Recurrent hepatitis C after liver transplantation: clinical and therapeutical issues

Hepatitis C virus (HCV) reinfection after liver transplantation is almost constant, assessed by the persistence of HCV RNA in 90% of cases. Acute hepatitis appeared in 75% of patients at a median of 4 months' post-transplantation. The 5-year actuarial rate of acute and chronic hepatitis on the graft is 75% and 60%, respectively. The rate of HCV cirrhosis on the graft is variable from 8 to 25% at 5 years. After transplantation, HCV viraemia is dramatically increased and correlates with the occurrence of acute hepatitis on the graft. Intrahepatic levels of HCV are high at the time of acute hepatitis, and decrease with constitution of chronic graft hepatitis lesions, implying an immunological response to the viral infection. A relationship between genotype 1b and the prevalence of HCV hepatitis on the graft has been suggested in European but not American series. The influence of the age of the recipient, quasispecies, viral compartmentalization, immunosuppressive treatment, and of HLA matching is being evaluated. The 5-year patient survival is around 65-80%. However, the occurrence of cirrhosis with a risk of graft failure may decrease the 10 and 15-year patient survival. Attempts to give prophylactic post-transplant antiviral treatment are under evaluation. Antiviral treatment of post-transplant graft lesions with combination therapy interferon–ribavirin gave promising results but indications and duration of treatment should be evaluated.
In conclusion, HCV reinfection is frequent, but medium-term survival is good. However, the long-term graft and patient survival remains unknown, and efficient prevention and treatment of HCV graft is mandatory.     

Treatment of hepatitis C in compensated cirrhotic patients is equally effective before and after liver transplantation

AIM: To investigate differences in tolerability and response to treatment in compensated cirrhotic patients affected by hepatitis C virus (HCV) infection before and after liver transplantation. METHODS: Forty-three HCV non-liver transplanted (LT) cirrhotics (mean age 55 ± 8 years, 65.1% male, Child-Pugh-A, genotype 1-4: 65.1%, 2-3: 34.9%) and 17 LT recipients with recurrent HCV-related cirrhosis (mean age 57 ± 9 years, 88.2% male, Child-Pugh-A, genotype 1-4: 76.5%, 2-3: 23.5%) were included in the analysis from retrospective series. All patients received recombinant or pegylated interferon plus ribavirin at a standard dose and duration. Adverse events were recorded and classified according to the Common Terminology Criteria for Adverse Events. The mean duration of follow-up was of 4.3 ± 1.8 years after the end of the treatment. RESULTS: An early virological response (EVR) was achieved in 30/43 (69.8%) non-LT and in 8/17 (47.1%) LT cirrhotics, a sustained virological response (SVR) in 18/43 (41.9%) and 5/17 (29.4 %), respectively. No sta- tistical difference was observed in EVR and SVR rates between the two groups. Among HCV non-LT cirrhotics, 6/43 (13.9%) discontinued the treatment prematurely, 11.6% of them receiving ≤ 80% of treatment; 8/17 (47%) LT cirrhotics withdrew the treatment, 35.2% of them receiving ≤ 80% of treatment. If compared with LT-ones (P = 0.015), an higher risk of treatment discontinuation could affect LT cirrhotics, who undergo more frequently ≤ 80% of treatment (P = 0.05). None of the non-LT cirrhotics died after the end of the treatment. With no regards to the achievement of SVR, LT cirrhotic patients showed a reduced survival in respect to non-LT ones (87% at 1 year, 76% at 3 and 5 years after the end of treatment).CONCLUSION: HCV antiviral treatment is equally effective in compensated cirrhotics both before and after LT, which patients show a higher risk of premature treatment withdrawal and a reduced survival, independently of the achievement of SVR.     

肝移植术后丙型肝炎复发患者抗病毒治疗效果及其对肝纤维化的影响

目的通过对肝移植术后丙型肝炎复发患者进行抗病毒治疗,研究抗病毒治疗效果以及对肝纤维化进展的影响。方法对本院2005年6月至2012年12月收治的23例肝移植术后丙型肝炎复发患者进行干扰素联合利巴韦林抗病毒治疗,观察病毒学应答情况、不良反应以及治疗前后肝组织病理情况。计数资料以例数表示,不同抗病毒疗效组间肝纤维化情况比较采用等级资料秩和检验。结果 12例患者因不良反应终止治疗。23例患者共获得结束时病毒学应答(ETVR)18例,其中6例获得持续病毒学应答(SVR),12例出现反跳。19例患者完成前后肝组织病理检查,SVR组肝纤维化减轻3例、持平1例、进展0例;停药后反跳组肝纤维化减轻2例、持平3例、进展5例;无应答组肝纤维化减轻0例、持平1例、进展4例;3组间抗纤维化效果比较,差异有统计学意义(χ2=7.330,P=0.026)。结论肝移植术后丙型肝炎复发患者抗病毒治疗SVR率较低,有效的抗病毒治疗可延缓肝纤维化进展,取得SVR的患者肝纤维化改善效果最佳。     

Management of recurrent hepatitis C virus after liver transplantation

Chronic hepatitis C virus(HCV) infection is the leading cause of death from liver disease and the leading indication for liver transplantation(LT) in the United States and western Europe. LT represents the best therapeutic alternative for patients with advanced chronic liver disease caused by HCV or those who develop hepatocarcinoma. Reinfection by HCV of the graft is universal and occurs in 95% of transplant patients. This reinfection can compromise graft function and patient survival. In a few cases, the histological recurrence is minimal and non-progressive; however, in most patients it follows a more rapid course than in immunocompetent persons, and frequently evolves into cirrhosis with graft loss. In fact, the five-year and ten-year survival of patients transplanted because of HCV are 75% and 68%, respectively, compared with 85% and 78% in patients transplanted for other reasons. There is also a pattern of recurrence that is very severe, but rare(< 10%), called fibrosing cholestatic hepatitis, which often involves rapid graft loss. Patients who present a negative HCV viremia after antiviral treatment have better survival. Many studies published over recent years have shown that antiviral treatment of post-transplant HCV hepatitis carried out during the late phase is the best option for improving the prognosis of these patients. Until 2011, PEGylated interferon plus ribavirin was the standard of care, resulting in a sustained virological response in around 30% of recipients. The addition of protease inhibitors, such as boceprevir or telaprevir, to the standard of care, or the use of other direct-acting antiviral drugs may involve therapeutic changes in the context of HCV recurrence. This may result a better prognosis for these patients, particularly those with severe recurrence or factors predicting rapid progression of fibrosis. However, the use of these agents in LT still requires clarification in terms of safety and efficacy.     

Outcomes after liver transplantation for combined alcohol and hepatitis C virus infection

Alcohol abuse and chronic hepatitis C virus(HCV)infection are two major causes of chronic liver disease in the United States.About 10%-15%of liver transplants performed in the United States are for patients with cirrhosis due to combined alcohol and HCV infection.Data on outcomes on graft and patient survival,HCV recurrence,and relapse of alcohol use comparing transplants in hepatitis C positive drinkers compared to alcohol abuse or hepatitis C alone are conflicting in the literature.Some studies report a slightly better overall outcome in patients who were transplanted for alcoholic cirrhosis vs those transplanted for HCV alone or for combined HCV and alcohol related cirrhosis.However,some other studies do not support these observations.However,most studies are limited to a retrospective design or small sample size.Larger prospective multicenter studies are needed to better define the outcomes in hepatitis C drinkers.     

The prevalence of hepatitis C virus (HCV) in infants and children after liver transplantation

Hepatitis C virus (HCV) is an important cause of liver injury following liver transplantation in adults. We hypothesized that the prevalence of HCV infection in children following liver transplantation would be lower than the prevalence in adults after liver transplantation because HCV-related liver disease leading to liver transplantation in children is low and children require less blood products than adults during transplantation. We therefore performed a cross-sectional study to determine the prevalence of HCV infection in children who had undergone liver transplantation. Serum samples were obtained from 62 of 65 (95.4%) consecutive patients surviving for more than six months after transplantation. Using a second-generation enzyme-linked, immunosorbent assay (ELISA-2) and a second-generation recombinant immunoblot assay (RIBA-II), antibodies to HCV were detected in 5.1% (3 of 59) of the subjects. Using a single-step, polymerase chain reaction (PCR), HCV RNA was detected in 6.2% (4 of 62). All HCV-positive children had undergone liver transplantation before the initiation of routine screening for HCV in blood donors; overall 30 patients were transplanted prior to routine screening of blood products for HCV. The prevalence of HCV in infants and children after liver transplantation in our study is substantially less than the rates reported in adults. This difference may be due, in part, to the lower volume of blood product exposure and to the fact that children, as opposed to adults, rarely have chronic HCV infection as a cause of end-stage liver disease.Accepted for poster presentation at the Update on Hepatic Transplantation, 1993 Annual Meeting of the AASLD.     

Management of recurrent hepatitis C after liver transplantation

Hepatitis C virus (HCV) reinfection is almost universal in patients transplanted for HCV-related cirrhosis. The medium-term survival after orthotopic liver transplantation (OLT) is similar to other transplanted patients, but the long-term survival remains uncertain. The prevention and an effective treatment of progressive liver disease are the primary aims in HCV recurrence. Interferon and ribavirin, as monotherapy or in combination, have been tried to treat or prevent HCV recurrence. Preliminary studies suggest a better chance of initial HCV clearance and better results in preventing HCV recurrence with combination therapy. IFN or ribavirin, as monotherapy, may normalize liver enzymes, but only gives rise to a transient virological response, without histological improvement. Combination IFN and ribavirin may be able to prevent progression of HCV-related graft disease, but indications and duration of treatment need further evaluation.
No clear association between type and dose of immunosuppressive and outcome of post-transplant HCV recurrence has been found. Strategies to minimize the effects of immunosuppressive drugs include dose reduction of all agents and the selective discontinuation of individual agents. Initial immunosuppression with a single drug may inhibit or delay the severe fibrosis, and further investigation with a single immunosuppressive regimen to evaluate the outcome of recurrent hepatitis C should be performed. The recent evidence that mycophenolate may have an antiviral effect needs a clinical confirmation.
Retransplantation survival is better with early retransplantation, and for indications not directly related to viral recurrence.     

Morbidity and mortality of recurrent hepatitis C infection after orthotopic liver transplantation

Summary. Through molecular virological testing it is now clear that HCV reinfection of the allograft is virtually universal in liver transplant recipients. Although histopathological recurrence of hepatitis C occurs in the majority of patients, it is absent in a substantial minority. To date, no prognostic factors, other than genotype lb, have been identified that accurately predict these dissimilar outcomes. The natural history of recurrent hepatitis C varies. Historically, it has been regarded as generally benign. However, with increasing numbers of patients transplanted for hepatitis C it is now clear that a subgroup of patients develops severe progressive cholestatic hepatitis associated with allograft failure and death without retransplantation. Within 5 years following OLT, approximately 15–20% of patients progress to chronic active hepatitis and another 15–20% become cirrhotic. A minority of patients develop glomerulopathy or vasculitis, which are often associated with cryoglobulinaemia. The impact of immunosuppressive medications and rejection episodes on histopathological recurrence of progressive hepatitis C remains controversial and requires further studies. Although actuarial survival rates of patients transplanted for hepatitis C differ among transplantation centres, it appears that histopathological recurrence of hepatitis C does have an adverse impact on actuarial survival compared to the survival of patients transplanted for autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis and metabolic liver diseases. When allograft failure develops in patients with recurrent hepatitis C, retransplantation is indicated, even though recent reports indicate that mortality may be increased, especially with concurrent renal insufficiency.     

Hepatitis C and liver transplantation

Hepatitis C virus (HCV) is important to the liver transplant recipient for several reasons. First, chronic HCV infection is a frequent cause of end-stage liver disease in North America and Europe, where the majority of liver transplants are performed. Second, recurrence of HCV after liver transplantation is almost universal so that many liver transplant recipients with and without overt hepatitis are viraemic. Third, HCV infection in the organ donor and/or in the blood transfused in the peri-transplant period make acquisition of HCV possible. Finally, liver transplantation for chronic HCV infection represents a major financial burden to the health-care system in the USA and worldwide. Histological hepatitis not due to HBV or cytomegalovirus (CMV) is present in 14–35% of allografts from patients undergoing liver transplantation, and the majority of this is due to HCV infection. HCV infection recurs post-transplant in almost all patients with pre-transplant infection. Proof that HCV does recur has been provided by the sequencing of the hypervariable domain of the E2/NS1 region. The magnitude of HCV infection is underestimated by using serological assays in this immunosuppressed population. Using the b-DNA assay, HCV-RNA levels have been shown to increase in patients with recurrent infection. The long-term consequences remain to be defined but post-transplantation HCV infection is generally much less devastating than post-transplantation HBV infection, and many patients have clinically silent disease. It is likely that a carrier state exists in immunosuppressed transplant recipients since high HCV-RNA levels occur in the absence of liver damage. In one study, 1, 2 and 3 year patient survival rates were shown to be comparable in patients with chronic active HCV infection and with cryptogenic cirrhosis (94, 89 and 87%, and 84, 84 and 73%, respectively). A more recent study from the University of Pittsburgh which compared the outcome of a larger number of HCV-infected patients (n= 237) with a large number of control patients with non-viral disease (n= 801), showed that indeed HCV infection does impact negatively on both patient and graft survival (1, 2 and 3 year patient survival in the study and control groups of 78, 68 and 66% and 84, 82 and 78%, respectively, P= 0.001). Undoubtedly with time, the full impact of recurrent HCV infection will become apparent, although short-term survival is sufficiently good to warrant continued transplantation of this group of patients. While the disease course in many patients is benign, aggressive post-transplant HCV infection leading to liver failure is well documented. Factors which determine why some patients are more susceptible to liver damage than others are currently under study. It is likely that many interrelated variables are involved, including the level of pre-transplant viraemia, genotype of the virus, amount of post-transplantation immunosuppression, and ability of the host immune system to recognize HCV and mount an immune response.     

Management of hepatitis B virus infection after liver transplantation

Chronic hepatitis B virus(HBV) infection is responsible for up to 30% of cases of liver cirrhosis and up to 53% of cases of hepatocellular carcinoma. Liver transplantation(LT) is the best therapeutic option for patients with end-stage liver failure caused by HBV. The success of transplantation, though, depends on receiving prophylactic treatment against post-transplant viral reactivation. In the absence of prophylaxis, liver transplantation due to chronic hepatitis B(CHB) is associated with high rates of viral recurrence and poor survival. The introduction of treatment with hepatitis B immunoglobulins(HBIG) during the 1990 s and later the incorporation of oral antiviral drugs have improved the prognosis of these patients. Thus, LT for CHB is now a universally accepted option, with an estimated 5 years survival of around 85% vs the 45% survival seen prior to the introduction of HBIG. The combination of lamivudine plus HBIG has for many years been the most widely used prophylactic regimen. However, with the appearance of new more potent oral antiviral agents associated with less resistance(e.g., entecavir and tenofovir) for the treatment of CHB, new prophylactic strategies are being designed, either in combination with HBIG or alone as a monotherapy. These advances have allowed for more personalized prophylaxis based on the individual risk profile of a given patient. In addition, the small pool of donors has required the use of anti-HBc-positive donors(with the resulting possibility of transmitting HBV from these organs), which has been made possible by suitable prophylactic regimens.     

Therapeutic management of recurrent hepatitis C after liver transplantation.

Recurrent hepatitis C ranges from minimal damage to cirrhosis developing in a few months or years in a substantial proportion of transplant recipients. Different virus, host and donor factors are involved in the pathogenesis of recurrence, but many are poorly understood. Therapeutic strategies can be utilized in the pre-, peri- or posttransplantation setting. Antiviral therapy using interferon and ribavirin and modifying immunosuppression are the main strategies to prevent progression disease. The efficacy of interferon and ribavirin is limited and side effects, reduction/withdrawal are frequent. Current sustained virological response rates are approximately 28%. An optimal immunosuppression regimen has not been established. The choice of calcineurin inhibitors has not clearly been shown to affect histological hepatitis C virus (HCV) but higher cumulative exposure to corticosteroids to treat acute rejection is associated with more severe recurrence. The manner in which the doses of immunosuppression are modified has more influence on HCV recurrence than the use of a specific drug per se. Debate about the influence of immunosuppressive regimens on HCV recurrence is ongoing. Potential antifibrotic therapy and new agents targeting HCV infection and replication are emerging and are anticipated to be added to our armentarium in battling recurrent HCV post-LT.     

Role of living donor liver transplantation in the treatment of hepatitis C virus infection

Hepatitis C virus (HCV) infection is one of the most common indications for liver transplantation worldwide. Because of the existing organ shortage, adult-to-adult living donor liver transplantation (LDLT) has become an important method of expanding the donor pool to meet the ever-increasing need. However, despite advantages such as the quality of the hepatic graft and the timing of the transplant, the exact role of LDLT in the treatment of HCV is still unclear. In this review, we aim to address some of these issues in an effort to highlight both the advantages and disadvantages, as well as to identify the main challenges, of using LDLT for treating patients with HCV infection.     

Risk factors for hepatitis C recurrence after liver transplantation

Summary.  Hepatitis C virus (HCV)-related end-stage liver disease is the main indication for liver transplantation performed in Europe and the United States. Recurrence of hepatitis C in the graft is universal and may lead to chronic hepatitis in most patients and to cirrhosis in 20–30% of patients within 5–10 years of transplantation. The natural history of HCV recurrence is highly variable but leads to a lower survival rate than other recurrent liver diseases. The immunosuppressed status and several other factors have been linked with the pattern and severity of recurrence. What remains controversial are those factors associated with fibrosis progression and how these could be modified to improve outcome of recurrent hepatitis C. No single factor but a combination of several factors is associated with fibrosis progression on the graft. The major factors associated with accelerated disease recurrence include: high viral load pre- (>10⁶ IU / mL) and / or early post-transplantation (>10⁷ IU / mL at 4 months), donor older than 40–50 years, prolonged ischaemic time, cytomegalovirus coinfection, over immunosuppression and / or abrupt changes in immunosuppression, HIV coinfection, infection by genotype 1b. Cautious follow-up of the pathology of the graft is mandatory including routine biopsies and / or noninvasive monitoring of fibrosis.     

Concise review: Interferon-free treatment of hepatitis C virus-associated cirrhosis and liver graft infection

Chronic hepatitis C is a major reason for development of cirrhosis and hepatocellular carcinoma and a leading cause for liver transplantation. The development of direct-acting antiviral agents lead to (pegylated) interferon-alfa free antiviral therapy regimens with a remarkable increase in sustained virologic response (SVR) rates and opened therapeutic options for patients with advanced cirrhosis and liver graft recipients. This concise review gives an overview about most current prospective trials and cohort analyses for treatment of patients with liver cirrhosis and liver graft recipients. In patients with compensated cirrhosis Child-Pugh-Turcotte (CTP) class A, all approved agents are safe and SVR rates do not significantly differ from patients without cirrhosis in general. In patients with decompensated cirrhosis CTP class B or C, daclastasvir, ledipasvir, velpatasvir, and sofosbuvir are approved, and SVR rates higher than 90% can be achieved. Especially for patients with a model of end stage liver disease score higher than 15 and therefore eligible for liver transplantation, data is scarce. Reported SVR rates in patients with cirrhosis CTP class C are lower compared to patients with a less severe liver disease. In liver transplant recipients with a maximum of CTP class A, SVR rates are comparable to patients without LT. Patients with decompensated graft cirrhosis should be treated on an individual basis.     

Pegylated interferon-alpha2a/ribavirin treatment of recurrent hepatitis C after liver transplantation

Abstract: Hepatitis C virus (HCV) infection invariably recurs after liver transplantation (LT), leading to significant morbidity and mortality. Although the combination of pegylated interferon-alpha (IFN-α)/ribavirin is the preferred treatment for these patients, the optimal schedule remains undetermined. In an uncontrolled trial, 19 patients with HCV infection recurring after LT received pegylated IFN-α_2a, 180 μg weekly, and ribavirin, 10 mg/kg body weight daily, for 48 weeks. The proportion of patients with undetectable HCV RNA in their serum after 12 weeks of treatment was 53%. Five patients (26%) dropped out of the study due to intolerance (in 2 cases), depression (in 1), or infectious complications (in 2). A sustained virological response (SVR), defined as undetectable serum HCV RNA 24 weeks after the end of treatment, was observed in 9/19 patients (47%). SVR was associated with an early virological response after 12 weeks of therapy ( P <0.001) and a treatment duration >80% ( P =0.02), but not with baseline HCV RNA level or a cumulative dose of pegylated IFN-α_2a or ribavirin >80% of the scheduled dose. All 4 patients with genotype 2 or 3 reached SVR, as compared with 33% of patients with genotype 1 or 4 ( P =0.03). A 48-week course of pegylated IFN-α_2a/ribavirin therapy is effective in patients with recurrent HCV infection after LT.     

An extended treatment protocol with pegylated interferon and ribavirin for hepatitis C recurrence after liver transplantation

AIM: To evaluate the efflicacy and tolerability of an extended treatment protocol and to determine the predictors of sustained virological response (SVR) after liver transplantation (LT).METHODS: Between August 2005 and November 2008, patients with recurrent hepatitis C virus (HCV) after LT were selected for treatment if liver biopsy showed at least grade 2 inflammation and/or stage 2 flibrosis. All patients were to receive pegylated interferon (PEG)/regimens combining ribavirin (RBV) for an additional 48 wk after HCV undetectability.RESULTS: Extended protocol treatment was initiated in thirty patients. Overall, 73% had end of treatmentresponse and 60% had SVR. Nineteen patients completed treatment per protocol, of them, sixteen (84%) had end of treatment response, and fourteen (74%) achieved SVR. Both early virological response and 24-week virological response were individually associated with SVR but this association was not signif icant on multivariate analysis. Eleven patients (37%) discontinued therapy due to adverse effects. Cytopenias were the most common and most severe adverse effect, and required frquent growth factor use, dose adjustments and treatment cessations. The risk of rejection was not increased.CONCLUSION: Recurrent HCV after LT can be safely treated with extended virological responseguided therpy using PEG/RBV, but requires close monitoring for treatment-related adverse effects, particularly cytopenias.     

乙型肝炎相关性肝移植后乙型肝炎复发的临床特点分析

目的 总结和探讨乙型肝炎相关性终末期肝病患者在肝移植术后乙型肝炎复发的临床特点.方法 回顾性分析2005年4月至2010年4月期间的253例乙型肝炎相关性肝移植患者的术后随访资料.结果 253例肝移植患者中乙型肝炎复发16例,复发率6.32%(16/253),中位复发时间为术后13个月,术后1、3、5年的累积复发率分别为3.81%(9/236)、6.58%(15/228)、7.14%(16/224).术前HBeAg阳性、HBV DNA阳性、YMDD变异是术后乙型肝炎复发的危险因素.复发患者的主要临床表现为慢性肝炎.所有患者复发后均停用乙型肝炎人免疫球蛋白,并调整核苷(酸)类似物,经治疗HBV DNA均＜500 IU/ml,肝功能稳定.结论 肝移植能有效治疗乙型肝炎相关性终末期肝病,在核苷(酸)类似物联合乙型肝炎人免疫球蛋白方案的预防下及复发后及时处理,乙型肝炎复发对预后影响不大.     

Treatment strategy for hepatitis C after liver transplantation

A significant proportion of patients with chronic hepatitis C virus (HCV) infection develop liver cirrhosis and complications of end-stage liver disease over periods of two to three decades and require liver transplantation, although re-infection is common and leads to further adverse events, given that such patients receive life-long immunosuppression. Because of the critical organ shortage worldwide, living-donor liver transplantation has an important role in many countries, especially in the Far East. Despite previous arguments, the results of recent well-designed studies suggest equivalent outcomes for deceased-donor and living-donor liver transplantation. No specific immunosuppression regimen has proven advantageous, but the general rule is “low and slow”. Combined pegylated interferon and ribavirin therapy is the current standard treatment, but compared to this therapy in the immunocompetent population, its efficacy in clearing the virus remains low. Moreover, its general application is hindered by the high prevalence of intolerability, lowering its efficacy from the aspect of intention to treat. Retransplantation becomes an option when treatment for disease progression fails, but it should be considered at an earlier stage in patients with a lower MELD (model for end-stage liver disease) score compared to that used for primary transplantation, which is a great challenge with the current critical organ shortage. The need for new anti-HCV drugs to further delay disease progression or even to enhance viral clearance, presumably specific HCV life-cycle inhibitors, is urgent. The liver transplant community must maintain an open mind regarding the development of these drugs and focus on their availability for early clinical trials in liver transplant recipients.