肝移植后乙型肝炎复发的危险因素及预后分析

目的探讨乙型肝炎相关性肝移植患者术后在核苷(酸)类似物联合小剂量乙型肝炎免疫球蛋白的预防下乙型肝炎复发的危险因素及预后。方法 253例乙型肝炎相关性肝移植患者术前即开始给予核苷(酸)类似物预防,术中和术后均给予核苷(酸)类似物联合乙型肝炎免疫球蛋白处理。结果在253例肝移植患者中,死亡29例(11.5%);术前基础病为HBV相关性肝癌患者的病死率为21.2%,显著高于非肝癌患者的5.2%(P=0.000);乙型肝炎复发16例(6.3%);复发后均停用乙型肝炎免疫球蛋白,并调整核苷(酸)类似物,结果患者HBV DNA均<500IU/ml,肝功能稳定;Log-rank检验显示乙型肝炎复发后及时治疗对患者生存无明显影响;经Logistic多因素回归分析表明,术前HBeAg阳性、HBV DNA≥105IU/ml、HCC和HBV/YMDD变异是乙型肝炎复发的危险因素。结论肝移植能够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免疫球蛋白预防后,仍有乙型肝炎复发,其对生存率的影响有待于观察。     

Recent advances in prevention of hepatitis B recurrence after liver transplantation

Liver transplantation is the only effective treatment for hepatitis B virus(HBV)-related end-stage liver disease.However,without antiviral prophylaxis,the recurrence rate of hepatitis B is as high as 80%-100%,which leads to a 50% mortality rate in the first 2 years after liver transplantation.Combination therapy of hepatitis B immunoglobulin(HBIG) and lamivudine demonstrated a higher efficacy of prophylaxis and further reduced the rate of recurrence to < 10%.The strategy of HBIG combined with lamivudine has been the standard treatment in many centers.However,the high rate of lamivudine resistance and the many disadvantages of HBIG have compelled surgeons to reconsider the longterm efficacy of this strategy for the prevention of HBV reinfection.Recently,new nucleos(t)ide analogues,such as entecavir and tenofovir,have been approved as first-line monotherapies for the treatment of chronic hepatitis B infection.These antiviral medicines have replaced lamivudine as the first choice in the prevention of HBV recurrence after liver transplantation.Various therapies that are composed of entecavir,tenofovir,and lamivudine plus adefovir,with or without HBIG have been adopted in several liver transplant centers.This article reviews the recent advances in prophylaxis for the recurrence of hepatitis B after liver transplantation.     

Posttransplantation: emerging and future therapies

Liver transplantation in patients infected with hepatitis B virus (HBV) commonly results in reinfection that, if untreated, often compromises the viability of the allograft and negatively influences survival. Posttransplant treatment with hepatitis B immune globulin (HBIG) is now the standard of care, but patients appear to require lifelong treatment to prevent reinfection. In the past several years, new management strategies in patients with HBV have been developed, with an aim to decrease HBV-DNA replication before transplantation. Such an approach should increase the success of transplantation by decreasing the risk of reinfection and thus preventing recurrent disease posttransplantation. Nucleoside analogues, either alone or in conjunction with HBIG, are currently in use and are being studied in clinical trials as a means of preventing viral recurrence. Ganciclovir, famciclovir, and lamivudine all have demonstrated efficacy, although they vary in terms of effectiveness. Resistance may develop with the use of these agents and leads to reinfection by the mutant virus. Combination therapy may minimize the risk of viral mutation. Research continues to search for more effective ways to prevent and, if necessary, treat viral recurrence in patients undergoing liver transplantation for HBV.     

Lamivudine plus low-dose hepatitis B immunoglobulin to prevent recurrent hepatitis B following liver transplantation

BACKGROUND AND AIMS: High-dose intravenous hepatitis B immunoglobulin (HBIG) may prevent recurrent hepatitis B virus (HBV) infection, but the cost has limited its widespread use in countries with endemic HBV infection. We report on long-term safety and efficacy of an alternative strategy of very low doses (400-800 IU/month) of intramuscular (IM) HBIG plus lamivudine. METHODS: Australian and New Zealand patients who received low-dose HBIG plus lamivudine following liver transplantation for HBV-related end-stage liver disease were studied. Prior to transplantation, patients with detectable serum HBV DNA received lamivudine 100 mg daily. Posttransplantation, all patients received lamivudine 100 mg daily plus IM HBIG 400 or 800 IU daily for 1 week then monthly thereafter. Serum HBV DNA levels were measured prior to lamivudine, at transplantation, and at 12 months posttransplantation. Serum titers of antibody to HBV surface antigen were measured at 1, 3, and 12 months posttransplantation. RESULTS: Between February 1996 and October 2004, 147 patients received low-dose HBIG plus lamivudine. Thirty-one percent were hepatitis B e antigen positive, and 85% were HBV DNA+ prior to transplantation. The median duration of pretransplantation lamivudine was 92 days (range, 1-1775). Median follow-up posttransplantation was 1860 days. Kaplan-Meier patient survival was 92% at 1 year and 88% at 5 years. The actuarial risk of HBV recurrence was 1% at 1 year and 4% at 5 years. Baseline HBV DNA titer was associated with HBV recurrence. CONCLUSION: Low-dose IM HBIG plus lamivudine provides safe and effective long-term prophylaxis against recurrent HBV at <10% the cost of the high-dose regimen.     

Hepatitis B and liver transplantation: Molecular and clinical features that influence recurrence and outcome

Hepatitis B virus (HBV) continues to be a major cause of morbidity and mortality worldwide. It is estimated that about 350 million people throughout the world are chronically infected with HBV. Some of these people will develop hepatic cirrhosis with decompensation and/or hepatocellular carcinoma. For such patients, liver transplantation may be the only hope for cure or real improvement in quality and quantity of life. Formerly, due to rapidity of recurrence of HBV infection after liver transplantation, usually rapidly progressive, liver transplantation was considered to be contraindicated. This changed dramatically following the demonstration that hepatitis B immune globulin (HBIG), could prevent recurrent HBV infection. HBIG has been the standard of care for the past two decades or so. Recently, with the advent of highly active inhibitors of the ribose nucleic acid polymerase of HBV (entecavir, tenofovir), there has been growing evidence that HBIG needs to be given for shorter lengths of time; indeed, it may no longer be necessary at all. In this review, we describe genetic variants of HBV and past, present, and future prophylaxis of HBV infection during and after liver transplantation. We have reviewed the extant medical literature on the subject of infection with the HBV, placing particular emphasis upon the prevention and treatment of recurrent HBV during and after liver transplantation. For the review, we searched PubMed for all papers on the subject of “hepatitis B virus AND liver transplantation”. We describe some of the more clinically relevant and important genetic variations in the HBV. We also describe current practices at our medical centers, provide a summary and analysis of comparative costs for alternative strategies for prevention of recurrent HBV, and pose important still unanswered questions that are in need of answers during the next decade or two. We conclude that it is now rational and cost-effective to decrease and, perhaps, cease altogether, the routine use of HBIG during and following liver transplantation for HBV infection. Here we propose an individualized prophylaxis regimen, based on an integrated approach and risk-assessment.     

Transplantation and prevention of reinfection

The outcome of orthotopic liver transplantation (OLT) for hepatitis B virus (HBV)-related liver disease depends on the prevention of allograft reinfection. Over the past decade, major advances have been made in the management of HBV transplant candidates. The advent of longterm hepatitis B immunoglobulin (HBIG) administration as a prophylaxis of HBV recurrence and the introduction of new antiviral agents against HBV infection, such as lamivudine (LAM) or adefovir, were a major breakthrough in the management of these patients. The results of OLT for HBV infection are similar to those results achieved with other indications. Pre-OLT antiviral treatment such as LAM can suppress HBV replication before OLT and, thus, decrease the risk of reinfection of the graft. Combination prophylaxis with LAM and HBIG after transplantation is highly effective in reducing the rate of HBV reinfection even in HBV-replicative cirrhotic patients. The optimal HBIG protocol in the LAM and adefovir era has yet to be defined: dosing of HBIG, routes of administration, and the possibility of stopping HBIG.     

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...     

Hepatitis B and Liver Transplantation: Update in Management before and after Transplantation

Patients who undergo liver transplantation (LT) for chronic hepatitis B virus (HBV) infection are at high risk of developing recurrent HBV in the absence of effective prophylaxis. Pre-LT management should focus on suppression of HBV DNA levels, which have been associated with HBV recurrence. Evidence linking hepatocellular carcinoma (HCC) recurrence to HBV recurrence has been less clear. Prophylaxis against recurrent HBV after LT with combination HBIG and antiviral therapy is the current standard of care and is effective in >90% of patients, but investigation is ongoing to determine the most cost-effective treatment regimens. While antiviral therapy with newer nucleos(t)ide analogues without HBIG is assumed to be effective, no recent studies have examined the long-term efficacy of salvage regimens for recurrent HBV. Large, prospective trials are urgently needed. Overall, LT for HBV is highly effective with appropriate pre- and post-LT antiviral therapy.     

Prevention and Treatment of Recurrent Hepatitis B after Liver Transplantation

Chronic hepatitis B is a global health problem that leads to development of various complications, such as cirrhosis, liver cancer, and liver failure requiring liver transplantation. The recurrence of hepatitis B virus (HBV) post-liver transplantation is a major cause of allograft dysfunction, cirrhosis of the allograft, and graft failure. Patients with high viral load at the time of transplantation, hepatitis B e antigen (HBeAg) positivity, or those with a history of anti-viral drug resistance are considered as high-risk for recurrent HBV post-liver transplantation, while patients with low viral load, including HBeAg negative status, acute liver failure, and hepatitis D virus (HDV) co-infection are considered to be at low-risk for recurrent HBV post-liver transplantation. Antivirals for patients awaiting liver transplantation(LT) cause suppression of HBV replication and reduce the risk of recurrent HBV infection of the allograft and, therefore, all HBV patients with decompensated cirrhosis should be treated with potent antivirals with high genetic barrier to resistance (entecavir or tenofovir) prior to liver transplantation. Prevention of post-liver transplantation recurrence should be done using a combination of hepatitis B immunoglobulin (HBIG) and antivirals in patients at high risk of recurrence. Low dose HBIG, HBIG-free protocols, and monoprophylaxis with high potency antivirals can still be considered in patients at low risk of recurrence. Even, marginal grafts from anti-HBc positive donors can be safely used in hepatitis B surface antigen (HBsAg) negative, preferably in anti-hepatitis B core (HBc)/anti-hepatitis B surface (HBs) positive recipients. In this article, we aim to review the mechanisms and risk factors of HBV recurrence post-LT in addition to the various treatment strategies proposed for the prevention of recurrent HBV infection     

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??Abstract??HBV-related end-stage liver disease and hepatocellular carcinoma (HCC) are the major indications for liver transplantation in China.With the introduction of hepatitis B immunoglobulin (HBIG) and oral nucleos(t)ide analogues (NAs)??new antiviral therapy has significantly improved the prognosis of liver transplantation.Pre-transplant antiviral therapy will significantly reduce the recurrence rates of HBV infection.All HBsAg-positive patients awaiting liver transplantation for HBV-related end-stage liver disease or HCC should be administered with a potent NA with high barrier to drug resistance to achieve the viral load as low as possible.Additional HBIG administration during the anhepatic phase will achieve a better control of HBV infection.HBIG should be used in combination with NAs post-transplantation to prevent HBV recurrence.As the fact that liver transplant recipients usually need life-long medication to prevent HBV recurrence??it is currently recommended that HBIG can be discontinued in patients under long-term administration of potent NAs with high barrier to drug resistance in combination with HBIG.     

The option of HBIG-free prophylaxis against recurrent HBV

Since the early 1990's, hepatitis B immune globulin (HBIG) has been central to the prevention of hepatitis B virus (HBV) recurrence after liver transplantation. When used in combination with oral nucleos(t)ide analogues, HBIG prevents reinfection with HBV in ?90% of transplant recipients. While HBIG is highly efficacious, its use is undermined by its high cost. Because of this limitation, there have been many studies of alternative regimens seeking to minimize the dose or duration of HBIG without sacrificing low HBV recurrence rates. Toward that goal, lower dose intramuscular HBIG in combination with oral nucleos(t)ide analogues has been shown to be highly efficacious in preventing disease recurrence and represents a significant cost savings when compared with high dose intravenous administration. The withdrawal of HBIG after a defined course of combination HBIG and oral antivirals has also been shown to be effective, particularly if combination antiviral therapy is used. The ability to achieve undetectable HBV DNA levels pre-transplantation in the majority of patients may contribute to the high efficacy of these HBIG "light" regimens. Additionally, the success of antiviral rescue therapy for those patients who fail prophylaxis and develop recurrent HBV infection post-transplant has provided the impetus to move increasingly towards HBIG-free approaches. New techniques to detect occult HBV in hepatic and extrahepatic sites may allow clinicians to define a subgroup of patients in whom withdrawal of HBIG or all prophylaxis may be applicable.     

Favorable outcome of orthotopic liver transplantation in a patient with subacute liver failure due to the emergence of a hepatitis B YMDD escape mutant virus.

BACKGROUND/AIMS: Patients with end-stage liver disease due to chronic hepatitis B infection in whom a YMDD escape hepatitis B virus (HBV) mutant has emerged under lamivudine treatment are generally denied liver transplantation (OLT). METHODS: We report the case of a male patient who was started on prophylactic treatment with lamivudine in the context of recurrent episodes of HBV reactivation during high dose immunosuppressive therapy for relapsing severe pulmonary sarcoidosis. RESULTS: Following the emergence of a YMDD escape mutant virus under lamivudine treatment, he developed subacute liver failure requiring liver transplantation. The patient was treated with a combination of intravenous hepatitis B immune globulin (HBIG) which was started perioperatively and also continued lamivudine after OLT. Twelve months after OLT, there was no evidence of HBV reinfection of the liver graft with the use of HBIG and lamivudine. CONCLUSIONS: This observation suggests that emergence of the YMDD mutation is not a contra-indication to OLT, providing adequate immunoprophylaxis using HBIG and lamivudine combination therapy.     

REVIEW: Hepatitis B and liver transplantation

Liver transplantation in hepatitis B virus (HBV)-infected patients is very commonly followed by recurrence of infection in the transplanted liver. Most recipients with HBV recurrence will develop chronic hepatitis that follows a more aggressive course than is seen in non-immuno-compromized subjects and this frequently results in graft failure. The presence of hepatitis B e antigen or significant levels of HBV-DNA in the serum is highly predictive of recurrence and this has led to the view that patients, whose serum is positive for these conventional markers of replication, should be excluded from transplantation. The key to improving the results of transplantation in patients with HBV infection lies in the development of effective strategies to prevent reinfection. High dose anti-HBs immunoglobulin is effective in patients who are coinfected with hepatitis D, those transplanted for fulminant hepatitis and cirrhotic patients who have very low levels of viral replication prior to transplantation. Unfortunately, immunoprophylaxis does not seem to influence the outcome in those patients with higher levels of replication. There are several new orally active nucleoside analogues that are potent inhibitors of hepatitis B replication that may be effective for both the prevention and treatment of recurrent disease. The most promising are lamivudine (2',3', dideoxy, 3', thiacytidine) and famciclovir (a guanosine analogue). Both agents have been extensively evaluated in animal models of HBV and have been shown to rapidly suppress viral replication. The initial experience with these agents in liver transplant recipients has been promising and a number of studies are currently underway to determine whether these drugs, used alone or in combination with immunoprophylaxis, are able to prevent recurrence in those patients at highest risk of post-transplant HBV recurrence.     

Current and Potential Future Chemopreventive Strategies Against Hepatitis B Virus Reinfection in Liver Transplant Recipients

Although the availability of effective oral therapies for hepatitis B virus (HBV) infection has reduced the need for liver transplantation (LT) for decompensated cirrhosis due to chronic infection, HBV remains an important cause of hepatocellular carcinoma and acute liver failure. Recurrent HBV infection occurs almost invariably post-LT in the absence of prophylaxis if viremia was detectable pre-LT, so prophylaxis remains necessary to prevent graft reinfection. Current approaches include the use of nucleos(t)ide analogues pre- and post-LT and hepatitis B immune globulin, but several novel antiviral agents are currently under investigation in non-transplant populations and may potentially prove to be useful in the LT setting in the future.     

Clinical management of hepatitis B virus infection correlated with liver transplantation

BACKGROUND:As a radical cure for post-hepatitis B virus (HBV)-related liver cirrhosis and hepatocellular carcinoma,liver transplantation has been applied in many medical centers.Before the use of effective measures,hepatitis B recurrence and the existence of HBsAg(+) donors,patients with hepatitis B-related diseases are contraindicated for liver transplantation.Application of interferon,hepatitis B immunoglobulin (HBIG),and nucleotide analogues (e.g.,lamivudine) has made great progress in the clinical care ...     

How will we use the new antiviral agents for hepatitis B?

There are two licensed drugs for chronic hepatitis B virus (HBV), interferon alfa and lamivudine, with similar efficacy rates. Lamivudine is less expensive and better tolerated than interferon alfa and is the drug of choice for patients with decompensated cirrhosis and recurrent HBV infection after liver transplantation. The major problem with lamivudine monotherapy has been the emergence of drugresistant HBV polymerase (YMDD) mutants. Thus, longterm use of lamivudine in other settings remains somewhat controversial. Alternative nucleoside analogues that are active against both wild-type and YMDD-mutant HBV are currently being tested. It is hoped that a combination of one or more of these agents with lamivudine will not only prove more effective than lamivudine alone but also decrease the rate of lamivudine resistance. Preliminary studies suggest that the combination of interferon and lamivudine is associated with an enhanced rate of virologic response when compared with either agent alone. From a theoretical perspective, the combination of interferon with one or more nucleoside analogues may be the most effective way to treat HBV infection in many clinical situations.     

Management of viral hepatitis in hematologic malignancies

Viral hepatitis is the third major cause of liver dysfunction in allogeneic transplant recipients and has become a significant concern in patients with hematological malignancies receiving chemotherapy. Thus, identification of patients at risk for viral hepatitis is very important when evaluating and treating hematological malignancies. Serologic screening for all patients should include anti-HCV, hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (anti-HBs), and hepatitis B core antibody (anti-HBc) testing. Current therapies for hepatitis B (HBV) virus infection are aimed at viral suppression, while treatment for hepatitis C (HCV) virus can eradicate infection in many treated patients. To prevent HBV viral reactivation, prophylaxis with nucleoside analogues should be initiated for all HBsAg-positive patients. HCV infection appears to have little impact on short-term survival after bone marrow transplantation (BMT), but eventually can impact long-term survival due to progression of liver disease. In this review we will highlight the mechanisms of virus reactivation, clinical manifestations, and management strategies to minimize acute and chronic morbidity in this population.     

Fulminant hepatitis B virus: Recurrence after liver transplantation in two patients also infected with hepatitis delta virus

Liver transplantation for hepatitis B virus (HBV)-related liver disease is complicated by HBV recurrence and, consequently, poor patient and graft survival. Patients transplanted for hepatitis delta virus (HDV)- related cirrhosis are reported to have a diminished incidence of HBV recurrence and improved graft survival. However, only a few reported HDV-infected patients had active HBV replicative disease before liver transplantation. In our experience, we transplanted two HDV-infected patients, both of whom had active HBV replication before liver transplantation. In one patient, hepatitis B surface antigen (HBsAg) recurred four months after transplantation. Two months later, Hepatitis Be antigen (HBeAg) and HBV-DNA became positive, and the patient died of fulminant recurrent hepatitis B and hepatitis delta. In the other patient, HBV persisted after transplantation, and 2 months later the patient required retransplantation for fulminant recurrent hepatitis B and hepatitis delta. With the second graft, the patient remained free of HBV infection for 1 year. Thereafter, the patient experienced HBV recurrence with active replication and died of fulminant hepatitis B and delta recurrence. In the first case and in the second graft of the second case, hepatitis B immunoglobulin (HBIG) immunoprophylaxis was administered in an attempt to prevent recurrence of HBV. The literature suggests that an HDV infection inhibits the replication of HBV and therefore plays a role in preventing the recurrence of HBV and improving survival. Our experience with two patients suggests that HDV infection, in the presence of active HBV replication, may not play a protective role.(Hepatology 1997 Feb;25(2):434-8)     

Hepatitis B immune globulin preparations and use in liver transplantation

Hepatitis B immune globulin remains a central component of prophylaxis in HBV-infected patients undergoing liver transplantation. HBIG monotherapy given at a high dosage and indefinitely can prevent recurrence in 65% to 80% of patients. Because treatment failures occur and combination therapy using HBIG plus a nucleoside analog is more uniformly effective, the current standard of care is combination HBIG plus a nucleoside analog. These combination protocols have reduced the rate of virologic breakthrough to 10% or less. Several questions remain. The optimal dose and duration of HBIG use is unclear. Moreover, the development of resistance to lamivudine (and other nucleoside analogs) before transplantation increases the risk for virologic breakthrough post-transplantation. For patients with pre-transplant evidence of active HBV replication caused by the presence of nucleoside analog resistance, HBIG may be the main or only form of prophylaxis. For these patients, HBIG doses sufficient to maintain anti-HBs titers comparable to the days of HBIG monotherapy seem warranted. New HBIG formulations have made anti-HBs therapy more safe and tolerable to patients but the cost of the drug remains significant. The cost factor is particularly important in developing countries or countries with more limited resources for management of liver transplant recipients. Thus, there remains a need to develop and test new forms of anti-HBs therapy, so that effective but less expensive forms of immunoprophylaxis can be made available.     

Safe and cost‐effective control of post‐transplantation recurrence of hepatitis B

A combination of hepatitis B immunoglobulin (HBIG) and nucleoside/nucleotide analogs (NUC) is the current standard of care for controlling hepatitis B recurrence after orthotopic liver transplantation (OLT). However, long‐term HBIG administration is associated with several unresolved issues, including limited availability and extremely high cost, and thus several protocols for treatment with low‐dose HBIG combined with NUC or HBIG‐free regimens have been developed. This article reviews recent advances in post‐OLT hepatitis B virus (HBV) control and future methodological directions. New NUC such as entecavir, tenofovir or lamivudine plus adefovir dipivoxil combinations induce a very low frequency of viral resistance. The withdrawal of HBIG after several months of OLT under new NUC continuation also has permissible effects. Even after HBV reactivation, NUC can usually achieve viral control when viral markers are strictly followed up. Another approach is to induce self‐producing anti‐HBV antibodies via vaccination with a hepatitis B surface antigen vaccine. However, HBV vaccination is not sufficiently effective in patients to treat liver cirrhosis type B after OLT because immune tolerance to the virus has already continued for several decades. Trials of its safety and cost‐effectiveness are required. This review advocates a safe and economical approach to controlling post‐OLT HBV recurrence.