SVR rates range from 8 to 39% (median 16%), in 5 to 33% of genotype 1 patients and 14 to 100% of genotype 2–3 patients respectively (Table 2). The main drawbacks are that treatment can only be administered to a low proportion of patients, and that drug dose reduction and discontinuation are necessary in approximately 70% and 30% of patients respectively.

Treatment of established infection

  1. Top of page
  2. Abstract
  3. Pre-transplantation antiviral therapy
  4. Post-transplantation prophylactic and pre-emptive therapy
  5. Treatment of established infection
  6. Conclusions
  7. Conflicts of interest
  8. References

Antiviral therapy is usually given when there is histological evidence of recurrent HCV disease. As in the non-transplant setting, the decision to treat should take into account all parameters: age, general status, genotype, severity of hepatitis (fibrosis stage ≥ 2 according to the METAVIR scoring system), rapidity of the progression of fibrosis, risk of graft loss, and expected tolerance to treatment. There are some patients who must be treated: those with fibrosing cholestatic hepatitis because of the poor short-term prognosis and those with rapidly evolving fibrosis on successive protocol biopsies. Liver stiffness > 8 KPa, hepatic venous pressure gradient > 6 mmHG or serum fibrosis markers may help define the most appropriate time to initiate antiviral therapy [28-30].

Interferon and ribavirin treatment

Studies showed that IFN plus RBV combination therapy achieves SVR rates of 17–30% [9, 12]. The reported SVR rate with PEG-IFN/RBV ranges from 18 to 45%. Three systematic reviews of PEG-IFN and RBV regimens showed an SVR rate of approximately 30% [11-13] (Table 3). Variables associated with SVR are non-1 genotype, absence of prior antiviral therapy, EVR and RVR, adherence to therapy and low pretreatment viral load [11-13] (Table 4). Pretreatment fibrosis stage and donor age were also found to be associated with SVR in some studies [10, 31, 32]. As in immunocompetent patients, the likelihood of response to antiviral therapy varies substantially with donor and recipient IL28B genotypes [33-35]. In the study reported by Charlton et al., both donor and recipient IL28B variations were strong and independent predictors of SVR, with minimal SVR rates in patients with donor and recipient poor-response IL28B genotype, intermediate SVR rates in patients with a good-response IL28B genotype in either the donor or the recipient, and excellent SVR rates in patients with good-response IL28B genotype in both the donor and recipient [35]. In this study, recipient IL28B genotype was associated with more rapid progression of fibrosis on the graft, although there was no decrease in survival. The influence of immunosuppression on the response to antiviral therapy is not well established. Some studies suggest that the rate of SVR in liver transplant patients with recurrent hepatitis C who are undergoing IFN/RBV therapy is higher in those receiving cyclosporin (csa) compared with those receiving tacrolimus (tac) [10, 36-38]. However, these results remain controversial. There are no published studies evaluating extended therapy (72 weeks) in liver transplant recipients who are slow responders (significant decrease in HCV RNA at week 12, but still positive). Berenguer et al. recently reported that the efficacy of antiviral therapy with PEG-IFN/RBV worsened over time [32]. The increase in donor age and the increased proportion of patients treated at advanced stages of disease are potential causes. We recently reported that tolerance to therapy decreases significantly in patients with fibrosis stage ≥ 3 at baseline liver biopsy, suggesting that antiviral treatment should be initiated at an early stage of hepatitis C recurrence on the graft [39]. Most studies show an improvement in biochemical and necroinflammatory activity in virological responders, but whether antiviral therapy slows disease progression in non-responders has not been established [10]. Several studies have shown that in patients with an SVR, antiviral therapy had a long-term beneficial effect on liver fibrosis [10], HVPG [10] and graft and patient survival [31, 40].

Table 3. Systematic reviews of antiviral therapy post-transplantation
Authors (ref)StudiesPatientsYearsETVRSVRComplianceAcute rejectionFactors associated with SVR
  1. ETVR, end of treatment virologic response; G, genotype; LT, liver transplantation; SVR, sustained virologic response.

Interferon and ribavirin
Wang (12)27 studies (2 controlled)12–54 patients per study6891980–200534% (30–37%)24% (20–27%)Dose reduction44% (38–50%)Discontinuation24% (21–27%)2% (1–3%)Absence of prior antiviral therapy post-LT(OR 1.9, 95% CI, 1.0–3.4, = 0.04)
Peginterferon and ribavirin
Wang (12)21 studies (1 controlled) 11–86 patients per study Peg IFN alfa-2b: 18 studies5871980–200542% (38–46%)27% (23–31%)Dose reduction 66% (61–70%) Discontinuation 26% (20–32%)5% (3–7%)Absence of prior antiviral therapy post-LT (univariate analysis = 0.02) Genotype non-1 (univariate analysis = 0.05)
Berenguer (11)19 studies (2 controlled) 12–61 patients per study Peg IFN alfa-2b: 16 studies6112004–200742.2% (17–68%)30.2% (0–50%) G1: 28.7% G2: 71–100% G3: 66–100%Dose reduction 68% (Peg-IFN: 39%, RBV 54%) Discontinuation 27.6%6.4% (0–25%)Early virologic response Genotype 2 Adherence to therapy Baseline viraemia
Xirouchakis (13)6 controlled studies 13–59 patients per study Peg IFN alfa-2b: 5 studies2642005–2007NA41% (29.6–77.7%)NA5%NA
Table 4. Variables associated with sustained virological response after transplantation
Pre-treatment variables
- Genotype
- Adherence to therapy / duration of therapy
- baseline viral load
- Absence of prior antiviral treatment pre- or post-transplant
- Severity of baseline fibrosis
- Donor age
- IL28B donor and recipient
On-treatment variables
- Rapid virologic response
- Early virologic response

Tolerance is a major issue. In systematic reviews dose reductions of RBV and/or PEG-IFN were necessary in around 70% of patients and the rate of treatment discontinuation was around 30% [11-13]. Transplant recipients are particularly susceptible to RBV-induced toxicity. The major side effect of RBV is a dose-dependent haemolytic anaemia. The dose of RBV could be increased with the use of epoetin alfa increased haemoglobin, however, controlled studies confirming the benefits of growth factor use in improving SVR rates are lacking. Several authors have initiated RBV at low doses and then escalated according to tolerance in relation to haemoglobin levels and renal insufficiency. The uses of blood levels to dose and adapt RBV doses have not been clearly evaluated. Overall, doses of RBV are generally lower in transplant than in non-transplant patients. Granulocyte macrophage colony stimulating factor or the thrombopoietin-receptor agonist eltrombopag may be used to increase neutrophil or platelet counts during antiviral treatment. The risk of acute rejection in systematic reviews was 2% (95% CI: 1–3%) for IFN and RBV and 5–6% for PEG-IFN and RBV [11-13]. Factors influencing the risk of rejection include the level of immunosuppression at the time of antiviral therapy, the type of therapy used: a higher risk was found with PEG-IFN compared with regular IFN, a lower risk with RBV and in relation to whether the patient had had prior episode of rejection. However, controlled studies did not find any differences in rejection rate between treated patients and untreated controls [6, 9, 10]. Chronic rejection seems to be a relatively rare complication from IFN based therapy [41]. Acute or chronic rejection is often associated with concomittant low or negative serum HCV RNA related to an improvement in hepatic microsomal function after viral clearance, leading to lower blood immunosuppressant levels. These data show the need to closely monitor calcineurin inhibitor levels during antiviral therapy. Some cases of immune-mediated hepatitis observed during or shortly after antiviral treatment, and mainly after viral clearance, have recently been reported [38, 41, 42]. Most cases respond to increased immunosuppression. In patients treated with antiviral therapy, particularly in those with undetectable HCV RNA, any flare in liver enzymes should suggest rejection or auto-immune hepatitis and a liver biopsy should be performed.

Protease inhibitor treatment

Direct acting antivirals (DAAs) such as protesase, polymerase or other non-structural proteins inhibitors are developed [43]. These DAAs will certainly change the outcome of recurrent hepatitis C after LT. No data exist on the efficacy and safety of antiprotease molecules combined with classic bitherapy for transplanted patients. However, these treatments will certainly improve the SVR rate in the post-transplant setting. Interaction with immunosuppressive drugs and additional adverse events will probably limit the use of these treatments. A phase I study by Garg et al. reported the effect of telaprevir on the pharmacokinetics of csa and tac in healthy volunteers [44]. Co-administration with telaprevir, an inhibitor of the enzyme cytochrome P450 3A, which is responsible for the metabolism of both csa and tac, increased csa dose-normalized exposure by approximately 4.6-fold and increased tac dose-normalized exposure by approximately 70-fold. As in HIV transplant patients, this effect on calcineurin inhibitor clearance should be carefully monitored [45].

Retransplantation (RT) is the only therapeutic option for long-term survival in patients with decompensated cirrhosis after LT. However, patient and graft survival rates after RT are inferior to those after primary LT [46]. It remains unclear whether the progression of fibrosis in the first graft will be the same in the second graft. The use of prognostic scores can identify candidates with a high risk of mortality [46].

Conclusions

  1. Top of page
  2. Abstract
  3. Pre-transplantation antiviral therapy
  4. Post-transplantation prophylactic and pre-emptive therapy
  5. Treatment of established infection
  6. Conclusions
  7. Conflicts of interest
  8. References

Most patients with HCV infection will develop recurrence after transplantation which impairs long-term patient and graft survival. Understanding of the long-term outcome of HCV-related liver transplant recipients and variables associated with outcome must be improved. Treatment of HCV infection before LT appears to be a reasonable approach to prevent recurrence. However, this option is applicable in around 50% of patients and tolerance is poor, particularly in patients with decompensated cirrhosis. Patients with compensated cirrhosis and a good virological profile are the best candidates for pretransplantation antiviral therapy. Pre-emptive therapy in the early post-transplant period is limited by the high rate of side effects. Treatment of established infection in the graft is the most common approach and achieves a SVR rate of 25–45%. Early antiviral treatment only seems justified in patients with data suggesting an unfavourable outcome. The new classes of potent DAA are not yet available. However, pre- and post-transplant patients will probably benefit the most from these new options.

Conflicts of interest

  1. Top of page
  2. Abstract
  3. Pre-transplantation antiviral therapy
  4. Post-transplantation prophylactic and pre-emptive therapy
  5. Treatment of established infection
  6. Conclusions
  7. Conflicts of interest
  8. References

DS disclosures consulting for Astellas, Novartis, Roche Pharma, MSD and Janssen, BR has no conflicts of interest declare.

References

  1. Top of page
  2. Abstract
  3. Pre-transplantation antiviral therapy
  4. Post-transplantation prophylactic and pre-emptive therapy
  5. Treatment of established infection
  6. Conclusions
  7. Conflicts of interest
  8. References