Hepatitis C virus (HCV) infection is one of the leading causes of end-stage liver disease and the main indication for liver transplantation (LT) in most countries . All patients who undergo LT with detectable serum HCV RNA experience graft reinfection . Hepatitis C virus recurrence is the most frequent cause of death and graft loss in these patients, accounting for two-thirds of graft failures . Until 2011, standard antiviral therapy, using pegylated interferon (PEG-IFN) and ribavirin (RBV), was the only effective therapy. Obtaining a sustained virological response (SVR) in the setting of LT can greatly improve overall and graft survival, but this only concerns one-third of transplanted patients. The development and approval of novel direct-acting antivirals (DAA) open a new era for HCV patients. More effective antiviral therapy must be used in patients with severe recurrence or rapid progression of fibrosis in the liver graft. This review describes the difficulties of managing HCV recurrence and current and future antiviral approaches after LT.
Hepatitis C virus (HCV) infection is one of the leading causes of end-stage liver disease and the main indication for liver transplantation (LT) in most countries. All patients who undergo LT with detectable serum HCV RNA experience graft reinfection. Between 20 and 30% of patients develop cirrhosis within 5 years post-LT. The outcome of transplant patients with cirrhosis on the graft is severe, with a rate of decompensation at 1 year of around 40%. To date, retransplantation is the only option for patients who develop decompensation. Until 2011, standard antiviral therapy, using pegylated interferon (PEG-IFN) and ribavirin (RBV), was the only effective therapy. Obtaining a sustained virological response (SVR) in the setting of LT greatly improves overall and graft survival, but this only concerns 30% of transplanted patients. Direct-acting antivirals (DAA) such as protease inhibitors, polymerase or other non-structural proteins inhibitors represent a new era in HCV-associated liver disease. Although their use in the field of liver transplantation seems to be essential, there are some limitations due to safety and tolerance. One limitation is the potential interaction with calcineurin inhibitors. We describe the preliminary results of triple therapy with boceprevir or telaprevir in terms of efficacy and safety in liver transplant recipients.
early virological response
hepatitis C virus
human immunodeficiency virus
human leucocyte antigen
sustained virological response
HCV recurrence after liver transplantation: a severe complication
Natural history of HCV recurrence
Hepatitis C virus infection is a main cause of end-stage liver disease worldwide leading to liver transplantation (LT) . The best option for transplant patients is to obtain an SVR with antiviral therapy before LT. Although this approach should always be considered, it is the subject of another review in this issue and will not be discussed here. If serum HCV ribonucleic acid (HCV RNA) remains detectable at LT, reinfection of the liver graft by HCV particles is constant and the natural history of HCV recurrence is accelerated compared with non-transplant patients. Between 20 and 30% of patients develop cirrhosis within 5 years after LT . The outcome of transplant patients with cirrhosis on the graft is severe, with a rate of decompensation of around 40% at 1 year . Because preventive therapy is lacking, the prognosis of HCV-infected liver transplant patients, whose survival is shorter than other recipients, can only be changed by antiviral therapy . Viral clearance is associated with better long-term outcomes, particularly in patients who achieve an SVR, which improves fibrosis and survival [6, 7]. To date, retransplantation is the only option in patients who develop decompensation. Survival reaches 61–75% and 68% at 5 and 10 years post-LT respectively [5, 8, 9].
A few patients experience severe HCV recurrence known as cholestatic hepatitis (CH) characterized by high HCV RNA levels and the presence of extensive, dense portal fibrosis with immature fibrous bands extending into the sinusoidal spaces, ductular proliferation, cholestasis and moderate mononuclear inflammation . The prognosis is very poor in patients who do not respond to antiviral therapy.
Risk factors of HCV recurrence
Certain factors are associated with an accelerated progression of fibrosis in patients with HCV recurrence leading to graft loss. For example, high HCV RNA levels in both serum and liver at the time of LT are associated with an increased risk of progression to cirrhosis, graft loss and death . Although the data are controversial, HCV genotypes 1b and 4 seem to be negative predictive factors for the recurrence of HCV, mainly because of a lower response to PEG-IFN/RBV therapy [12-14]. The host and donor factors associated with poorer outcome included female gender, older donor age, steatosis of the graft, the degree of human leucocyte antigen (HLA) matching or the IL28b genotype of the donor and the recipient [4, 15, 16]. After LT, both cytomegalovirus and human herpes virus 6 infections have been associated with a rapid progression of HCV recurrence .
Impact of immunosuppressive regimen
The management of HCV recurrence is directly related to the immunosuppressive regimen of the recipient for two reasons. First, the degree and composition of the immunosuppressive regimen influence the progression of fibrosis . Second, potential drug–drug interactions must be taken into account before immunosuppressive drugs and new DAA are begun .
Calcineurin inhibitors (CNI), tacrolimus (Tac) and cyclosporine (CsA), are the basis of the immunosuppressive regimen at present. It has been suggested that CsA may have potential antiviral action because Cyclophilin A, the target protein of CsA, is involved in the viral replication of HCV . Although HCV replication is observed in vitro with CsA, the beneficial role of CsA on HCV recurrence remains uncertain. Several studies did not show any difference between CsA and Tac in the outcome of HCV recurrence . On the contrary, a retrospective study suggests that the effect of CsA was deleterious compared with Tac in more than 8000 recipients . CsA could take advantage of Tac during antiviral therapy as some studies suggest that CsA enhances sustained virological response (SVR) rates in liver transplant patients treated with PEG-IFN/RBV [23, 24]. Moreover, fewer interactions are described with CsA than Tac during co-administration with a protease inhibitor (see below).
The use of steroids in HCV-infected recipients is still under debate. The use of a steroid bolus to treat acute rejection should certainly be avoided because it worsens the progression of fibrosis and is associated with poor long-term outcome . On the contrary, two randomized, prospective, multicentre trials including liver transplant patients with chronic HCV concluded that the steroid-free regimen was safe and effective, but did not show any advantage for HCV recurrence compared with the traditional regimen [26, 27]. The use of steroids in HCV-infected recipients should not be discouraged. The impact of other immunosuppressive drugs such as mycophenolate mofetil, interleukin-2 inhibitors on HCV recurrence remains unclear and large prospective studies are needed.
Management of HCV recurrence
Monitoring and timing of the initiation of antiviral therapy
The best strategy to prevent the recurrence of HCV is to eradicate HCV infection prior to LT. Otherwise, two approaches can be considered for the timing of antiviral therapy after LT: treatment before the development of injury to the graft in the early phase within one month (preemptive strategy) or treatment when chronic hepatitis is diagnosed.
At present, the preemptive strategy is not recommended because several studies have shown that it is difficult to initiate antiviral therapy with IFN during the post-operative period and that efficacy is poor [28-32]. Patients with severe end-stage liver disease prior to LT are frequently ineligible for this approach. When the preemptive strategy is feasible, an SVR is obtained in 8–39% (5–33% of genotype 1 patients and 14–100% of genotype 2–3 patients). About 30% of patients discontinue treatment and dose reductions are required in 70%, because of side effects such as bacterial infections, haematological toxicity and rejections (0–26%). However, the preemptive strategy should be reassessed with new DAAs.
It is generally admitted that antiviral therapy should be initiated in the presence of histologically proven HCV recurrence. However, the decision also takes into account age, general condition and the stage of fibrosis, usually >F1 on the METAVIR score . Antiviral therapy should be initiated in the presence of severe and rapid progression of fibrosis with a higher risk of graft loss, especially CH. If a liver graft biopsy is not performed, other non-invasive markers can help make the treatment decision. For liver stiffness, a value < 8.7 kPa had a 90% negative predictive value and a higher cut-off is usually accepted to define significant fibrosis . The measurement of the hepatic venous pressure gradient can help, with a gradient >6 mmHg for significant fibrosis . Although non-invasive markers can discriminate the stage of fibrosis, a liver graft biopsy is essential before antiviral therapy is begun to obtain crucial data in transplant patients such as the presence of rejection, biliary obstruction or the degree of steatosis. Finally, we have reported that tolerance to therapy decreases significantly in patients with a fibrosis stage >3, suggesting that antiviral therapy should be initiated before advanced fibrosis develops .
Current antiviral strategy: the standard dual therapy
Standard antiviral therapy includes PEG-IFN/RBV. Several studies have shown that an SVR is achieved in 8–45% and three systematic reviews of PEG-IFN/RBV showed an SVR rate of 30% [35-37]. However, a decreased efficacy of dual therapy has been reported . The authors suggest that organ shortages force transplant teams to accept grafts from older donors, which influences the prognosis of HCV recipients. Baseline cirrhosis on the liver graft before therapy is responsible for a poorer SVR and outcome.
Factors associated with SVR are summarized in Table 1. Most studies have shown that an early virological response (EVR) is the principal predictive factor associated with an SVR [6, 39]. The duration of therapy is usually 48 weeks. No published studies have evaluated 72 weeks of extended therapy in recipients with positive HCV RNA at week 12. One recent study showed that the SVR was not improved by long-term maintenance therapy with RBV, but showed an overall per-protocol SVR rate of 47% (80% in G2/3 patients and 37% in G1 patients) .
|Baseline viral load|
|IL28B donor and recipient|
|Absence of prior antiviral therapy|
|Severity of baseline fibrosis|
|During therapy||Adherence to therapy|
|Duration of therapy|
|Rapid virological response|
|Early virological response|
Future strategy: preliminary results of the use of direct-acting antiviral
Direct-acting antivirals such as protease inhibitors, polymerase or other non-structural proteins inhibitors represent a new era in HCV treatment. Although their use in the field of liver transplantation seems essential, there are some limitations for safety and tolerance. One limitation is the potential interaction with CNI . The two PI, boceprevir and telaprevir, represent the first generation of DAA in genotype 1 patients and are characterized as potent inhibitors of cytochrome P450 3A4. In a recent study in healthy volunteers, boceprevir has been shown to increase the area under the curve of CsA and Tac by 2.7 and of 17 respectively . In another recent study, the concomitant administration of immunosuppressive therapy with telaprevir in healthy volunteers increased CsA and Tac exposures approximately 4.6-fold and 70-fold respectively . We recently reported our experience with boceprevir in 5 liver transplant genotype 1 patients. The estimated oral clearance was reduced by 50% with CsA and up to 80% with Tac . In 2012, several teams have communicated preliminary results of DAAs use after LT, which are summarized in Table 2 [44-47]. We reported the first multicentre study of 29 patients with HCV genotype 1 recurrence treated with triple therapy after LT in five French liver transplant centres . Difficult-to-treat patients with advanced fibrosis were included as well as non-responders to a previous course of standard therapy post-LT, HIV co-infected and CH patients. If HIV co-infected patients were excluded (n = 4), interim results show complete RVR rates after 4 weeks of triple therapy in 43% with boceprevir and in 45% with telaprevir. At 12 weeks of triple therapy, a complete early virological response (EVR) was obtained in 71% of patients treated with boceprevir and 73% of patients treated with telaprevir. Finally, the CsA dose should be reduced by 1.3-fold with boceprevir and four-fold with telaprevir. The Tac dose should be reduced by five-fold with boceprevir and 35-fold with telaprevir . The practical management of initiating DAAs is summarized in Fig. 1. DAAs could completely change the prognosis of patients with severe HCV recurrence. A patient with CH at 3 months post-LT was treated with a triple regimen of PEG-IFN/RBV and daclatasvir and achieved SVR . Although these results must be confirmed and their use clearly defined, DAA offer new perspectives for HCV liver transplant patients (Fig. 2).
|First author (ref)||Coilly ||Kwo ||MacCashland ||Burton |
|4-weeks lead-in phase (%)||76%||100%||0%||100%|
|Week 4 (%)||44%||29%||NA||63%|
|Week 8 (%)||NA||71%||42%||53%|
|Week 12 (%)||76%||NA||NA||NA|
|Adverse events and management of anaemia|
|RBV dosage reduction (%)||52%||100%||100%||83%|
|Blood transfusion (%)||8%||86%||21%||56%|
|Kidney failure (n)||1||0||NA||8|
Current and future tolerability of antiviral therapy
Tolerance to antiviral therapy is a major issue in liver transplant patients. They are particularly exposed to the haematological toxicity of PEG-IFN/RBV and infections. The most important adverse event is anaemia, mainly because of RBV-induced haemolysis. The dose of RBV is generally lower than in non-transplant patients because dosage is adapted to renal function, which is often abnormal in liver transplant patients due to the use of CNI. Trough blood concentrations could help adjust the RBV dose. The RBV dose can be increased with the use of EPO, but this has not been shown to improve SVR.
Data are also lacking on the impact on SVR of the use of granulocyte colony-stimulating factor or thrombopoietin-receptor agonist to increase neutrophil and platelets counts, although these agents are currently used in liver transplant patients.
A specific adverse event in recipients is the risk of acute rejection, which occurs in 6% of patients during antiviral therapy, although there was no significant difference with an untreated control group [29, 49]. The use of PEG-IFN compared with regular IFN seems to worsen the occurrence of acute rejection (6% vs. 2%) . Increasing immunosuppression is effective in most cases. Chronic rejection is an uncommon event during antiviral therapy. Finally, these adverse events lead to a dose reduction in RBV and/or PEG-IFN in around 70% of patients and to discontinuation of therapy in 30% of patients [35-37].
There are no published studies on the efficacy and safety of DAAs after liver transplantation. Tolerance will probably be a limiting factor. DAAs have their own specific side effects such as dermatological toxicity, and the incidence and severity of anaemia are increased by 20% with first-generation DAAs in non-transplant patients . In preliminary communications, triple therapy leads to the nearly constant use of EPO, a dose reduction in RBV in almost 75% of patients and the use of blood transfusions . These data suggest that anaemia should be carefully monitored and managed. In our experience, EPO should be initiated early before the haemoglobin level is below 10 g/dl. We identified five serious infections in our series leading to two deaths . Several IFN-free trials with different DAAs are ongoing in non-transplant patients with interesting preliminary results . Second generation DAA and a PEG-IFN-free regimen should improve tolerance.
Hepatitis C virus recurrence is a constant and serious complication in liver transplant recipients and is the primary cause of graft loss and death in these patients. PEG-IFN/RBV, the current standard of care, has been extensively studied in this population. Although an SVR is only achieved in 30% of patients with poor tolerance, until this year, this was the only existing effective treatment in this context. DAAs must be carefully evaluated after liver transplantation in relation to drug–drug interactions and tolerance, but these agents have opened a new era in HCV infection that should also benefit liver transplant recipients.
The authors have no disclosure.