Strategies to reduce hepatitis C virus recurrence after liver transplantation

Hepatitis C virus (HCV) is a major health problem that leads to chronic hepatitis, cirrhosis and hepatocellular carcinoma, being the most frequent indication for liver transplantation in several countries. Unfortunately, HCV re-infects the liver graft almost invariably following reperfusion, with an accelerated history of recurrence, leading to 10%-30% of patients progressing to cirrhosis within 5 years of transplantation. In this sense, some groups have even advocated for not retransplanting this patients, as lower patient and graftoutcomes have been reported. However, the management of HCV recurrence is being optimized and several strategies to reduce post-transplant recurrence could improve outcomes, decrease the rate of re-transplantation and optimize the use of available grafts. Three moments may be the focus of potential actions in order to decrease the impact of viral recurrence: the pretransplant moment, the transplant environment and the post-transplant management. In the pre-transplant setting, it is not well established if reducing the pre transplant viral load affects the risk for HCV progression after transplant. Obviously, antiviral treatment can render the patient HCV RNA negative post transplant but the long-term benefit has not yet been fully established to justify the cost and clinical risk. In the transplant moment, factors as donor age, cold ischemia time, graft steatosis and ischemia/reperfusion injury may lead to a higher and more aggressive viral recurrence. After the transplant, discussion about immunosuppression and the moment to start the treatment (prophylactic, pre-emptive or once-confirmed) together with new antiviral drugs are of interest. This review aims to help clinicians have a global overview of posttransplant HCV recurrence and strategies to reduce its impact on our patients.     

Survival and recurrence of hepatitis C after liver transplantation in patients coinfected with human immunodeficiency virus and hepatitis C virus

The efficacy and safety of albinterferon alfa-2b (alb-IFN), a novel recombinant protein consisting of interferon alfa-2b genetically fused to human albumin, was evaluated in a phase 2b, open-label study of patients with genotype 1, chronic hepatitis C. In all, 458 IFN-alfa treatment-na?ve patients were randomized to 48-week treatment with peginterferon alfa (PEG-IFNalpha)-2a 180 microg one time per week (qwk), or alb-IFN 900 or 1,200 microg once every two weeks (q2wk), or 1,200 microg once every four weeks (q4wk), administered subcutaneously, plus weight-based oral ribavirin 1,000 or 1,200 mg/day. Hepatitis C virus RNA was measured by real-time polymerase chain reaction (limit of detection: 10 IU/mL). The primary efficacy endpoint was sustained virologic response (hepatitis C virus RNA <10 IU/mL 24 weeks after the end of treatment). By intention-to-treat analysis, sustained virologic response rates were 58.5% (69/118) with alb-IFN 900 microg q2wk, 55.5% (61/110) with 1,200 microg q2wk, and 50.9% (59/116) with 1,200 microg q4wk, and 57.9% (66/114) with PEG-IFNalpha-2a (P = 0.64 for overall test). Discontinuation rates due to adverse events were 9.3% with alb-IFN 900 microg q2wk, 18.2% with 1,200 microg q2wk and 12.1% with 1,200 microg q4wk, and 6.1% with PEG-IFNalpha-2a (P = 0.04). Hematologic reductions were lowest in the q4wk group and comparable across other groups. At week 12, mean treatment-associated missed workdays were significantly lower with alb-IFN 900 mug q2wk versus PEG-IFNalpha-2a (1.1 versus 4.3 days; P = 0.006). CONCLUSION: Alb-IFN administered q2wk or q4wk may offer comparable efficacy, with an improved dosing schedule, compared with PEG-IFNalpha-2a.     

Hepatitis C virus recurrence after liver transplantation

Cirrhosis due to hepatitis C virus (HCV) is now the most common indication of liver transplantation in Western Europe and the United States. In the absence of effective prophylaxis, recurrent HCV infection is almost inevitable. Though the natural history and intermediate term outcome of recurrent HCV are now better documented, those factors which may influence the recurrence of hepatitis and consequent progression of graft disease remain unclear. Interferon (IFN) as a sole agent for the treatment of recurrent infection has proved unsatisfactory. Early intervention with a combination of IFN and ribavirin seems promising, and this approach may prevent or delay progression of HCV related graft disease after liver transplantation.     

Clinical significance of hepatitis C virus genotypes

The advent of genotyping assays has stimulated investigators around the world to study the molecular epidemiology of hepatitis C virus (HCV) infection in specific patient categories, as well as possible correlations with the clinical and histological features of chronic liver disease and response to antiviral treatment. While a general consensus has been reached on the worldwide epidemiology and distribution of HCV types in certain risk categories (i.e. intravenous drug users), the association between genotype 1b and severe liver disease is still controversial. Although generalized use of genotyping is not presently recommended for clinical or epidemiological monitoring, several studies emphasize to the importance of HCV genotyping as part of a therapeutic algorithm. This recommendation is based on overwhelming evidence in support of a correlation between genotype 1 and a poor response to interferon-a alone or in combination with ribavirin.     

肝移植术后乙型肝炎复发的处理——13例分析

目的总结和探讨乙型肝炎相关终末期肝病肝移植术后乙型肝炎复发的处理方法。方法回顾性分析我院13例肝移植术后患者发生乙型肝炎再感染或复发后的处理措施及疗效。结果13例患者分别采取拉米夫定改为阿德福韦、恩替卡韦或加大乙型肝炎免疫球蛋白用量的方法,其中5例HBsAg经治疗后转阴,5例HBsAg明显下降,总有效率76.9%。结论肝移植术后HBIG、恩替卡韦、阿德福韦能不同程度控制肝移植术后乙型肝炎复发。     

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.     

肝移植后丙型肝炎复发的防治

丙型肝炎病毒（HCV）感染导致的肝硬化和原发性肝癌是肝移植（LT）的主要适应证之一。遗憾的是,LT后HCV感染的复发相当普遍,并处于活动性进展。在LT受体中,慢性HCV感染导致的肝硬化在LT后5年的发生率约为30％,一旦出现肝硬化,1年后发生临床失代偿的概率接近50％,使移植后患者的生存期明显缩短。所以,LT后HCV的预防与治疗一直为各移植中心所关注。本综述将讨论这方面的进展。     

Clinical significance of hepatitis C virus (HCV) infection in liver transplant recipients

Hepatitis C virus (HCV) infection was studied in 60 liver transplant recipients. Antibodies to HCV were tested by both a second-generation ELISA test and a four-recombinant immunoblot assay (4-RIBA) just before the transplant and every three months thereafter. HCV RNA detection was performed by polymerase chain reaction (PCR) at least three times after the transplant in all the patients. Thirty-nine patients tested negative by ELISA before LT (group A), 14 patients tested positive by both serological tests (group B), and seven tested positive only by ELISA (group C). Posttransplant hepatitis was diagnosed in 11/14 in group B in comparison with 3/39 in group A (P<0.001) and 1/7 in group C (P<0.05). HCV RNA was detected in the sera of 14/14 patients in group B but in only 1/7 in group C and 6/39 in group A. Only 2/15 patients developed posttransplant hepatitis in the absence of HCV RNA detection. These data suggest that HCV is the major cause of hepatitis after LT. Patients HCV seropositive by RIBA test before the transplant formed a group of high-risk patients for developing viremia and hepatitis afterwards.Part of this work was presented at the XIVth International Congress of the Transplantation Society. Paris. August 1992.This work was supported by a grant from Fondo de Investigaciones Sanitarias de la Seguridad Social (FISS 92/0357).     

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...     

Clinical significance of hepatitis C virus genotypes and quasispecies

Hepatitis C virus (HCV) is a major cause of morbidity and mortality worldwide. The infection becomes chronic in about 85% of infected individuals, in the face of a strong humoral and cellular immune response. One of the most important features of HCV is its high degree of genetic variability, which is due to the inherent low fidelity of the viral replication machinery. As a consequence, HCV circulates in vivo as a population of divergent, albeit closely related, genomes exhibiting a distribution that follows the model referred to as a quasispecies. The genetic variability of HCV is complex and has been classified into four hierarchical strata: genotypes, subgenotypes, isolates, and quasispecies. Over the past few years, an extraordinary interest has been focused on the biologic and clinical implications of the genetic variability of HCV. Although there is consensus that the genotypes may influence the out come of antiviral therapy, their clinical significance in the natural history of the disease, as well as in transmission, infectivity, and pathogenesis of HCV infection, remains elusive. Conversely, evidence has accumulated that the quasispecies nature of HCV provides a large reservoir of biologically different viral variants that may have important clinical implications for viral persistence by immune escape mechanisms, for the generation of antiviral drug resistance, and for the development of an effective vaccine. This article reviews the state of the art on the biologic and clinical implications of the genetic variability of HCV.     

Clinical significance of TT virus in chronic hepatitis C

BACKGROUND AND AIMS: Much is still unknown about the clinical significance of TT virus (TTV), which has been reported as a candidate for non A-G hepatitis virus. The aim of this study was to clarify the clinical significance of TTV in patients coinfected with TTV and hepatitis C virus (HCV). METHODS: The 95 subjects studied had chronic hepatitis C (CHC), and underwent interferon (IFN) therapy. TT Virus DNA was detected by using polymerase chain reaction. The nucleotide sequences were determined by using a dideoxy chain termination method. A phylogenetic tree was drawn up by using the neighbor-joining method. RESULTS: TT Virus DNA was detected in 37.9% of patients with the use of an open reading frame 1 (ORF1) primer, and in 88.4% of patients by using a 5' untranslated region (5' UTR) primer. Using both sets of primers, no differences were found between TTV-DNA-positive and -negative subjects with CHC in the clinical findings. Serum TTV DNA was eradicated in 30.6% of patients with the ORF1 primer, and in 19.1% of patients with the 5' UTR primer at 6 months after the cessation of IFN therapy. The levels of TTV DNA before IFN therapy were significantly lower in the viral eradication group than in non-eradication group. The changes in alanine aminotransferase (ALT) concentrations were significantly correlated with changes in HCV-RNA in CHC patients with TTV. Moreover, there was no correlation between the changes in TTV DNA and the course of ALT. CONCLUSION: Hepatocellular injury in patients with chronic hepatitis who are coinfected with HCV and TTV appears to primarily be caused by HCV and is less attributable to TTV.     

Prevention of hepatitis C recurrence after liver transplantation: An update

Hepatitis C related liver failure and hepatocarcinoma are the most common indications for liver transplantation in Western countries.Recurrent hepatitis C infection of the allograft is universal and immediate following liver transplantation,being associated with accelerated progression to cirrhosis,graft loss and death.Graft and patient survival is reduced in liver transplant recipients with recurrent Hepatitis C virus(HCV) infection compared to HCV-negative recipients.Many variables may impact on recurrent HCV liver disease.Overall,excess immunosuppression is believed to be a key factor;however,no immunosuppressive regimen has been identified to be more beneficial or less harmful.Donor age limitations,exclusion of moderately to severely steatotic livers and minimization of ischemic times could be a potential strategy to minimize the severity of HCV disease in transplanted subjects.After transplantation,antiviral therapy based on pegylated IFN alpha with or without ribavirin is associated with far less results than that reported for immunocompetent HCV-infected patients.New findings in the field of immunotherapy and genomic medicine applied to this context are promising.     

肝移植术后原发性肝癌复发与乙型肝炎病毒再感染的关系

目的 探讨肝移植术后原发性肝癌复发与HBV再感染的关系.方法 对2004年1月-2008年12月在中山大学附属第三医院因乙型肝炎相关性终末期肝病行肝移植手术并长期随访的340例患者回顾性分析.患者被列入肝移植等待名单后给予核苷(酸)类似物抗病毒治疗,术中和术后均给予核苷(酸)类似物联合低剂量乙型肝炎免疫球蛋白进行预防.术后定期随访并监测患者HBV再感染的发生率及生存率,用多因素COX回归分析筛选出影响术后HBV再感染的危险因素.计量资料用t检验、计数资料用x2检验进行统计学处理.用Kaplan-Meier方法进行生存率分析,对HBV再感染危险因素用COX多因素回归分析,对HBV再感染与原发性肝癌复发的时间进行Spearman线性相关分析.结果 340例患者术后发生HBV再感染33例,术后1、3、5年再感染率分别为7%、10%、13%.HBV再感染的时间为1～21个月,中位数为5个月.原发病为原发性肝癌(风险比为2.98;95%可信区间为1.08～8.25,P＜0.05)、术前HBV DNA载量＞5log10拷贝/ml(风险比为3.99;95%可信区间为1.85～8.62,P＜0.01)是发生HBV再感染的危险因素.原发性肝癌复发者HBV再感染发生率高于未复发者,分别为27.9%和8.7%(风险比为4.58; 95%可信区间为1.88～11.12;P＜0.01).12例患者肝移植术后发生HBV再感染和原发性肝癌复发,两者的复发时间具有相关性(r=0.583,P＜0.05).结论肝移植术后原发性肝癌复发是HBV再感染的危险因素.

Abstract：

Objective To investigate the relationship between hepatocellular carcinoma (HCC)recurrence and hepatitis B virus (HBV) recurrence. Method The clinical data of 340 patients underwent liver transplantation due to HBV related end-stage liver disease and received long-term follow up in our hospital from Jan 2004 to Dec 2008 were retrospectively analyzed. All patients received nucleoside analogues therapy formally before entering into the waiting list and nucleoside analogues combined low-dose HBIG therapy during and after transplantation. Patients were regularly followed up at the outpatient, monitoring the HBV recurrence and survival. Multivariate Cox regression analysis was used to evaluate the risk factors for hepatitis recurrence. Result 33 patients suffered from HBV recurrence post transplantation.The 1-, 3- and 5- year recurrence rates were 7.0%, 10% and 13% respectively. The median HBV recurrence time was 5 months (1-21 months). COX regression analysis revealed that risk factors for HBV recurrence were HCC (HR = 2.98; 95% CI 1.08-8.25; P＜0.05) and pre-transplantation HBV-DNA load over 5 log10 copies/ml (HR = 3.99; 95% CI 1.85-8.62; P＜0.01). Further stratified analysis showed that patients who suffered from carcinoma recurrence had a higher incidence of HBV recurrence than those who did not, which were 27.9% and 8.7% (HR =- 4.58;95% CI 1.88-11.12; P＜0.01) respectively. 12 patients suffered from both HCC and HBV recurrence. Spearman correlation analysis demonstrated a strong correlation between HBV and HCC recurrence times (r= 0.583, P＜0.05). Conclusion Post transplantation HCC recurrence is a risk factor for HBV recurrence.     

The impact of sirolimus on hepatitis C recurrence after liver transplantation

BACKGROUND

While some immunosuppression strategies may accelerate hepatitis C virus (HCV) recurrence after liver transplantation (LT), the impact of sirolimus (SRL) is not known.

OBJECTIVE

To assess the risk of biopsy-proven HCV recurrence and patient survival using known and suspected risk factors for HCV recurrence as covariates.

METHODS

A retrospective analysis of 141 consecutive patients, including 88 who received de novo SRL therapy, who had undergone a first LT for HCV cirrhosis was conducted. Known and suspected risk factor covariates including transplant era, donor and recipient age, Model for End-stage Liver Disease score, cold ischemia time, immunosuppressive drugs and steroid treatment rejection rates were used in the assessment.

RESULTS

Overall, 72.3% of the cohort developed biopsy-proven HCV recurrence. The incidence of HCV recurrence was not significantly different for patients treated with SRL (75% versus 69.8%; P=0.5). There was no difference found for time to recurrence, nor did mean activity or fibrosis scores differ at the time of initial recurrence. However, on follow-up using serial biopsies in patients with recurrence, the mean activity and fibrosis scores were significantly lower in the SRL group. Donor age and acute rejection episodes were the only factors affecting the HCV recurrence rate (expB 1.02 [95% CI 1.01 to 1.03]); P=0.03; and expB 2.8 [95% CI 1.8 to 4.3]; P<0.01], respectively). SRL treatment did not alter patient survival rates. Among patients treated with SRL-based immunosuppression, higher drug area under the curve levels were associated with a trend to lower disease activity and fibrosis at diagnosis; however, higher SRL levels were associated with shorter recurrence-free survival (P=0.038).

CONCLUSION

Results of the present analysis suggest that de novo SRL-based immunosuppression can be safely used in patients undergoing LT for HCV-associated liver disease; however, SRL-based immunosuppression did not significantly affect the timing or severity of post-transplant HCV recurrence. HCV recurrence in SRL-treated patients had lower progressive activity and fibrosis levels on serial biopsy.     

Current prophylactic strategies against hepatitis B virus recurrence after liver transplantation

Prophylactic strategies against hepatitis B virus （HBV） recurrence after liver transplantation （LT） are essential for patients with HBV-related disease. Before LT, lamivudine （LAM） was proposed to be down-graded from first- to second-line therapy. In contrast, adefovir dipivoxil （ADV） has been approved not only as first-line therapy but also as rescue therapy for patients with LAM resistance. Furthermore, combination of ADV and LAM may result in lower risk of ADV resistance than ADV monotherapy. Other new drugs such as entecavir, telbivudine and tenofovir, are probably candidates for the treatment of hepatitis-B-surface-antigen-positive patients awaiting LT. After LT, low-dose intramuscular hepatitis B immunoglobulin （HBIG）, in combination with LAM, has been regarded as the most cost-effective regimen for the prevention of post-transplant HBV recurrence in recipients without pretransplant LAM resistance and rapidly accepted in many transplant centers. With the introduction of new antiviral drugs, new hepatitis B vaccine and its new adjuvants, post-transplant HBIG-free therapeutic regimens with new oral antiviral drug combinations or active HBV vaccination combined with adjuvants will be promising, particularly in those patients with low risk of HBV recurrence.     

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.