Low-dose intramuscular hepatitis B immune globulin and lamivudine for long-term prophylaxis of hepatitis B recurrence after liver transplantation

The combination of lamivudine and hepatitis B immunoglobulins (HBIg) to prevent recurrence of HBV hepatitis has significantly improved the survival of patients transplanted for HBV-related end-stage liver disease. Generally, HBIg are administered intravenously. We evaluated the efficacy, tolerability, and cost savings of long-term intramuscular HBIg and lamivudine in 28 patients (23 men and 5 women), who received liver transplants for acute or chronic HBV-related liver disease. Twelve patients started lamivudine before and 16 at the time of liver transplantation. HBIg were administered intravenously during the first week (50 to 70,000 IU) and intramuscularly thereafter (1200 IU every 3 to 6 weeks) to maintain an HbsAb titer >100 IU/L. Mean follow-up was 20 +/- 13 months. Only one patient experienced HBV recurrence (9 months after transplantation). This patient had failed to follow the scheduled prophylaxis. Cumulative survival at 3 years was 83%. Intramuscular HBIg were well tolerated in all cases. Cost analysis comparing intramuscular vs intravenous HBIg administration showed that 39,490 Euros were saved per patient per year. These preliminary results show that low-dose intramuscular HBIg and lamivudine are efficacious and cost-effective for long-term prophylaxis of hepatitis B recurrence after liver transplantation.     

Short-term high-dose followed by long-term low-dose hepatitis B immunoglobulin and lamivudine therapy prevented recurrent hepatitis B after liver transplantation

Hepatitis B immunoglobulin (HBIg) and lamivudine combination has been accepted as the best way to control hepatitis B recurrence after liver transplantation. However, the optimal dose of HBIg and the target titer of hepatitis B surface antibody (HBsAb) remain unclear. We report our satisfactory experience with high-dose HBIg in the early period followed by low-dose HBIg with lamivudine. Subjects comprised five patients with fulminant hepatitis (FH) and 18 patients with liver cirrhosis (LC) who underwent liver transplantation. HBIg at a dosage of 200 IU/kg per day was administered for one week postoperatively. Thereafter, HBIg was administered only for HBsAb titer <100 IU/L. After six months, HBIg was withdrawn in FH and administered in LC only for HBsAb titer <10 IU/L. Lamivudine was administered to two FH and all LC cases. Although two patients with LC showed transient hepatitis B surface antigen (HBsAg) recurrence, all patients remained HBsAg-negative at the final follow-up date. This method allows reliable and cost-effective control of hepatitis B recurrence.     

Lamivudine or lamivudine combined with hepatitis B immunoglobulin in prophylaxis of hepatitis B recurrence after liver transplantation: a meta-analysis

There is a controversy over whether the different outcomes of prophylaxis of hepatitis B virus (HBV) recurrence are attributable to different treatments. A systematic review and a meta-analysis were conducted to evaluate lamivudine monotherapy and combined therapy of lamivudine and hepatitis B immunoglobulin (HBIG) in HBV infected liver recipients. A fixed effects model was used for statistical pooling of relative risks (RR) for the different outcomes. Six articles (551 patients) fulfilled the inclusion criteria. Statistically significant differences were observed between lamivudine monotherapy and lamivudine + HBIG therapy in hepatitis B recurrence [ P  < 0.0001; RR = 0.38; 95% CI (0.25, 0.58)], YMDD mutant [ P  = 0.002; RR = 0.40; 95% CI (0.23, 0.72)] and hepatitis B recurrence in HBV-DNA positive patients before orthotopic liver transplantation [ P  < 0.00001; RR = 0.31; 95% CI (0.21, 0.45)]. No significant differences were observed in patient survival [ P  = 0.59; RR = 1.02; 95% CI (0.95, 1.09)], graft survival [ P  = 0.56; RR = 1.02; 95% CI (0.95, 1.09)] and diseases leading to death between the two groups [HBV recurrence leading to death: P  = 0.05; RR = 0.47; 95% CI (0.22, 1.02); hepatocellular carcinoma recurrence leading to death: P  = 0.13; RR = 0.34; 95% CI (0.09, 1.36)]. In conclusion, combination of lamivudine and HBIG can effectively decrease the recurrence rate of HBV and the incidence of YMDD mutant, but it can not improve patient survival and graft survival significantly. Well-designed large-sample trials are needed to evaluate the efficiency of combined therapy of lamivudine and HBIG in prophylaxis of HBV recurrence in liver graft recipients.     

拉米夫定预防肝移植术后乙型肝炎病毒再感染的研究

目的 探讨和评价拉米夫定预防原位肝移植术后乙型肝炎病毒（HBV）再感染的效果。方法 41例患者，术前诊断为肝炎后肝硬化（失代偿期）者22例，慢性重型肝炎并肝炎后肝硬化（失代偿期）者12例，慢性重型肝炎者7例，其中HBVDNA阳性16例。41例患者均采用背驮式原位肝移植，术前15例给予拉米夫定治疗，术后41例患者均服用拉米夫定。结果 10例患者术后出现HBV再感染，其中9例为YMDD变异毒株感染，术后1、2年的HBV再感染率分别为9．8％（4／41）、24．4％（10／41）。术前血清HBVDNA阴性者术后HBV再感染率（12．0％，3／25）明显低于HBVDNA阳性者（43．8％，7／16）。术前长期服用（超过6个月）拉米夫定者和未服用拉米夫定者术后HBV再感染率分别为66．7％、23．1％，均明显高于术前短期（未超过6个月）服用拉米夫定者（0，P〈0．05）。结论 术前服用拉米夫定可降低乙型肝炎患者肝移植后HBV再感染率，但服药时间不宜超过6个月；长期、单一的应用拉米夫定易导致病毒变异而出现耐药毒株感染。     

Prevention of hepatitis B recurrence after liver transplantation using lamivudine or lamivudine combined with hepatitis B Immunoglobulin prophylaxis.

The aim of our study was to determine the outcomes of liver transplant recipients receiving either lamivudine (LAM) monotherapy or LAM combined with low-dose intramuscular (IM) hepatitis B Immunoglobulin (HBIG) therapy. We performed a retrospective review of the medical records of patients that had had liver transplantation in a single center for HBV-related liver diseases from December 1999 to June 2004. A total of 165 patients received LAM monotherapy (51 patients) or combined prophylaxis (114 patients) post-liver transplantation (LT) with a mean follow-up of 20.13 months. Hepatitis B relapsed in 21 patients of the hepatitis B surface antigen (HBsAg) carriers who received LAM monotherapy, with a 1- and 2-yr actuarial risk of 27.4% and 39.7%. Recurrence occurred in 16 patients of 114 patients receiving the combined prophylaxis, with a 1- and 2-yr recurrence rate of 13.5% and 15.2% (P = 0.024). A total of 25 cases (67.6%) with YMDD mutants were detected in all the 37 patients, 14 cases (66.7%) in the monotherapy group and 11 cases (68.8%) in the combination group. In conclusion, LAM and low-dose intramuscular HBIG treatment demonstrates a better result than LAM monotherapy, as prophylaxis against post-LT reinfection of the graft, but the safety and efficacy as a substitution for high-dose intravenous HBIG with LAM needs to be investigated further.     

乙肝相关性终末期肝病肝移植后乙肝复发的防治

目的探讨乙肝相关性终末期肝病肝移植术后乙肝病毒再感染的防治。方法回顾性分析我院1999年10月到2007年10月肝移植109例乙肝相关性终末期肝病患者,移植后给予抗病毒预防乙型肝炎病毒再感染,拉米夫定治疗组50例、拉米夫定和乙肝免疫球蛋白（乙肝免疫球蛋白）联合治疗组59例,观察临床表现,血清HbsAg、血清HbeAg、血清HBVDNA及必要时肝穿刺免疫组织化学检测HbsAg等指标。结果109例接受了3个月一8年的抗病毒治疗随访。①拉米夫定治疗组50例,10例复发,复发率为20％,复发病例中2例分别于术后5个月、8个月死于乙肝复发爆发性肝炎;余8例给予阿德夫韦和乙肝免疫球蛋白后,肝功能好转,目前在随访中。②拉米夫定和乙肝免疫球蛋白联合治疗59例,2例复发,给予调整免疫抑制药后,肝功能好转。两组比较差异有统计学意义（χ^2=7．622,P〈0．05）。结论用拉米夫定和乙肝免疫球蛋白联合应用可以有效预防肝移植后乙型肝炎病毒的再感染。     

European hepatitis B immunoglobulin trials: prevention of recurrent hepatitis B after liver transplantation

Orthotopic liver transplantation is used for treatment of liver cirrhosis and organ failure due to chronic hepatitis B infection. However, in the absence of effective antiviral therapy, patients can develop recurrent hepatitis B leading to graft failure. In this report, a review is presented of several European studies that have demonstrated the efficacy of hepatitis B immunoglobulin (HBIg) in lowering the rate of recurrence or the severity of the recurrent infection. Clinical protocols and results of these studies are described in detail. Several important conclusions can be derived from the clinical results. HBIg is most effective when administered in high doses for a long time. Characteristics of the recipients, such as the presence or absence of viral DNA, can also affect the rate of recurrence. Intramuscular injection of HBIg has minimal side effects and results in reduced cost relative to intravenous injection.     

Intramuscular hepatitis B immune globulin combined with lamivudine for prophylaxis against hepatitis B recurrence after liver transplantation.

Immunoprophylaxis using intravenous (IV) hepatitis B immune globulin (HBIG) decreases the recurrence of hepatitis B virus (HBV) infection after orthotopic liver transplantation (OLT). However, IV HBIG is expensive, has significant side effects, and is inconvenient to administer. An alternative approach for prophylaxis using intramuscular (IM) HBIG and oral lamivudine was prospectively evaluated in this study. Ten consecutive patients with cirrhosis with HBV infection who underwent OLT were included in this study. Nine of 10 patients received lamivudine, 150 mg/d, for an average duration of 8.6 months before OLT. Two of 10 patients with detectable HBV DNA at the time of OLT received 10,000 U (45 mL) of IV HBIG daily for 7 consecutive days, followed by 5 mL of IM HBIG weekly for the next 3 weeks, then every 3 weeks. The other 8 patients were HBV DNA negative at OLT and received one dose of IV HBIG (45 mL) during surgery, followed by 5 mL of IM HBIG weekly for 4 weeks, then every 3 weeks. All patients received lamivudine, 150 mg/d, after OLT. During a mean follow-up of 15.6 months, 9 of 10 patients achieved a protective hepatitis B surface antibody (HBsAb) titer greater than 200 IU/L and had no evidence of HBV recurrence. One patient failed to develop an adequate HBsAb titer and developed histological and virological evidence of recurrence. One patient died unrelated to HBV recurrence. Our preliminary data suggest that this combination prophylaxis with IM HBIG and lamivudine is effective and potentially cost saving.     

Cost-effective and safe ambulatory long-term immunoprophylaxis with intramuscular instead of intravenous hepatitis B immunoglobulin to prevent reinfection after orthotopic liver transplantation

BACKGROUND: Hepatitis B (HBV)-infected patients receive an anti-HBs immunoprophylaxis [hepatitis B immunoglobulin (HBIG) titre of more than 100 IU/L] in combination with lamivudine to prevent reinfection after orthotopic liver transplantation (OLT). In comparison with intramuscular (i.m.) HBIG, costs for intravenous (i.v.) HBIG are found to be extremely high. We therefore studied patients' outcome (i) after a switch from i.v. to i.m. HBIG and (ii) the outcome after the patients were initially treated with i.m. HBIG after discharge from the hospital. METHODS: (i) Six outpatients were switched from 2000 IU i.v. HBIG (Hepatect) administered every 2 wk to 2000 IU i.m. HBIG (Hepatitis-B-Immunoglobulin Behring) given once a month. (ii) Six other outpatients were directly treated with i.m. HBIG every 4 wk after OLT. All patients also received 100 mg lamivudine/d. RESULTS: Patients switched from i.v. to i.m. HBIG had stable anti-HBs titres (i.v. HBIG: 180 +/- 37 IU/L vs. i.m. HBIG: 173 +/- 23 IU/L). Patients directly treated with i.m. HBIG also had sufficient anti-HBs titres (176 +/- 31 IU/L). Intramuscular application of HBIG was well tolerated by all patients and no side-effects were observed in patients receiving i.m. HBIG. In comparison with the protocol using i.v. HBIG, the costs of i.m. treatment were 60% lower. CONCLUSION: Long-term administration of i.m. HBIG saves up to 60% of the usual costs for i.v. prophylaxis of HBV reinfection in patients after OLT. In combination with lamivudine, long-term i.m. HBIG therapy is as efficient as i.v. HBIG treatment, but its lower costs clearly favour its use in preventing HBV reinfection after OLT.     

Long‐term outcome of patients with lamivudine after early cessation of hepatitis B immunoglobulin for prevention of recurrent hepatitis B following liver transplantation

Yuefeng M, Weili F, Wengxiang T, Ligang X, Guiling L, Hongwei G, Wencai L, Xiaoguang W, Wei M, Zhongyi F. Long‐term outcome of patients with lamivudine after early cessation of hepatitis B immunoglobulin for prevention of recurrent hepatitis B following liver transplantation.
Clin Transplant 2011: 25: 517–522. © 2010 John Wiley & Sons A/S. Abstract: Background: The aim of this study is to examine the efficacy of long‐term prophylaxis with lamivudine (LAM) after a course of post‐operative hepatitis B immunoglobulin (HBIG) in patients who underwent liver transplantation (LT) for hepatitis B virus (HBV)‐related disease. Result: The medical records of HBV‐infected patients who underwent a LT in our institution between July 2001 and May 2005 were reviewed. There were 15 liver transplant recipients who were administered HBIG for <18 months and used LAM as a maintenance prophylaxis regime enrolled in this study. At enrollment, all patients were hepatitis B surface antigen (HBsAg) positive and three patients were HBeAg positive. There were 13 patients who were HBV DNA positive with a mean viral load of 5.4 log copies/mL, and among them, 12 recipients were on antiviral therapy with LAM (100 mg/d orally) for 12–168 d, resulting in HBV DNA negative levels in nine patients prior to their transplant. HBV recurrence post‐LT was noted in two patients who had very high‐HBV DNA levels pre‐LT. Both of these patients showed LAM‐resistant mutation at the time of recurrence. The 11 patients who were HBV DNA negative before LT (low‐risk patients) had no HBV recurrence during a follow‐up at a median of 58 months post‐LT. This included five patients who had intermittent low‐level HBV DNA post‐LT (HBsAg negative), of whom two had YMDD mutation and these two were given adefovir in addition to LAM. Conclusion: Our retrospective study demonstrated excellent long‐term outcomes in the low‐risk patients treated with LAM after a short course of HBIG.     

阿德福韦在预防肝移植后乙肝复发中的作用

目的评价adefovir在预防肝移植后乙肝复发中的应用效果及安全性.方法统计30例应用lamivudine出现耐药及病毒变异的肝移植病例加用adefovir后病人：ALT、HBV-DNA、Cr以及HBeAg的变化,以及观察adefovir的副作用.结果应用adefovir12周后,ALT恢复正常者占65.5%,HBVDNA转阴（＜10^4拷贝/ml）占76.7%,HBeAg转阴44%,未发现严重的肾功能异常及其它副作用.结论肝移植术后应用lamivudine出现耐药及病毒变异病例,及时加用adefovir可有效改善肝功能、抑制肝炎复发.     

Prophylactic use of low-dose, on-demand, intramuscular hepatitis B immunoglobulin and lamivudine after liver transplantation

The combination of hepatitis B immunoglobulin (HBIG) and antivirals (nucleos[t]ide analogs) has extended the applicability of orthotopic liver transplantation (OLT) for patients with hepatitis B virus (HBV)-related liver disease. However, HBIG administrations have an extremely high cost. Herein, we evaluated our results with low-dose, on-demand, intramuscular HBIG plus lamivudine (LAM) prophylaxis after OLT. The HBV DNA status in 40 patients at the time of OLT determined the treatment: group A (n = 22), HBV DNA (-), no antiviral pretreatment; group B (n = 11), HBV DNA (-), after LAM; group C (n = 3), HBV DNA (+) after LAM (LAM resistance/Adefovir [ADV] unavailable); group D (n = 2), HBV DNA (+), no antiviral pretreatment; and group E (n = 2), HBV DNA (-) after LAM + ADV (LAM resistance/ADV available). Five patients died within 12 months after OLT unrelated to HBV infection. The remaining 35 patients were followed for a median duration of 16 months (range, 6-93 months). Only two recipients from group C, who were transplanted despite LAM resistance + no ADV pretreatment, revealed recurrent HBV infections at 14 and 16 months posttransplantation; they were then treated successfully with ADV as it became available. The third group C recipient had undetectable HBV DNA at 18 months after OLT. The mean cumulative doses of HBIG administered within the first, second, and third years were 34,014, 5258, and 5090 IU, respectively. In conclusion, low-dose, on-demand, intramuscular HBIG plus (LAM +/- ADV) prophylaxis is a safe, efficient, and cost-effective regimen to prevent recurrent HBV infection following OLT. OLT despite untreated LAM resistance may require sustained higher serum HBsAb levels after surgery.     

肝移植术后乙肝复发预防策略

移植是目前治疗肝炎肝硬化终末期的有效手段,但术后乙肝复发或再感染是导致移植肝失功的主要原因,严重影响移植病人的预后.因此,预防乙肝复发是肝移植整体工作的一项重要环节.现结合昆明医学院第一附属医院器官移植中心50例病例进行分析总结.     

肝移植后乙型肝炎的复发和防治

目的 探讨乙型肝炎所致肝硬变患者施行原位肝移植后乙型肝炎复发的影响因素、临床诊断和治疗方案。方法 ２例乙型肝炎后肝硬变晚期患者在原位肝移植前后接受了基本相同的抗乙型肝炎病毒（ＨＢＶ）治疗。结果 １例术前乙型肝炎病毒表面抗原（ＨＢｓＡｇ）、ｅ抗原（ＨＢｅＡｇ）和ＨＢＶ ＤＮＡ均阳性的患者,术后２个月时乙型肝炎复发,死于乙型肝炎复发所致的肝、肾功能衰竭;另１例仅ＨＢｓＡｇ和ＨＢｅＡｇ阳性的患者术后已存     

Comparison of famciclovir and lamivudine in the long-term treatment of hepatitis B infection after liver transplantation

BACKGROUND: Preliminary results of short-term famciclovir and lamivudine therapy in patients with hepatitis B virus (HBV) infection after liver transplantation revealed promising results. In a retrospective study the efficacy of long-term treatment with these substances was compared. METHODS: A total of 53 HBV-infected adults (48 reinfections and 7 de novo infections) received antiviral treatment. A total of 32 of these patients were treated with famciclovir 3x500 mg, 20 of them were later switched to lamivudine. Fourteen patients received lamivudine, 150 mg/day orally, as first line therapy and 7 patients after failure of famciclovir-prophylaxis. Follow-up time was 8 to 62 months (mean 35 months). Response to therapy (HBV-DNA negative) was compared using Kaplan-Meier estimates. Potential influence factors (HBV-DNA and HBeAg pretransplant, HDV coinfection, pretreatment with famciclovir and immunosuppression) on treatment response were analyzed by log. Rank test (univariate); then a multivariate analysis (Cox multiple stepwise regression model) was applied. RESULTS: A total of 19 and 76% of the patients treated with famciclovir and lamivudine resp. became HBV-DNA negative; 0 and 24% HBsAg negative. Lamivudine was also effective as second line therapy. In a multivariate analysis of all 73 treatment courses, lamivudine treatment and HDV-coinfection were significant factors for better treatment response; regarding only the lamivudine group, negative HBeAg pretransplant was significant. Viral breakthrough after prolonged treatment occurred in 55% (lamivudine) to 80% (famciclovir) of treatment courses but was only accompanied by mild hepatitis. CONCLUSIONS: Lamivudine and famciclovir are potent drugs for the treatment of HBV-infection after liver transplantation. The antiviral capacity of lamivudine is superior even after pretreatment with famciclovir but after prolonged treatment viral breakthrough is often observed.