An Efficacy and Cost-Effectiveness Analysis of Combination Hepatitis B Immune Globulin and Lamivudine to Prevent Recurrent Hepatitis B After Orthotopic Liver Transplantation Compared With Hepatitis B Immune Globulin Monotherapy

Orthotopic liver transplantation (OLT) for hepatitis B virus (HBV) infection was limited until recently by poor graft and patient outcomes caused by recurrent HBV. Long-term immunoprophylaxis with hepatitis B immune globulin (HBIG) dramatically improved post-OLT survival, but recurrent HBV still occurred in up to 36% of the recipients. More recently, combination HBIG and lamivudine has been shown to effectively prevent HBV recurrence in patients post-OLT. The aim of the current study is to determine long-term outcome and cost-effectiveness of using combination HBIG and lamivudine compared with HBIG monotherapy in patients who undergo OLT for HBV. A retrospective chart review identified 59 patients administered combination HBIG and lamivudine and 12 patients administered HBIG monotherapy as primary prophylaxis against recurrent HBV. Lamivudine, 150 mg/d, was administered orally indefinitely. HBIG was administered under a standard protocol (10,000 IU intravenously during the anhepatic phase, then 10,000 IU/d intravenously for 7 days, then 10,000 IU intravenously monthly) indefinitely. A decision-analysis model was developed to evaluate the potential economic impact of prophylaxis against HBV with combination therapy compared with monotherapy. Recurrent HBV was defined as the reappearance of hepatitis B surface antigen (HBsAg) after its initial disappearance post-OLT. In the combination-therapy group, no patient redeveloped serum HBsAg or HBV DNA during mean follow-ups of 459 and 416 days, respectively. In the monotherapy group, 3 patients (25%) had reappearance of HBsAg in serum during a mean follow-up of 663 days. Combination therapy resulted in a dominant, cost-effective strategy with an average cost-effectiveness ratio of $252,111/recurrence prevented compared with $362,570/recurrence prevented in the monotherapy strategy. Combination prophylaxis with HBIG and lamivudine is highly effective in preventing recurrent HBV, may protect against the emergence of resistant mutants, and is significantly more cost-effective than HBIG monotherapy with its associated rate of recurrent HBV. (Liver Transpl 2000;6:741-748.)     

Lamivudine After Hepatitis B Immune Globulin Is Effective in Preventing Hepatitis B Recurrence After Liver Transplantation

The prevention of recurrent hepatitis B virus (HBV) infection after orthotopic liver transplantation (OLT) with hepatitis B immunoglobulin (HBIG) is expensive and requires indefinite parenteral administration. Lamivudine is a nucleoside analogue capable of inhibiting HBV replication. The aim of this study is to determine the efficacy of lamivudine in the prevention of recurrent HBV infection after a course of HBIG in patients who were hepatitis B surface antigen (HBsAg) positive and hepatitis Be antigen (HBeAg) negative before OLT. Patients at high risk for recurrent HBV infection (HBeAg positive and HBV DNA positive) were excluded. Thirty HBsAg-positive, HBeAg-negative patients underwent OLT from January 1993 to June 1997. All 30 patients were administered HBIG after OLT and, after 2 years, were given the option of continuing with HBIG or switching to lamivudine. Five patients were excluded: 3 patients were lost to follow-up and 2 patients died of technical complications. Three patients terminated HBIG therapy at 8, 24, and 29 months after OLT, and reinfection with HBV occurred in 1 patient. Six patients elected to continue HBIG therapy for life; 1 patient died of melanoma and the remaining 5 patients are HBsAg negative, with an average follow-up of 73 months. Sixteen patients were converted to lamivudine after a course of HBIG, and all 16 patients are HBsAg negative, with an average follow-up of 51 months after OLT. Five patients have been on lamivudine monotherapy for more than 24 months. These results suggest that lamivudine administered after a posttransplantation course of HBIG can effectively prevent the recurrence of HBV infection in patients who are HBsAg positive and HBeAg negative before OLT. (Liver Transpl 2000;6:434-439.)     

拉米夫定及乙型肝炎免疫球蛋白预防肝移植后乙型肝炎复发的疗效观察

目的:研究单用拉米夫定或与乙型肝炎(乙肝)免疫球蛋白(HBIG)联合应用对乙肝相关肝病病人肝移植术后预防乙肝复发的效果。方法:应用酶联免疫试验(EIA)检测HBsAg、抗鄄HBs、HBeAg、抗鄄HBe及抗鄄HBc;用聚合酶链反应法(PCR)检测乙肝病毒(HBV)DNA。26例单用拉米夫定15例,联合应用拉米夫定和HBIG11例。结果:26例乙肝相关肝病病人于肝移植术后随访3～24个月,2例死亡,4例出现乙肝复发,其余20例病人HBsAg持续阴性。结论:肝移植是治疗乙肝终末期病人的有效方法,拉米夫定与HBIG联合应用可有效预防肝移植术后乙肝复发。     

Natural History of Patients with Recurrent Chronic Hepatitis C Virus and Occult Hepatitis B Co-Infection after Liver Transplantation

It is uncertain whether occult hepatitis B virus co-infection will hasten progressive liver disease in chronic hepatitis C patients after liver transplantation. This study evaluated fibrosis progression and severe fibrosis in 118 consecutive hepatitis B surface antigen-negative patients with virological and histological evidence of recurrent chronic hepatitis C infection co-infected with occult hepatitis B virus after liver transplantation. HBV DNA was detected from serum at the time of recurrent chronic hepatitis C infection by polymerase chain reaction. Each subject underwent a repeat liver biopsy 5 years post-liver transplantation. Occult hepatitis B virus co-infection was present in 41 of the 118 (34.7%) patients. At 5 years post-liver transplantation, 13 of the 41 occult hepatitis B virus co-infected patients compared with 16 of the 77 patients without occult hepatitis B virus co-infection developed fibrosis progression (31.7% vs. 20.8%, respectively, p = 0.39). Eight of 41 the occult hepatitis B virus co-infected patients compared with 13 of the 77 patients without occult hepatitis B virus co-infection had severe fibrosis (19.5% vs. 16.9%, respectively, p = 0.97). In conclusion, occult hepatitis B virus co-infection in patients with recurrent chronic hepatitis C infection was not associated with accelerated fibrosis progression or severe fibrosis after liver transplantation.     

Significance of Hepatitis B Virus Genotype in Liver Transplantation for Chronic Hepatitis B

Hepatitis B virus (HBV) genotype influences chronic hepatitis B disease profile but its relevance in liver transplantation (LTx) is not known. HBV genotype was identified by direct sequencing from pre-transplant sera of 119 patients who underwent LTx using lamivudine prophylaxis (genotype A,1; B,43; C,74; D,1). The baseline characteristics and outcome of 43 genotype B and 74 genotype C patients were compared. Genotype B patients had significantly more pre-transplant acute flare, worse liver functions and higher model for end-stage liver disease score. Fewer genotype B patients had HBeAg (13% vs. 32%; p=0.017), but HBV DNA seropositivity (by bDNA assay) was comparable (26% vs. 23%; p=0.727). The 3-year graft survival was 83% for genotype B and 89% for genotype C (p=0.2). The rate of HBsAg clearance or seroreversion was the same. The cumulative rate of viral breakthrough due to lamivudine-resistant mutants at 3 years was 4% for genotype B and 21% for genotype C (p=0.017). Liver biopsy after viral breakthrough showed recurrent hepatitis B in 7 of 10 genotype C patients, including 2 with fibrosing cholestatic hepatitis, and no histologic recurrence in 2 genotype B patients. In conclusion, HBV genotypes B and C are associated with different patterns of end-stage liver diseases that required transplantation, and genotype C may carry a greater risk and severity of recurrence due to lamivudine-resistant mutants.     

Pretransplant MELD Score As a Predictor of Outcome After Liver Transplantation for Chronic Hepatitis C

The Model of End-Stage Liver Disease (MELD) score, an accurate predictor of mortality in patients awaiting liver transplantation (OLTX), did not predict graft or patient survival in the post-transplant setting. Our aim was to test the model in patients who underwent OLTX for chronic hepatitis C. Two hundred and eighty-seven adult patients who underwent primary OLTX for chronic hepatitis C between December 1993 and September 1999 were studied from a prospectively maintained database. The group was stratified by MELD scores of less than 15, 15-24, and greater than 24. Patient survival, graft survival, and interval liver biopsy pathology were reviewed. Both patient and graft survival at 3, 6, and 12 months were significantly lower in the higher MELD score groups, as was patient survival at 24 months (p-values, 0.01-0.05). The difference in survival between the low, medium, and high MELD score groups increases in time. The survival without bridging fibrosis in the allograft at 1 year post-transplant was significantly lower with higher MELD scores (p = 0.037). The decrease in survival seen in hepatitis C patients with MELD scores greater than 24 raises questions of transplant suitability for these patients. Therapeutic modalities to decrease post-transplant graft injury in these patients should be explored.     

Recurrent Hepatitis B and D Virus Infection in a Liver Transplant Recipient

Hepatitis B virus (HBV) and hepatitis delta virus (HDV) co-infections progress rapidly and lead to cirrhosis. In Japan, the prevalence of HBV and HDV co-infected patients is low. Therefore, there are few reports of patients with HBV and HDV co-infection having undergone liver transplantation. Herein, we report a rare case of recurrence of HBV and HDV in a 41-year-old man who underwent living donor liver transplantation 4 years prior.     

Case Report of Lamivudine-Resistant Hepatitis B Virus Infection Post Liver Transplantation from a Hepatitis B Core Antibody Donor

The use of allografts from donors with hepatitis B core antibody in liver transplantation (LT) is associated with the risk of de novo hepatitis B virus (HBV) infection. Prophylaxis using hepatitis B Immune globulin (HBIg) and lamivudine alone or in combination has been reported. Yet, there are no standardized regimens and long-term efficacy is not known. We report a case of a patient who underwent LT for alcoholic liver disease who received an allograft from a donor with Hepatitis B core antibody. The patient had no previous exposure to HBV, was vaccinated against HBV, and had demonstrated Hepatitis B surface antibody present in serum before and 6 months after transplantation. Prophylaxis with short-term HBIg (1 week) and indefinite lamivudine was given. De novo HBV infection developed more than 3 years after LT with a lamivudine-resistant polymerase mutant containing the rtM204I and rtl180L/M mutations. We reviewed the risk of de novo post-LT HBV infection in recipients of livers from hepatitis B core antibody positive donors. High risk were HBV naïve recipients, moderate risk recipients had isolated hepatitis B surface antibody (anti-HBs) or hepatitis B core antibody (anti-HBc), while low-risk recipients had both anti-HBs and anti-HBc. We reviewed prophylaxis protocols reported in the literature and made recommendations for management.     

The Impact of IL28B Genetic Variants on Recurrent Hepatitis C in Liver Transplantation: Significant Lessons from a Dual Graft Case

IL28B genetic polymorphism is related to interferon‐sensitivity in chronic hepatitis C, but the significance of grafts carrying different genotypes from recipients is still unclear in liver transplantation. A 51‐year‐old Japanese male carrying a minor genotype underwent dual liver transplantation for liver cirrhosis due to hepatitis C virus (HCV). The left lobe graft carried a major genotype, and the right a minor genotype. He achieved virological response during the course of pegylated‐interferon and ribavirin therapy against recurrent hepatitis C for 2 years, but HCV relapsed immediately at the end of the therapy. Two years after antiviral therapy, liver biopsy was performed from each graft. The specimens showed A1F0 in the left lobe graft and A2F2 in the right. Moreover, quantitative polymerase chain reaction was performed using RNA extracted from each specimen to see there was no HCV RNA in the left lobe whereas there was in the right. This case provides clear evidence that IL28B genetic variants determine interferon sensitivity in recurrent hepatitis C following liver transplantation, which could result in new strategies for donor selection or for posttransplant antiviral therapy to HCV positive recipients.     

Liver Transplantation for Hepatitis B and C Virus-Related Cirrhosis: Mid-Term Results

Hepatitis C virus (HCV) recurrence after orthotopic liver transplantation (OLT) is almost universal; cirrhosis develops in up to 30% of cases. Currently there is interest in the midterm outcomes of HCV patients with concomitant hepatitis B virus (HBV) infection among OLT recipients. We therefore retrospectively analyzed our database of patients who underwent OLT for HCV-HBV-related cirrhosis. Between April 1992 and December 2008, 350 patients underwent OLT, including 20 (5.7%) transplanted for HBV-HCV cirrhosis. We assessed patient and graft survivals at 1 and 5 years, as well as the progression of fibrosis. Protocol liver biopsies were available yearly after OLT. The survival curves were analyzed by the Kaplan-Meier approach and chronic hepatitis evaluated according to the Ishak scoring system. At a median follow-up of 68.4 ± 53 months, the 1- and 5-year patient and graft survival rates were 80% and 70%, respectively. The 5-year fibrosis progression rate was 0.17 ± 0.08 units of fibrosis. The only patient who developed histologic cirrhosis within 10 years of follow-up showed a lamivudine-resistant HBV recurrence. Patients transplanted for HBV-HCV coinfection showed a lower fibrosis progression rate compared with HCV monoinfected subjects.     

A Case Study: Refractory Recurrent Autoimmune Hepatitis Following Liver Transplantation in Two Male Patients

Autoimmune hepatitis (AIH) recurs after liver transplantation and significantly impacts graft function and patient survival. In this case report, we present 2 cases of male patients with refractory recurrent AIH after liver transplantation. Each patient lost their first graft due to refractory continuous AIH. We have not noticed a similar refractory course for our female patients with AIH post-transplantation at our center. Based on our single-center experience there appears to be a gender disparity in the aggressive nature of AIH recurrence after transplantation. Despite the aggressive nature of recurrent AIH in both patients, graft loss occurred beyond 3 years for both patients and did not influence the 1- and 3-year patient survival. If these findings are validated, they may have significant impact on post-transplantation immunosuppression management in male patients.     

Efficacy and Safety of Hepatitis B Virus Vaccination Following Hepatitis B Immunoglobulin Withdrawal After Liver Transplantation

BackgroundHepatitis B immunoglobulin (HBIG) and oral nucleoside/nucleotide analogs have been the mainstay of hepatitis B virus (HBV) prophylaxis after liver transplantation. However, long-term HBIG administration could have disadvantages, such as an increase in medical costs and the development of mutant HBV strains. This study aimed to investigate the safety and efficacy of HBV vaccination after the withdrawal of HBIG after liver transplantation.MethodsThis prospective open-label single-arm observational clinical trial enrolled 41 patients who underwent liver transplantation between 2010 and 2016 because of a condition related to chronic HBV infection. At the time of enrollment, all patients had taken entecavir and discontinued HBIG administration. When hepatitis B surface antibody titer was undetectable after the withdrawal of HBIG, a recombinant HBV vaccine was injected intramuscularly at month 0, 1, and 6.ResultsAfter excluding 5 patients who dropped out and 2 patients who had a persistent hepatitis B surface antibody titer, 9 (26.5%) of 34 patients had a positive vaccination response. The median hepatitis B surface antibody titer at seroconversion was 86 (12-1000) IU/L, and those at the end of follow-up were 216 (30-1000) IU/L. No patients experienced HBV recurrence during the study period. Sex (female, odds ratio 32.91 [1.83-592.54], P = .018) and the dosing interval of HBIG before withdrawal (≥90 days, 16.21 [1.21-217.31], P = .035) were independent contributing factors for positive response to the vaccination.ConclusionHBV vaccination still deserves consideration as active immunoprophylaxis after liver transplantation because it could provide added immunity to nucleoside/nucleotide analogs monotherapy with excellent cost-effectiveness.     

Combined Lamivudine and Hepatitis B Immunoglobulin for the Prevention of Hepatitis B Recurrence after Liver Transplantation: Long-Term Results

For the prevention of recurrent hepatitis B virus (HBV) infection after liver transplantation (LT), the efficacy of hepatitis B immunoglobulin (HBIg) has been largely demonstrated. The aim of this pilot study was to determine if the addition of lamivudine to HBIg in the prevention of HBV recurrence after LT could be more effective. Sixty HBsAg-positive/HBV DNA-negative patients underwent LT from October 1990 to December 2001. All 60 patients received intravenous HBIg to maintain serum anti-HB levels above 500 IU/L, indefinitely. Since 1997, 17 patients have received combined oral lamivudine (150 mg/day) and HBIg, and were compared with the historical cohort of 43 patients. In the historical control group, the recurrence rate was 10/43 (23%) after a 98-month median follow-up. Five patients died from HBV-related liver disease. After a 30-month median follow-up, none of the 17 patients in the combined prophylaxis group experienced HBV recurrence, and HBV DNA was undetectable by PCR in at least three serum samples per patient. HBV recurrence was significantly lower when compared with the historical control group (10/43 vs. 0/17, p < 0.01). Our results suggest that combined lamivudine and HBIg can avoid the recurrence of HBV infection in patients who are HBsAg-positive/HBV DNA negative before LT.     

乙型肝炎患者肝移植术后乙型肝炎复发的预防

目的 探索乙型肝炎DNA阳性的终末期肝病患者肝移植前快速转阴及肝移植术后复发的防治。方法 4例乙型肝炎两对半小三阳、HBV-DNA(-)的患者术前开始联合口服拉米夫定(1amivudine)及泛昔洛韦．术后3个月内治疗同前，3个月后仅口服拉米夫定维持至今；2例乙型肝炎两对半大三阳、HBV-DNA( )的患者,术前除口服拉米夫定及泛昔洛韦外，同时肌注乙肝免疫球蛋白共14d，肝移植术中无肝期快速静脉滴注15000u静脉用乙肝免疫球蛋白，术后3个月内联合口服拉米夫定及泛昔洛韦，术后3个月内治疗同前，3个月后仅口服拉米夫定维持至今。结果 1例患者术后第19天死于肺部霉菌感染,1例患者第49天死于肝动脉及门静脉栓塞；4例患者长期存活，生存时间最长的患者已接近3年，术后全部患者均未发现有乙型肝炎复发。结论 拉米夫定、乙肝免疫球蛋白及泛昔洛韦联合使用可使乙型肝炎DNA阳性的终末期肝病患者在肝移植前快速转阴，并能预防乙肝复发。     

肝移植术后乙肝复发的预防和治疗

目的 探讨乙肝相关疾病患者肝移植术后乙型肝炎病毒(HBV)再感染的防治。方法 复习有关文献并进行综述。结果 与HBV有关的急、慢性肝病是肝移植的主要适应证，但未作预防者移植后HBV再感染率可达80％～100％，对移植肝的存活和患者的生存有重大的影响。如何防治肝移植后乙型肝炎的复发，成为急需解决的问题。经过一系列的摸索，目前已有许多用于防治HBV再感染的药物，包括抗乙肝免疫球蛋白、干扰素、核苷类似物等，其各自有不同的应用特点，在单独及联合用药方面也有了新的研究进展。结论 肝移植是治疗乙肝相关疾病的有效方法，围手术期的积极药物治疗，对提高乙肝相关疾病患者肝移植的成功率至关重要。