Review of the pharmacological management of hepatitis B viral infection before and after liver transplantation

The progress in treatment against hepatitis B virus(HBV)with the development of effective and well tolerated nucleotide analogues(NAs)has improved the outcome of patients with HBV decompensated cirrhosis and has prevented post-transplant HBV recurrence.This review summarizes updated issues related to the management of patients with HBV infection before and after liver transplantation(LT).A literature search using the PubMed/Medline databases and consensus documents was performed.Pre-transplant therapy has been initially based on lamivudine,but entecavir and tenofovir represent the currently recommended first-line NAs for the treatment of patients with HBV decompensated cirrhosis.After LT,the combination of HBV immunoglobulin(HBIG)and NA is considered as the standard of care for prophylaxis against HBV recurrence.The combination of HBIG and lamivudine is related to higher rates of HBV recurrence,compared to the HBIG and entecavir or tenofovir combination.In HBIG-free prophylactic regimens,entecavir and tenofovir should be the first-line options.The choice of treatment for HBV recurrence depends on prior prophylactic therapy,but entecavir and tenofovir seem to be the most attractive options.Finally,liver grafts from hepatitis B core antibody(anti-HBc)positive donors can be safely used in hepatitis B surface antigen negative,preferentially anti-HBc/anti-hepatitis B surface antibody positive recipients.     

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 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.     

Prevention of lamivudine‐resistant hepatitis B recurrence after liver transplantation with entecavir plus tenofovir combination therapy and perioperative hepatitis B immunoglobulin only

T. Karlas, J. Hartmann, A. Weimann, M. Maier, M. Bartels, S. Jonas, J. Mössner, T. Berg, H.L. Tillmann, J. Wiegand. Prevention of lamivudine‐resistant hepatitis B recurrence after liver transplantation with entecavir plus tenofovir combination therapy and perioperative hepatitis B immunoglobulin only.
Transpl Infect Dis 2011: 13: 299–302. All rights reserved Abstract: Combination therapy with antivirals plus hepatitis B immunoglobulin (HBIg) has become the standard treatment for prevention of post‐liver transplant hepatitis B virus (HBV) recurrence. However, HBIg therapy is inconvenient and expensive. Alternative therapeutic approaches with modern nucleos(t)ide analogues are limited so far. The present case report describes prevention of HBV recurrence with entecavir and tenofovir. A 48‐year‐old male patient with hepatitis B‐induced decompensated liver cirrhosis initially improved on lamivudine (LAM) until LAM resistance (rtL180M and rtM204V) emerged followed by renewed decompensation. Therefore, tenofovir was added to LAM leading to undetectable HBV DNA (<200 copies/mL). Six months later, low‐level viremia (479 copies/mL) was detected. Treatment was escalated to tenofovir plus entecavir. HBV DNA became negative again, and the patient underwent orthotopic liver transplantation. HBIg was administered during transplantation (10,000 IU) and on the second and third postoperative days (total dose 26,000 IU). Subsequently, the anti‐hepatitis B surface (HBs) titer rose to 1477 IU/L at day 4 post transplantation. Although HBIg should have been continued, the patient remained on combination therapy with tenofovir plus entecavir only. The anti‐HBs titer decreased and became negative 4 months later. However, under continued combination therapy with oral antivirals, HBV DNA and hepatitis B surface antigen remained negative during the entire follow‐up of 21 months after liver transplantation. Combination therapy with entecavir plus tenofovir may prevent post‐liver transplant hepatitis B recurrence even without HBIg maintenance therapy. This case illustrates that combination oral antiviral therapy might substitute for HBIg as indefinite prophylactic regimen due to profound antiviral efficacy and low risk of viral resistance. Efficacy and safety must be further investigated in randomized controlled trials.     

Efficacy and safety of prophylaxis with entecavir and hepatitis B immunoglobulin in preventing hepatitis B recurrence after living‐donor liver transplantation

Aim: Hepatitis B recurrence after liver transplantation can be reduced to less than 10% by combination therapy with lamivudine (LAM) and hepatitis B immunoglobulin (HBIG). The aim of this study was to evaluate the efficacy and safety of prophylaxis with entecavir (ETV), which has higher efficacy and lower resistance rates than LAM, combined with HBIG in preventing hepatitis B recurrence after living‐donor liver transplantation (LDLT). Methods: Twenty‐six patients who received ETV plus HBIG (ETV group) after LDLT for hepatitis B virus (HBV)‐related end‐stage liver disease were analyzed by comparing with 63 control patients who had received LAM plus HBIG (LAM group). Results: The survival rates of the patients treated with ETV plus HBIG was 73% after both 1 and 3 years, and there was no statistical difference between the patients in the ETV group and LAM group. No HBV recurrence was detected during the median follow‐up period of 25.1 months in the ETV group, whereas the HBV recurrence rate was 4% at 3 years and 6% at 5 years in the LAM group. No patients had adverse effects related to ETV administration. Conclusion: ETV combined with HBIG provides effective and safe prophylaxis in preventing hepatitis B recurrence after LDLT.     

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。     

The role of entecavir in preventing hepatitis B recurrence after liver transplantation

OBJECTIVE: Although hepatitis B recurrence after liver transplantation has been reduced to 0%–10% since the application of the combination therapy of hepatitis B immunoglobulin (HBIG) and lamivudine, the viral mutation resistance of lamivudine is still an obstacle to the outcome of liver transplantation. Here we evaluate the role of entecavir in preventing hepatitis B recurrence after liver transplantation.

METHODS:

Patients who received a liver transplantation for hepatitis B virus (HBV)‐related end‐stage liver disease in our center from March 2006 to December 2008 were enrolled in this study. All patients received entecavir (0.5 mg orally, daily) or lamivudine (100 mg orally, daily) together with a long‐term low dosage of HBIG to prevent hepatitis B recurrence after transplantation. Serum viral markers (HBsAg, anti‐HBs, HBeAg, anti‐HBc and anti‐HBe) and HBV‐DNA level were determined. RESULTS: Thirty patients receiving entecavir and 90 patients receiving lamivudine were matched with the same age and sex in both groups. No reinfection of hepatitis B was detected in the entecavir group. The hepatitis B surface antigen of patients in the entecavir group became negative within one week and no patient had any adverse effect relating to entecavir. There was no difference in the cumulative survival rate between the entecavir group and the lamivudine group (P > 0.05). CONCLUSION: This study shows that entecavir combined with low dosages of HBIG is effective and safe in preventing hepatitis B recurrence after liver transplantation, but its long‐term effect is still under investigation and a large‐sample study will be carried out in the future.     

Prevention of hepatitis B virus recurrence after liver transplantation in cirrhotic patients treated with lamivudine and passive immunoprophylaxis

BACKGROUND/AIMS: Treatment with hepatitis B virus immune globulins (HBIG) or lamivudine has reduced the rate of hepatitis B recurrence after liver transplantation to approximately 50%. METHODS: To further decrease hepatitis B recurrence, 33 hepatitis B virus (HBV)-related cirrhotic patients were treated with lamivudine before liver transplantation and with lamivudine together with low-dose HBIG (46 500 IU the first month followed by 5,000 lU/monthly) after surgery. RESULTS: While on lamivudine, serum HBV DNA level decreased significantly in all patients and in 11 (33%) the Child-Pugh score improved. Twenty-six patients were transplanted. Among the 25 who survived for longer than 12 months, only one (4%) experienced a hepatitis B recurrence over an average follow-up of 31 months, a rate significantly lower (P = 0.0002) than the 50% recurrence rate among a historical control group of 12 patients. However, low-level HBV replication was detected sporadically throughout the follow-up in 64% of patients. CONCLUSIONS: Over the medium-term, combined prophylaxis with lamivudine and HBIG significantly decreases the risk of hepatitis B recurrence after liver transplantation. Though low-level HBV infection recurred in two thirds of patients, the pathogenic expression of HBV was prevented.     

Prophylactic managements of hepatitis B viral infection in liver transplantation

Liver transplantation (LT) is a considerably effective treatment for patients with end-stage hepatitis B virus (HBV)-related liver disease. However, HBV infection often recurs after LT without prophylaxis. Since the 1990s, the treatment for preventing HBV reinfection after LT has greatly progressed with the introduction of hepatitis B immunoglobulin (HBIG) and nucleos(t)ide analogues (NAs), resulting in improved patient survival. The combination therapy consisting of high-dose HBIG and lamivudine is highly efficacious for preventing the recurrence of HBV infection after LT and became the standard prophylaxis for HBV recurrence. However, mainly due to the high cost of HBIG treatment, an alternative protocol for reducing the dose and duration of HBIG has been evaluated. Currently, combination therapy using low-dose HBIG and NAs is considered as the most efficacious and cost-effective prophylaxis for post-LT HBV reinfection. Recently, NA monotherapy and withdrawal of HBIG from combination therapy, along with the development of new, potent high genetic barrier NAs, have provided promising efficacy, especially for low-risk recipients. This review summarizes the prophylactic protocol and their efficacy including prophylaxis of de novo HBV infection from anti-HBc antibody-positive donors. In addition, challenging approaches such as discontinuation of all prophylaxis and active immunity through hepatitis B vaccination are discussed.     

Management of hepatitis B in liver transplant recipients

Summary.  Advances in hepatitis B virus (HBV) antiviral prophylaxis have dramatically improved graft and patient survival for patients undergoing liver transplantation for hepatitis B related end-stage liver disease. In particular, the availability of hepatitis B immune globulin (HBIg) in combination with nucleos(t)ide analogues such as lamivudine and adefovir, have transformed outcomes. The availability of newer antivirals such as adefovir, tenofovir and entecavir either as monotherapy or in combination offer an increasing number of antiviral options. Despite these advances, significant challenges remain. Factors that affect the efficacy of anti-viral therapy include detectable HBV viraemia at the time of transplant and emergence of HBV mutants (especially in patients with prior exposure to lamivudine). HBV prophylaxis protocols are expensive especially with use of high-dose HBIg and newer nucleos(t)ide analogues. This review summarizes current HBV prophylaxis protocols and management of recurrent disease post-transplantation. There is an increasing need for individualization of therapy based on prior drug exposures, level of HBV DNA at time of transplantation and type of prophylaxis used.     

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.     

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.     

Randomized trial of lamivudine versus hepatitis B immunoglobulin for long-term prophylaxis of hepatitis B recurrence after liver transplantation

BACKGROUND/AIMS: The long-term prophylaxis of hepatitis B after liver transplantation requires further optimization. In a randomized trial we investigated a regimen where the initially given hepatitis B immunoglobulin (HBIg) is replaced by long-term lamivudine treatment. METHODS: Twenty-four liver transplant recipients (all HBsAg-positive/HBV DNA-negative before transplantation), who had received HBIg for at least 6 months without HBV recurrence, were randomized to receive lamivudine (n = 12) or HBIg (n = 12) for 52 weeks. The efficacy criteria involved seronegativity for HBsAg and undetectable HBsAg/ HBcAg in the liver. RESULTS: Twenty-one of 24 patients completed the study without hepatitis B virus (HBV) recurrence (11 on HBIg, ten on lamivudine), while three patients became HBsAg-positive. Amongst those without HBV recurrence HBV DNA was detectable only by polymerase chain reaction, intermittently in serum and lymphocytes, and in liver specimens from six of eight patients receiving HBIg and five of seven receiving lamivudine. YMDD variant was found in four cases with no viral antigen expression. Eight patients continued lamivudine after the study and during an additional 6-22 months remained HBsAg-negative with normal graft function. CONCLUSIONS: Substitution of HBIg with lamivudine is effective for prevention of HBV recurrence in low-risk liver transplant recipients and offers a convenient and cost-effective alternative for long-term HBV prophylaxis.     

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.     

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     

Hepatitis B prophylaxis post liver transplantation with newer nucleos(t)ide analogues after hepatitis B immunoglobulin discontinuation

Newer nucleos(t)ide analogues (NUCs) have better resistance profiles making hepatitis B immunoglobulin (HBIG)‐sparing protocol an attractive prophylactic approach against hepatitis B virus (HBV) recurrence after liver transplantation (LT). We evaluated the risk of HBV recurrence after withdrawal of HBIG in patients who had been under HBIG plus NUCs after LT. Stable patients without HBV recurrence after LT while receiving combination of HBIG plus NUCs for at least 12 months were eligible for HBIG discontinuation. The patients were at low risk for HBV recurrence (only 4.5% had detectable HBV DNA at the time of LT, and 32% had HBV/hepatitis D virus co‐infection). All patients were followed up with HBV serum markers, HBV‐DNA, and evaluation of renal function, including glomerular filtration rate. Forty‐seven recipients discontinued HBIG and were maintained on newer NUCs. Median follow‐up post‐HBIG withdrawal was 24 months (range: 6–40 months). Twenty‐eight (60%) patients continued on lamivudine in combination with adefovir dipivoxil (n = 23, 82%) or tenofovir (n = 5, 18%); 10 (21%) and 9 (19%) of the 47 patients continued on tenofovir and entecavir monoprophylaxis, respectively. Although 3 (6.3%) patients developed detectable hepatitis B surface antigen, all of them had undetectable HBV DNA and no clinical manifestations of HBV recurrence. Renal function was similar between the different groups of patients. In conclusion, maintenance therapy with newer NUCs after discontinuation of HBIG prophylaxis was effective, but further studies in larger cohorts with longer follow‐up are needed.     

Μanagement of patients with hepatitis B and C before and after liver and kidney transplantation

New nucleos(t)ide analogues(NAs) with high genetic barrier to hepatitis B virus(HBV) resistance(such as entecavir, tenofovir) have improved the prognosis of patients with HBV decompensated cirrhosis and have prevented HBV recurrence after liver transplantation(LT). NAs are considered the most proper approach for HBV infection in patients under renal replacement therapy but their doses should be adjusted according to the patient's creatinine clearance. In addition, physi-cians should be aware of the potential nephrotoxicity. However, patients with chronic hepatitis C and decom-pensated cirrhosis can receive only one therapeutic option before LT, as well as for Hepatitis C virus(HCV) recurrence after LT, which is the combination of sub-cutaneous Peg-IFN and ribavirin. Generally, therapy for HCV after renal transplantation should be avoided. Although the optimal antiviral therapy for HCV infec-tion has not been established, attention has turned to a new, oral direct acting antiviral treatment which marks a promising strategy in prognosis and in amelioration of these diseases.     

乙型肝炎患者肝移植后抗病毒治疗的远期效果分析

目的通过观察乙型肝炎相关肝移植受体在拉米夫定或（和）乙型肝炎免疫球蛋白预防性用药时,体内HBV标志物的变化,探讨预防复发及个体优化治疗措施。方法ELISA法、HBV DNA荧光定量PCR、免疫组织化学法定期检测术前及术后各时期血清及肝穿刺组织中的HBV标志物,回顾性观察96例受体术后HBV标志物在随访中的动态变化。结果术后最长7年随访时间内共有17例（17.71%）乙型肝炎复发患者。2年乙型肝炎实际总体复发率为22.0%,术前病毒复制状态对术后乙型肝炎复发有影响（P〈0.05）;82.4%（14/17）乙型肝炎复发者发生在术后3年内,是3年后复发人数的4.7倍（P〈0.01）;3年内复发者中,术前为HBV活跃复制者占78.6%（11/14）。抗-HBc和抗-HBe检出率随时间下降,但仍长期存在。结论术后乙型肝炎复发依然存在。对于术前非HBV活跃复制受体,在术后严格联合预防用药且有补救方案前提下,以术后3年作为时间尺度来尝试停用或降低乙型肝炎免疫球蛋白用量,从而建立一套不同病毒及免疫状态下的个体用药方案值得进一步研究。     

Prophylaxis against hepatitis B virus recurrence after liver transplantation: A registry study

AIM: To evaluate the prophylactic efficacy of hepatitis B immunoglobulin(HBIG) in combination with different nucleos(t)ide analogues.METHODS: A total of 5333 hepatitis B surface antigenpositive patients from the China Liver Transplant Registry database were enrolled between January 2000 and December 2009. Low-dose intramuscular(im) HBIG combined with one nucleos(t)ide analogue has been shown to be very cost-effective in recent reports. Hepatitis B virus(HBV) prophylactic outcomes were compared based on their posttransplant prophylactic protocols [group A(n = 4684): im HBIG plus lamivudine; group B(n = 491): im HBIG plus entecavir; group C(n = 158): im HBIG plus adefovir dipivoxil]. We compared the related baseline characteristics among the three groups, including the age, male sex, Meld score at the time of transplantation, Child-Pugh score at the time of transplantation, HCC, pre-transplantation hepatitis B e antigen positivity, pre-transplantation HBV deoxyribonucleic acid(HBV DNA) positivity, HBV DNA at the time of transplantation, pre-transplantation antiviral therapy, and the duration of antiviral therapy before transplantation of the patients. We also calculated the 1-, 3- and 5-year survival rates and HBV recurrence rates according to the different groups. All potential risk factors were analyzed using univariate and multivariate analyses.RESULTS: The mean follow-up duration was 42.1 ± 30.3 mo. The 1-, 3- and 5-year survival rates were lower in group A than in groups B(86.2% vs 94.4%, 76.9% vs 86.6%, 73.7% vs 82.4%, respectively, P 0.001) and C(86.2% vs 92.5%, 76.9% vs 73.7%, 87.0% vs 81.6%, respectively, P 0.001). The 1-, 3-and 5-year posttransplant HBV recurrence rates were significantly higher in group A than in group B(1.7% vs 0.5%, 3.5% vs 1.5%, 4.7% vs 1.5%, respectively, P = 0.023). No significant difference existed between groups A and C and between groups B and C with respect to the 1-, 3- and 5-year HBV recurrence rates. Pretransplant hepatocellular carcinoma, high viral load and posttransplant prophylactic protocol(lamivudine and HBIG vs entecavir and HBIG) were associated with HBV recurrence.CONCLUSION: Low-dose intramuscular HBIG in combination with a nucleos(t)ide analogue provides effective prophylaxis against posttransplant HBV recurrence, especially for HBIG plus entecavir.     

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.