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Keywords:

  • antiviral therapy;
  • boceprevir;
  • direct acting antiviral;
  • hepatitis C;
  • interferon;
  • liver transplantation;
  • ribavirin;
  • sofosbuvir;
  • telaprevir

Abstract

  1. Top of page
  2. Abstract
  3. Conclusion
  4. References

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 have developed cirrhosis at 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 approximately 40%. To date, retransplantation is the only option in patients with decompensated liver disease. Until 2011, standard antiviral therapy with pegylated interferon (PEG-IFN) and ribavirin (RBV), was the only effective therapy. Obtaining a sustained virological response (SVR) in patients with LT greatly improves overall and graft survival but this only occurs in 30% of transplanted patients. Direct acting antivirals (DAAs) such as protease inhibitors (PI), polymerase or other non-structural proteins inhibitors represent a new era in HCV associated liver disease. Although their use in the field of LT will certainly be essential there are some limitations because of safety and tolerance. One limitation is the potential interaction with calcineurin inhibitors. We describe the results of triple therapy with boceprevir (BOC) or telaprevir (TVR) for efficacy and safety and comment on future therapeutic strategies in liver transplant recipients.

Abbreviations
BOC

boceprevir

CH

cholestatic hepatitis

CNI

calcineurin inhibitors

CsA

cyclosporine

CYP

cytochrome

DAA

direct acting antiviral

EPO

erythropoietin

EVR

early virological response

HCV

hepatitis C virus

HIV

human immunodeficiency virus

HLA

human leukocyte antigen

LT

liver transplantation

NA

not available

PEG-IFN

pegylated interferon

PI

protease inhibitors

RBV

ribavirin

RNA

ribonucleic acid

RVR

rapid virological response

SVR

sustained virological response

Tac

tacrolimus

TVR

telaprevir

Despite the recent improvement in treatment strategy, hepatitis C virus (HCV) associated end-stage liver disease is still the main indication for liver transplantation (LT) in Western countries [1]. Recurrent HCV is the most frequent cause of death and graft loss in these patients, and represents two-thirds of graft failures [2]. Although obtaining a sustained virological response (SVR) in patients with LT can greatly improve overall and graft survival, this only occurs in one-third of transplanted patients (20–30% in genotype 1 patients and 40–50% in genotype 3 patients) [3]. Until 2011, dual therapy based on the combination of pegylated interferon (PEG-IFN) and ribavirin (RBV), was the only effective therapy. The development and approval of novel direct acting antiviral agents (DAAs) is the beginning of a new era for the treatment of HCV patients. At present genotype 1 patients are treated with first generation NS3/4 protease inhibitors (PI): boceprevir (BOC) or telaprevir (TVR). In the near future, new, less toxic, more effective DAAs should be available and will certainly change the management of post-transplant antiviral C therapy [4]. This review describes the management of triple therapy in HCV transplant patients and future antiviral approaches after LT.

HCV recurrence after liver transplantation: the transplant physician's bane

Natural history of HCV recurrence

HCV infection is one of the main causes of end-stage liver disease worldwide leading to LT [1]. The best option is to obtain a SVR with antiviral therapy before LT and eliminate the risk of recurrent HCV infection. In the next decade this goal may be reached in most patients using new DAAs. This approach is the subject of another review in this issue and will not be discussed here. If serum HCV ribonucleic acid (HCV RNA) is 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 [5]. Survival reaches 61–75% and 68% at 5 and 10 years post-LT respectively [6-8]. The outcome of transplant patients with cirrhosis on the graft is severe, with a rate of decompensation of around 40% at one year [2]. To date, retransplantation is the only option in patients with decompensated liver disease. 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 the treatment of recurrent infection [6]. A SVR is associated with better long-term outcomes, improved graft fibrosis and survival [9].

Two to 8% of 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 [10]. 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 recurrent HCV infection and resulting graft loss [11]. For example, high HCV RNA levels in both serum and the liver at the time of or early post-LT are associated with an increased risk of progression to cirrhosis, graft loss and death [12]. Although the data are controversial, HCV genotypes 1 and 4 seem to be negative predictive factors for the recurrence of HCV, mainly because of a lower response to PEG-IFN/RBV therapy [13-15]. The host and donor factors associated with poorer outcome included female gender, older donor age, steatosis of the graft, the degree of human leukocyte antigen (HLA) matching or the IL28B genotype of the donor and the recipient [5, 16, 17]. After LT, both cytomegalovirus and human herpes virus 6 infections have been associated with rapid progression to recurrent HCV [18].

Impact of immunosuppressive regimen

The management of recurrent HCV 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 [19]. Second, potential drug-drug interactions must be taken into account before using first generation PI therapy [20].

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 [21]. However, several studies did not show any difference between CsA and Tac in the outcome of HCV recurrence [22]. On the contrary, a retrospective study suggests that the effect of CsA was deleterious compared with Tac in more than 8000 recipients [23]. 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 [24]. Recently, a meta-analysis of seven studies with 40 or more patients in each group (with 1634 patients in all) have shown that dual therapy with CsA was more effective than Tac in achieving a SVR (RR = 1.23, 95% CI = 1.09–1.38, < 0.001). Moreover, fewer interactions have been described with CsA than with Tac during co-administration with a PI (see below).

The use of steroids in HCV-infected recipients is still a subject of 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 [25]. 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 impact of other immunosuppressive drugs such as mycophenolate mofetil, interleukin-2 inhibitors on HCV recurrence is still unclear and large prospective studies are needed.

Management of recurrent HCV infection in 2013: a transition

Monitoring and timing of the initiation of antiviral therapy

The best strategy to prevent recurrent HCV infection is to eradicate HCV prior to LT. The results of prophylactic treatment with anti-HCV monoclonal antibodies are disappointing. 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 1 month after transplantation (preemptive strategy) or treatment when chronic hepatitis has been diagnosed.

At present, the pre-emptive 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 pre-emptive strategy is feasible, a SVR is obtained in 8–39% (5–33% in genotype 1 patients and 14–100% in genotypes 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 accepted that antiviral therapy should be initiated in the presence of histologically proven HCV recurrence. However, this decision must also take into account age, the patient's general condition and the stage of fibrosis, usually >F1 on the METAVIR score. Antiviral therapy should be initiated in the presence of severe fibrosis 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. A cut-off value of 8.7 kPa for liver stiffness had a sensitivity and a negative predictive value for significant fibrosis and portal hypertension >0.90 in all cases [33]. The measurement of the hepatic venous pressure gradient can help, with a gradient >6 mmHg for significant fibrosis [34]. Although non-invasive markers can discriminate the stage of fibrosis, regular protocol biopsies of the graft are essential before antiviral therapy is begun to obtain crucial data such as the progression of graft fibrosis, the presence of rejection, biliary obstruction or the degree of steatosis. Finally, we have reported that tolerance to therapy decreases significantly in patients with fibrosis stage >3, suggesting that antiviral therapy should be initiated before advanced fibrosis develops [9].

There is no doubt that the best timing to treat recurrent HCV recurrence may be updated in the very near future. The current strategy to wait for significant fibrosis on the liver graft before initiating antiviral treatment is supported by the poor tolerability of IFN-based regimens early after LT. The next generation of IFN-free DAAs should result in earlier treatment, although there is currently no firm data to support this.

Dual therapy: Is there still a place?

Until recently, standard antiviral therapy has included PEG-IFN/RBV. Several studies have shown SVR rates of 18–45% and three systematic reviews of PEG-IFN/RBV showed SVR rates of 30% [3, 35, 36]. Factors associated with SVR are non-1 genotype, the absence of prior antiviral therapy, an early virological response (EVR) or rapid virological response (RVR), adherence to therapy, low pretreatment viral load and a favourable IL28B genotype [3, 8, 16, 35-37]. Baseline cirrhosis on the liver graft before therapy is predictive of a poorer SVR and outcome. A recent study showed that the SVR was not improved by long-term maintenance therapy with RBV and an overall per protocol SVR rate of 47% (80% in G2/3 patients and 37% in G1 patients) [38]. A study on the retreatment of transplant patients with PEG-IFN/RBV therapy showed that an SVR, which was achieved in approximately one-third of retreated patients, can be predicted with the same variables as for naïve LT recipients [39].

Although the difficulties of dual therapy will be replaced by a new DAA-based regimen, dual therapy is still the standard of care in non-genotype 1 patients. In genotype 1 patients, standard therapy is now triple therapy with first generation PI. Based on the increase of SVR from 45–50% to 60–70% in non-transplant patients, first generation PI are now widely used in most countries that have approved BOC or TVR [40]. Although there are great hopes for their use in the field of LT there are some limitations for safety and tolerance.

Efficacy of triple therapy

Recently, several studies have been published on the preliminary results of BOC and TVR use after LT. The results are summarized in Table 1 [41-43]. Pungpapong et al., reported the results in three centres that used BOC (n = 25) and TVR (n = 35) in 60 patients with fibrosis stage ≥2 for a follow-up of 66 weeks (mean = 35 weeks). Maintenance immunosuppression was changed to CsA whenever possible before PI was initiated. At week 4 of PI therapy, HCV RNA was undetectable (RVR) in six (17%) and six patients (24%) in the TVR and BOC groups respectively. At week 12 of therapy HCV RNA was undetectable (EVR) in 28 (80%) and 10 patients (40%) in the TVR and BOC groups respectively. Three patients (week 18, 20 and 22) and one patient (week 19) developed viral breakthrough in the TVR and BOC groups respectively [42].

Table 1. Efficacy data on triple therapy for HCV recurrence after liver transplantation
First author (ref)Coilly [41]Pungpapong [42]Werner [43]
  1. a

    The virological response is defined as an undetectable HCV viral load after × weeks of triple therapy, with or without lead-in phase.

  2. BOC, boceprevir; EOT, end of treatment (Week 48); HCV, hepatitis C virus; NA, not available; RBV, ribavirin; ref, reference; SVR12, sustained virological response 12 weeks after treatment discontinuation; TVR, telaprevir.

Patients (n)37609
Regimen
 BOC/TVR (n/n)18/1925/350/9
 4-weeks lead-in phase (%)70%47%0
Virological responsea
 Week 4 (%)56%/47%24%/17%NA/44%
 Week 8 (%)NA40%/NANA
 Week 12 (%)89%/58%NA/80%NA/89%
 EOT (%)72%/40%NANA
 SVR12 (%)71%/20%NANA

We performed a multicentre study of 37 patients treated with triple therapy (TVR n = 19, BOC n = 18) after LT [41]. This study included difficult to treat patients with advanced fibrosis (83% with fibrosis stage ≥ 2) as well as non-responders to a previous course of standard therapy, post-LT and CH patients (16%). A RVR was obtained in 19/37 patients (51%) (BOC: 56%; TVR: 47%) at week 4 of triple therapy. A complete EVR was achieved in 27 patients (73%) (BOC: 89%; TVR: 58%) and an end of treatment response was observed in 28 patients (76%) (BOC: 72%; TVR: 40%). Finally, a SVR12 was obtained in one of the five eligible patients (20%) in the TVR group and five of the seven eligible patients (71%) in the BOC group. Six patients (16%) developed viral breakthrough. Complete NS3 sequence information was obtained in seven patients who experienced treatment failure, non-response or a breakthrough. At least one mutation related to PI was detected in all of them.

Other groups have reported their experience with new PIs in the post-transplant period. The numbers of patients being treated in these individual centres are small and at present only EVR data are available. Data are based on single centre studies and it is difficult to make specific recommendations except that PI based triple therapy has been shown to be feasible in this difficult population. Data for a SVR and predictive factors of a SVR in a large population are needed to determine which liver recipients will benefit from triple therapy. The results of the phase IIIb study of TVR (REPLACE) in stable liver transplant patients with genotype 1 disease is also expected (Clinicaltrials.gov: NCT01571583).

Safety of triple therapy

Tolerance to antiviral therapy is a major issue in liver transplant patients. Systematic reviews of dual therapy have shown that dose reductions of RBV and/or PEG-IFN were necessary in around 70% of patients and the rate of treatment discontinuation was approximately 30% [3, 35, 36]. Liver recipients are particularly exposed to the PEG-IFN/RBV haematological toxicity and infections.

Table 2 summarizes the occurrence and management of adverse events during triple therapy after LT. Haematological toxicity is the most frequent adverse event. Although quasi-constant, cytopaenia is easily manageable and life-threatening events are uncommon.

Table 2. Safety data on triple therapy for HCV recurrence after liver transplantation
First author (ref)Coilly [41]Pungpapong[42]
  1. BOC, boceprevir; BPAR, biopsy-proven acute rejection; Hb, haemoglobin level; HCV, hepatitis C virus; EPO, erythropoietin; NA, not available; NC, neutrophil count; RBV, ribavirin; PC, platelets count; ref, reference; TVR, telaprevir.

Patients (n)3760
Cytopaenia
 Anaemia (Hb <8 g/dl) (%)32%NA
 Leucopaenia (NC <1 g/L) (%)40%NA
 Thrombopaenia (PC <50 g/L) (%)32%NA
Management
 RBV dosage reduction (%)70%93%
 EPO use (%)97%85%
 Red blood cell transfusion (%)35%53%
 GCSF use (%)8%33%
 Elthrombopag use (%)0%5%
Other adverse events
 BPAR (n)03
 Kidney failure (n)523
 Infection (n)107
 Death (n)32

The most severe complication is infection, which may lead to hepatic decompensation and/or death. Werner et al., reported one patient with pneumonia who had to discontinue TVR 2 weeks after it was begun [43]. Pungpapong et al., reported seven cases of infection (six in the TVR group, one in the BOC group): one patient with a periodontal abscess, two patients with a urinary tract infection, one patient with sinusitis, one patient with lower extremity cellulitis, one patient with pneumonia and one patient with herpes zoster reactivation. Two patients died and three patients with pretreatment cirrhosis developed hepatic decompensation [42]. In our series, there were 10 infections and three patients died. Infections included two patients with community-acquired pneumonia, one with cytomegalovirus infection, one with pneumocystosis and aspergillosis in the same patient, four urinary tract infections one erysipelas and one peritonitis [41]. Although infections have been observed during dual therapy, the severity and absence of predictive factors of infection during triple therapy suggest that the candidate should be carefully screened. Triple therapy should be avoided in weak, undernourished patients with previous episodes of hepatic decompensation.

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, 44, 45]. The use of PEG-IFN compared with regular IFN seems to worsen the occurrence of acute rejection (6% vs. 2%) [35]. Increasing immunosuppression is effective in most cases. Chronic rejection is an uncommon event during antiviral therapy. During triple therapy, the risk of biopsy proven acute rejection seems to be similar to control groups and varies from 4% to 6% [41-43].

Renal insufficiency has also been reported despite the heterogeneity of the definition of renal events. In our experience, glomerular filtration is reduced by more than 10 ml/min with a nadir at 24 weeks of triple therapy [41].

No serious dermatological events have been reported with triple therapy after LT.

Practical management of drug-drug interactions during triple therapy

Because PI are potent inhibitors of cytochrome P450 3A4 and P-glycoprotein, the CNI trough blood concentration is increased after TVR or BOC is begun. This was confirmed by pharmacokinetic studies in healthy volunteers. BOC increases the area under the curve of CsA and Tac by 2.7 and of 17 respectively [46]. TVR increased CsA and Tac exposure by approximately 4.6-fold and 70-fold respectively [47].

In our experience in liver transplant patients, the CsA dose should be reduced by 1.8-fold with BOC and 3.4-fold with TVR. The Tac dose should be reduced by 5.2-fold with BOC and 23.8-fold with TVR. When PI is discontinued the CNI dose should be increased to reach the baseline level. In 27% of patients, the steady state CNI concentration exceeded the baseline level [41].

Data on the interaction with other immunosuppressive drugs are limited. There are no data on the interactions between mycophenonolate and PI. No pharmacokinetic interactions are expected except pharmacodynamic interactions and a potential increase in haematological toxicity [20]. With BOC, prednisone and prednisolone AUC were increased by 22% and 37%, respectively, in healthy volunteers [48]. There are no data available on TVR. mTOR inhibitors are also metabolized by CYP3A4. This results in interactions with first generation PI. In our experience, the estimated clearance of everolimus was decreased by 55% in one patient with BOC [49]. O'Leary et al. reported a 24-fold higher sirolimus AUC than values previously reported in the literature when TVR was used to treat 16 patients with HCV after LT [50].

These findings suggest that post-LT CsA dosing may be less difficult to manage with TVR or BOC. There is no consensus on how to adapt the immunosuppressive regimen before beginning triple therapy but many centres systematically switch from Tac to CsA [20]. In our experience, trough blood concentrations of CNI must be closely monitored whatever the drug used. With Tac, TVR should be begun during a short hospital stay.

Future therapy

Although first generation PI can be used after LT in genotype 1 patients these regimens are associated with serious toxicity and drug-drug interactions that limit their potential benefit. At present, data are limited on SVR rates with first generation PI. Triple antiviral therapy with TVR or BOC was less effective in patients with genotype 1a, IL-28B polymorphism CT or TT and non-responders to a previous PEG-IFN/RBV regimen. The second wave of DAAs includes NS3/4A protease, HCV polymerase or NS5a inhibitors [51]. The combination of NS5a inhibitors and second generation NS3/4A protease or polymerase inhibitors without IFN, but with RBV gave excellent results (SVR >90%) in the non-transplant setting with efficacy in all genotypes, lower toxicity and shorter treatment. Considering the rapidly changing HCV therapeutic landscape and the potential use of IFN-free regimens, SVR rates will probably improve significantly. However, at present data are limited to small groups of patients without advanced liver disease.

There are very few data on new DAAs in transplant patients. One patient with CH 3 months post-re-LT was treated with a 24 week triple regimen of PEG-IFN/RBV and daclatasvir and achieved a SVR [52]. The same group has reported the combination of daclatasvir and sofosbuvir without PEG-IFN/RBV in a patient with severe recurrent HCV [53]. Two phase 2 studies investigating sofosbuvir and RBV and/or ledipasvir for 12 or 24 weeks in patients with recurrent HCV infection is on-going (Clinicaltrials.gov:NCT01687270; Clinicaltrials.gov: NCT01938430). Although these results must be confirmed and their use clearly defined, DAAs offer new perspectives for pre- and post-transplant patients with HCV (Fig. 1).

image

Figure 1. Proposed algorithm for antiviral strategy after liver transplantation.

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Conclusion

  1. Top of page
  2. Abstract
  3. Conclusion
  4. References

Recurrent HCV is a constant, severe complication in liver transplant recipients and is the primary cause of graft loss and death in these patients. PEG-IFN/RBV has been extensively studied in this population. Although a SVR is only achieved in 30% of patients, and tolerance is poor, this was the only existing effective treatment in these patients until 2011. DAAs must be carefully evaluated following LT for drug-drug interactions and tolerance but these agents are the beginning of a new era in the treatment of HCV infection that should also benefit liver transplant recipients.

References

  1. Top of page
  2. Abstract
  3. Conclusion
  4. References