S. Ciesek; H. Wedemeyer
Posted: 01/17/2012; J Viral Hepat. 2012;19(1):1-8. © 2012 Blackwell Publishing
Abstract and Introduction
Hepatitis C virus (HCV) infection is a major cause for liver transplantation worldwide. Still, HCV re-infection of the graft occurs in almost all cases. Most liver transplant recipients experience episodes of graft hepatitis associated with fibrosis progression and graft failure. Clinical management of graft hepatitis can be challenging as in addition to rejection and HCV-induced hepatitis various other factors might be involved including toxic liver injury, steatohepatitis, ischaemic bile duct lesions or infections with other pathogens. Treatment options are often contradictory for different causes of graft hepatitis, and the role of distinct immunosuppressive drugs has been discussed controversially. Corticosteroids increase the infectivity of HCV by altering expression levels of entry factors and other immunosuppressive agents may have diverse effects on HCV replication and fibrosis progression. Interferon alpha-therapy of hepatitis C shows limited efficacy and tolerability in liver transplant recipients and may also cause rejection. In this review we summarize the current knowledge on mechanisms of liver injury in post-transplant hepatitis C, discuss the pros and cons of immunosuppressive agents in this specific setting and describe potential novel approaches to prevent HCV reinfection.
Around 160 million people are chronically infected with the hepatitis C virus (HCV), representing 2.2% of the world population.[1,2] The geographic distribution of HCV-infected individuals varies largely between 0.1% in Northern Europe and up to 20% in Egypt.[3–6] HCV is a highly variable enveloped RNA virus that infects hepatocytes. Based on sequence analyses, HCV can be grouped into seven different genotypes and more than 100 subtypes within the Flaviviridae family.[7,8]
Patients with acute HCV infection stay asymptomatic in the majority of cases and fail to clear the virus spontaneously.[9,10] Chronic hepatitis C can lead to hepatic inflammation, fibrosis, cirrhosis (10–20%) and hepatocellular carcinoma (HCC; 1–4% per year in cirrhotic patients).[4,9,11] Until 2011 the standard of care for chronic HCV infection has been combination therapy with pegylated interferon alpha (PEGIFN-α) and ribavirin inducing a sustained virological response (SVR), i.e. HCV RNA negativity 6 months after completion of therapy, in 40–50% of patients infected with the most prevalent HCV genotype 1.[13,14] Successful treatment is associated with an improved clinical long-term outcome even though HCC can still develop in cirrhotic patients after HCV has been eliminated.[11,15] Very recently, two inhibitors of the HCV NS3/4A protease, boceprevir and telaprevir have been approved for the treatment of chronic hepatitis C. Triple therapy with a protease inhibitor, PEG-IFNa and ribavirin has substantially improved response rates now approaching 70%-80% for HCV genotype 1 infection.
HCV Recurrence After Liver Transplantation
Chronic infection with HCV is a major cause of end-stage liver disease and a leading indication for orthotopic liver transplantation (OLT) worldwide. However, re-infection of the graft by HCV particles present in the blood stream is almost universal and at least 25% of patients will develop liver cirrhosis after transplantation within 5–10 years.[17,18] Once cirrhosis is established, transplanted patients show an accelerated natural history with decompensation rates of as high as 40% after 12 months. To date, there is no safe and effective way to prevent HCV recurrence. Moreover, patients with recurrent hepatitis can develop a severe cholestatic hepatitis C syndrome characterized by jaundice shortly after transplantation in the absence of biliary obstruction, particular high HCV RNA levels and a very high risk for liver failure. Subsequently, graft loss caused by recurrent HCV infection is the most important reason to consider re-transplantation. Some data suggest that the outcome of hepatitis C after liver transplantation has worsened during the last decades. Across different countries and transplantation programs, the 5-year post-transplantation survival rate for hepatitis C patients is significantly lower as compared to patients who underwent liver transplantation for other chronic liver diseases. Factors being associated with graft loss in HCV-infected patients included an older donor age, steatosis of the donor organ, specific immunosuppressive regimens (discussed later), female sex, a high necroinflammatory activity in the allograft 1 year after transplantation and high HCV viral loads (Table 1).[21–23] In addition, several additional factors have been discussed to influence the long-term outcome of graft hepatitis C such as herpes virus infections, the degree of human leucocyte antigen (HLA) matching or the IL28b genotype of the donor and the recipient.[26,27]
Cellular immune responses by both T cells and NK cells are thought to play a major role in the pathogenesis of chronic hepatitis C after transplantation. HCV-specific T-cell responses have been linked with improved histological and clinical outcomes[28,29] and are also associated with spontaneous HCV clearance after liver transplantation. Genotypes of killer cell immunoglobulin-like receptors and their donor HLA ligands which determine NK cell activities may also play an important role in the recurrence and progression of hepatitis C in liver transplant recipients. An interesting study from Japan showed that adoptive immunotherapy 3 days after liver transplantation with activated lymphocytes extracted from the liver allograft perfusate can result in markedly reduced HCV RNA titres of the recipient confirming the importance of immune cells to control HCV infection after liver transplantation.
In general, HCV RNA levels are higher after OLT than before and high virus titres are associated with a worse long-term outcome of these patients. More specifically, serum HCV RNA levels increase rapidly from the second-week post-transplantation and peak by the fourth postoperative month. HCV RNA levels at 1 year after liver transplantation are 10- to 20-fold higher than pretransplant levels. Viral quasispecies composition differs after liver transplantation as compared to pretransplant sera and may also be involved in the long-term outcome of graft hepatitis. However, detailed mechanisms of how high viral loads and distinct viral compositions contribute to the accelerated disease progression in graft hepatitis C are still poorly defined.
Prevention of HCV Re-infection After Liver Transplantation
Considering the severe clinical course of post-transplant hepatitis C, one of the major unmet needs is the development of strategies to prevent re-infection of the liver graft after transplantation. Pretransplant treatment with PEG-IFNa and ribavirin of patients on the waiting list to prevent HCV reinfection is possible only in few individuals as PEG-IFNa treatment can induce severe infectious complications in decompensated liver disease.[37,38] Moreover, no prophylactic vaccine is yet available to prevent HCV infection. Thus, alternative strategies to prevent HCV reinfection during or very early after transplantation should be explored.
In general, agents preventing viral cell entry should be of particular value (Fig. 1). These include antibodies against one or all essential HCV cellular entry factors, neutralizing antibodies against the HCV envelope proteins E1 and/or E2 envelope or drugs targeting HCV entry by interaction with the virion or a cellular entry factor.
Figure 1. Targets to prevent hepatitis C virus recurrence.
Four cellular factors have been described as essential for HCV entry: the tetraspanin molecule CD81, the scavenger receptor class B member I (SR-BI) and the tight junction proteins claudin-1 and occludin. Interestingly, neutralizing antibodies against CD81 are able to block HCV entry in vitro and also in immunodeficient mice transplanted with human hepatocytes, the best currently available small animal model of HCV infection. Anti-CD81 antibodies are currently in early clinical development but programs using antibodies against the other three entry factors are less advanced.
Neutralizing antibodies against the HCV envelope proteins E1 and E2 could also represent a promising approach to avoid HCV re-infection. However, efforts to elicit neutralizing antibody responses by immunization with E1E2 envelope proteins have had limited success. The main challenge here is the enormous genetic variability of the virus. Present within the chronically infected host is not a single isolate of HCV but rather a population of related yet different viral variants that has been referred to as a 'quasispecies swarm'. The swarm contains a vast repertoire of preformed variants that allow rapid escape from selective pressures such as neutralizing antibodies or anti-viral drugs. It has been shown that during chronic infection, HCV continuously escapes from the host's neutralizing antibody response.[35,42] Nonetheless, efforts to target HCV glycoproteins continue and recently, Garrone et al. reported the development of a vaccine platform to generate HCV-neutralizing antibodies that are based on retrovirus-derived virus-like particles pseudotyped with heterologous E1 and/or E2 proteins. These particles induced neutralizing antibodies in mice and also in macaques and cross-neutralized other HCV genotypes. Overall, the application of broad cross-neutralizing anti-HCV antibodies to prevent HCV reinfection still seems to be reasonable approach. This strategy has been highly successful in hepatitis B virus infection where the combination of passive immunization with anti-HBs antibodies and HBV polymerase inhibitors is able to prevent HBV reinfections in all patients.
Another possibility to inhibit HCV entry is the development of small molecules targeting one of the four cellular entry factors. ITX 5061 is an orally bioavailable compound blocking the HCV receptor scavenger receptor BI protein. ITX-5061 had a good safety profile in animal toxicology studies and also in clinical studies. Currently, the potency of ITX-5061 is evaluated in an open-label, proof-of-concept Phase 1b study in liver-transplanted patients (http://www.clinicaltrials.gov).
Silibinin, a major component of silymarin, is a plant-derived compound that is used for the treatment of HCV infection although its precise mechanism of action is still not known in detail. In 2010, it was shown for the first time that high doses of intravenous silibinin monotherapy prevented graft re-infection after OLT in a patient with chronic hepatitis C which has been confirmed in another case report. However, a much larger controlled study is needed to verify that intravenous silibinin is indeed safe and effective to prevent HCV re-infection after liver transplantation.
Recently, two other already well-known molecules have been shown to inhibit HCV entry: the green tea catechin EGCG and the tyrosine kinase inhibitor erlotinib. Erlotinib blocks HCV entry by inhibition of the activity of the EGF-receptor which is required for formation of CD81-claudin-1 co-receptor associations. EGCG inhibits viral attachment to the target cell as well as cell-to-cell transmission between adjacent cells. Both drugs are already FDA approved for other clinical applications; and EGCG is known to be innocuous in humans, readily available and cheap. Both inhibitors may provide a new approach to prevent HCV infection in the setting of liver transplantation, and future clinical studies are needed to test these in vitro observations in patients.
Besides entry blockers, more advanced direct acting antivirals (DAA) targeting other phases of the replication cycle may also be useful to prevent HCV re-infection. However, almost all DAAs in development have only been tested in compensated chronic HCV infection and their role in the peri-transplant setting remains to be defined. Clearly, this is challenging as the peri-transplant population is more vulnerable. Rapid emergence of drug resistance will prevent monotherapy with certain classes of DAAs including HCV protease inhibitors. However, nucleoside or nucleotide analogous inhibiting the HCV polymerase as well as cyclophilin inhibitors show a very high resistance barrier and thus will likely be part of interferon-free regimens aiming to prevent HCV replication in the transplanted graft.[16,52] Potential drug–drug interactions have to be considered as several DAAs in clinical development for HCV infection are metabolized via the cytochrome P450 3A4 and thus may interfere with immunosuppressive agents.
Thus, several approaches to prevent graft re-infection are currently being pursued. At this stage, no clear favourite has emerged and the goal to prevent HCV reinfection may well remain elusive for several years to come.
Treatment of HCV Re-infection After Transplantation
As long as no potent drugs or neutralizing antibodies are available to prevent HCV recurrence after liver transplantation, re-infection can still be treated with a combination of pegylated interferon alpha and ribavirin. However, the efficacy of this treatment is limited mainly by the poor tolerability in liver transplant recipients, and thus SVR rates are lower than in immunocompetent nontransplanted individuals. Overall, SVR rates after liver transplantation for HCV genotype 1 infection are around 25–30%. Furthermore, prolonged therapy seems to be required even in patients infected with the easier to treat genotypes 2 and 3 and extending antiviral therapy for more than 48 weeks might prevent virological relapse in many patients.[54,55] IL28B genotypes of both the donor and the recipient are associated with response to PEG-IFNa-based treatment after liver transplantation, and determination of the IL28b genotype may therefore be useful in clinical practice to decide which patient should receive antiviral therapy. Importantly, successful treatment reduces liver-related complications in recurrent HCV infection.
Even though interferon alpha can be beneficial for many patients, it has to be considered that antiviral therapy can promote rejection especially in the early phase after transplantation. Thus, liver transplant recipients receiving standard antiviral therapy need to be monitored for acute cellular rejection and chronic ductopenic rejection. In addition, de novo autoimmune hepatitis may develop and immunological phenomena may even occur after treatment has been stopped. As the clinical course of HCV infection is largely influenced by co-factors, it is of particular importance in liver transplant recipients to avoid co-morbidities including ischaemic-type bile duct lesions and liver steatosis.
The use of the novel NS3/4A protease inhibitors seems to be limited in patients after liver transplantation as it has been shown that telaprevir increases tacrolimus blood levels by approximately 70-fold – precluding its use outside of clinical trials. Co-administration with telaprevir also affected cyclosporine exposure and cyclosporine half-life, but to a lesser extent. No data on drug–drug interactions between calcineurin inhibitors (CNI) and boceprevir are currently available. Clinical trials are under way to determine the safety of efficacy of triple therapy of hepatitis C in liver transplant recipients. Whether combinations of PEG-IFNa with other NS3/4A protease inhibitors or with calcineurin inhibitor-free immunosuppressive regimens are feasible remains to be determined.
Currently, more than 100 novel HCV inhibitors are under preclinical and clinical investigation. These can broadly be divided in direct antiviral agents (DAA) and host factor targeting antivirals (HTA). While DAAs target the virus directly and include NS3/4A protease inhibitors (first & second generation), NS5B polymerase inhibitors and NS5A inhibitors, HTAs target essential cellular factors like cyclophilin A, microRNA122 and CD81 antibodies. Disadvantages of some but not all DAA classes are that they are not effective against all HCV genotypes and that viral resistance is anticipated to become a major problem. HTAs may show broad activity across HCV genotypes and pose a higher barrier to drug resistance in comparison with DAA. It is expected that some of the novel drugs will reach the market in 2015; however, none of the new anti-HCV drugs are currently being evaluated in HCV-infected liver transplant recipients. The ultimate goal will be to introduce safe interferon-free combination therapies without significant drug–drug interactions leading to cure from HCV infection within a limited time frame.
Immunosuppression and Graft Hepatitis C
As HCV re-infection cannot be prevented and curative treatment is unsuccessful in the majority of cases, the question arises whether there are ways to optimize post-transplant management, most notably the immunosuppressive regimen used, to minimize the risk of transplant hepatitis and graft loss. Advances in the development of novel immunosuppressive drugs have resulted in an improved clinical outcome after transplantation and transformed liver transplantation into a routine clinical procedure with overall reasonable long-term results. However, individualization of immunosuppressive therapy owing to the underlying disease is still a major goal to enhance graft survival especially in HCV-positive individuals. Furthermore, it has been suggested that the type of immunosuppressive therapy might be responsible for the worse outcome of HCV-positive individuals after liver transplantation observed in recent years.
Calcineurin inhibitors form the backbone of immunosuppression in the majority of liver transplant recipients. The discovery of CNI in the early 1970s and the FDA approval of cyclosporine A (CsA) in 1983 were major milestones for the immunosuppressive management of transplant recipients and increased 1-year graft survival rates from 24% in the late 70s to up to 60% in the 80s. Two CNIs, tacrolimus (Tac) and CsA, are currently approved for immunosuppression after liver transplantation. There is a large experience with both compounds and some differences in efficacy and the side effect profile became evident over the years. Therapy with Tac is associated with a higher incidence of post-transplant diabetes mellitus, while CsA treatment leads more frequently to dyslipidaemia, hypertension, hirsutism and gingival hyperplasia. Tacrolimus treatment may also cause more often hearing impairments, which is a common phenomenon in liver-transplanted patients. Tac is about 100 times more potent than CsA and exerts its action by binding to the FK binding protein 12 (FKBP12), while CsA binds to cyclophilins (e.g. cyclophilin A). Importantly, both of these complexes inhibit calcineurin, a pivotal enzyme in T-cell receptor signalling and activation, which dephosphorylates the transcription factor NF-AT (nuclear factor activating T cell). NF-AT regulates the activity of genes coding for IL-2 and other cytokines in T cells and thus inhibition of calcineurin prevents T-cell activation. Effects on other immune cells have also been noted, e.g. the function of regulatory T cells may be altered by both CsA and Tac.
Cyclophilin A, the target protein of CsA, is not only involved in T-cell activation but also serves HCV as an essential host factor for viral replication. For this reason, CsA very efficiently suppresses HCV RNA replication in vitro. In contrast, treatment with Tac has no effect on HCV RNA levels. This observation has led to the clinical development of non immunosuppressive CsA analogues for the treatment of HCV infection. The cyclophilin A inhibitor alisporivir is currently the most advanced HTA in development, phase II studies have shown good efficacy and very low rates of viral resistance[52,67] and phase III studies for the treatment of chronic hepatitis C patients are ongoing. While alisporivir seems promising in the nontransplant population, the antiviral effect of CsA did not lower HCV viremia in patients after liver transplantation or in a humanized mouse model. Even though, some earlier studies suggested that immunosuppression with cyclosporine might be associated with a better histological outcome of graft hepatitis C. However, the far majority of several subsequent studies did not identify major differences between CsA and Tac in the outcome of HCV infection after liver transplantation as nicely summarized by Berenguer et al. already in 2007. Conversely, a recent retrospective study with more than 8000 HCV-positive liver-transplanted individuals showed that patient death, graft failure, failure owing to recurrent disease and acute cellular rejection were slightly enhanced in the CsA-treated group in comparison with the Tac group. These results may cast doubt on the targeted long-term administration of CsA to HCV-infected liver transplant recipients. However, as part of strategies to avoid HCV re-infection, it might be helpful to employ a CsA-based immunosuppressive regimen in the early phase after transplantation as CsA has a clear additive antiviral effect in vitro. Moreover, some studies suggested that immunosuppression with CsA enhances SVR rates in liver transplant patients treated with interferon alpha and ribavirin.[53,74] Finally, CsA may have advantages concerning drug–drug interactions if novel HCV protease inhibitors are explored as CsA drug levels were less affected than Tac levels when co-administered with telaprevir.
Besides the question of the optimal CNI for HCV-positive liver transplant recipients, the use of steroids after transplantation of HCV patients has been a matter of debate for several years. While it is widely accepted that steroids should be avoided in individuals with HBV infection after liver transplantation, conflicting data have been published for hepatitis C. Clearly, repeated administration of high doses of corticosteroids to treat rejection is associated with more rapid fibrosis progression and poor long-term outcome of graft hepatitis C. Several studies confirmed that there is a strong correlation between steroid bolus therapies of acute rejection episodes and severe recurrence of hepatitis C.[76–78] Moreover, an interim analysis of the American HCV-3 study showed that a steroid-free immunosuppression regime was superior to steroid containing regimes regarding fibrosis progression which is in line with European experience demonstrating that immunosuppression without steroids reduces bacterial infections and improves histological short-term evolution of HCV recurrence. Besides the immunosuppressive effects of glucocorticoids, a recent in vitro study has revealed a direct stimulation of HCV infection by steroids. This was mediated through an upregulation of SR-BI and occludin, two crucial HCV entry factors, suggesting a novel direct mechanism of steroid-dependent exacerbation of HCV infection after liver transplantation. Taken together, it is widely accepted that immunosuppressive regimens after liver transplantation for hepatitis C should avoid steroid boli therapies, if possible. Overall, immunosuppression without steroids is safe after liver transplantation and has been shown to reduce infectious and metabolic complications. However, low-dose corticosteroids may not necessarily have to be avoided in HCV infection after liver transplantation. If steroids are used, slow rather than rapid tapering should be preferred.
The impact of other immunosuppressive agents including mycophenolate mofetil, azathioprine or interleukin-2 inhibitors on HCV recurrence remains controversial. For all of these drugs, conflicting studies have been published indicating both positive and negative effects on the course of HCV re-infection after transplantation. However, large high-quality prospective studies with a long-term follow-up are lacking. Thus, no recommendation can be given at this stage for preferential usage or avoidance of any of these compounds in the context of graft hepatitis C.
Prevention and treatment of HCV re-infection after liver transplantation remains a major unsolved clinical challenge. HCV-positive patients have poorer long-term outcomes after liver transplantation in comparison with patients with other underlying liver diseases. While treatment with pegylated interferon alpha and ribavirin can cure up to one-third of HCV-positive liver-transplanted patients, there are many promising drugs in clinical and preclinical development targeting either the virion or essential host factors. Strategies to prevent HCV re-infection include neutralizing antibodies or drugs targeting cellular HCV entry factors. Unfortunately, it will take at least several years until most of these drugs will reach routine clinical practice. Immunosuppressive medications may alter the course of hepatitis C after transplantation but conclusive data on the use of distinct regimens for HCV-infected transplant recipients are lacking. Thus, almost 30 years after the approval of the first calcineurin inhibitor and 23 years after the discovery of HCV, the optimal immunosuppressive strategy in HCV-positive liver transplant recipients still remains to be defined. However, acute rejection episodes and the need for steroid boli should be avoided as steroid bolus treatment is associated with reduced graft and patient survival and increase HCV infectivity.
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