Additional interferon alpha for lamivudine resistant hepatitis B infection after liver transplantation: a preliminary report

Resistance formation is a major problem in antiviral treatment of hepatitis B recurrence after liver transplantation. One possible therapeutic approach is an antiviral combination therapy with synergistic drugs. Four patients who were transplanted for chronic hepatitis B were analyzed retrospectively. All patients had reinfection of the graft and breakthrough of hepatitis B virus (HBV) during consecutive famciclovir and lamivudine monotherapy. Subsequently a combination therapy of lamivudine and interferon alpha 2a (3 times 3 million units weekly) was initiated. Addition of interferon markedly reduced viral replication rate in all patients. Three patients became HBV-DNA negative despite lamivudine resistance, but only two had a sustained response. No patient seroconverted to anti-HBe or lost HBsAg, but all patients showed a normalization of alanine aminotransferase and aspartate aminotransferase levels. No severe complications, and especially no rejection episodes occurred. Therefore lamivudine combined with interferon might be used for the therapy of hepatitis B reinfection after liver transplantation.     

Preoperative antiviral treatment and postoperative prophylaxis in HBV-DNA positive patients undergoing liver transplantation.

BACKGROUND: Despite passive immunoprophylaxis a significant number of patients, especially if hepatitis B virus (HBV) DNA is positive prior to transplantation, develop HBV recurrence. This number might be reduced by lowering viral replication pretransplant with antiviral agents and by postoperative combination of antiviral agents and passive immunoprophylaxis. PATIENTS AND METHODS: A total of 74 HBV-DNA positive patients who underwent liver transplantation between 9/88 and 4/00 were analyzed retrospectively. Before lamivudine or famciclovir were available, in total 40 patients did not receive any preoperative antiviral therapy. Since 11/93, 17 patients were treated with famciclovir 1500 mg daily, after 4/96 17 patients with lamivudine 150 mg daily prior liver transplantation. Posttransplant all patients received passive immunoprophylaxis aiming at a titer of more than 100 U/liter. In the 34 patients with preoperative antiviral therapy an additional prophylaxis with the respective antiviral agent was applied. RESULTS: Under preoperative famciclovir and lamivudine 30 and 71% of patients became HBV-DNA negative, respectively. Actuarial reinfection rate 2 years after liver transplantation was 48% without antiviral prophylaxis, which was not statistically different from 55% under perioperative famciclovir therapy. In contrast only 18% developed HBV recurrence under perioperative lamivudine treatment. During both antiviral regimens neither pre nor posttransplant severe side effects were observed. CONCLUSION: Perioperative application of famciclovir is not recommendable, whereas lamivudine seems to lower recurrence rates significantly. Whether the observed effect is due to pre- or postoperative application remains to be addressed in further studies. In addition the long-term course has to be awaited.     

Seroconversion after the addition of famciclovir therapy in a child with hepatitis B virus infection after liver transplantation who developed lamivudine resistance

There is very little information about hepatitis B virus (HBV) infection in children after liver transplantation. This is the first report of the addition of famciclovir in a child who developed lamivudine resistance.A 5-year-old boy who was serum HBsAg-negative and was not vaccinated against HBV underwent living-related liver transplantation for fulminant hepatitis A. The donor was his mother, who was serum HBcAb-positive. No immunoprophylaxis was administered. HBV infection developed after 18 months and was treated with 3 mg/kg daily of lamivudine. Serum alanine aminotransferase normalized and HBV DNA load decreased significantly. Sixteen months later, lamivudine resistance developed; a mutation (M552I) was confirmed by sequencing through the YMDD locus of the HBV polymerase gene. The addition of 750 mg daily of famciclovir led to seroconversion and the disappearance of serum HBV DNA.Lamivudine in combination with famciclovir might be a therapeutic option for HBV reinfection after liver transplantation, also in children. Suppression of viral replication to undetectable values is possible even in the lamivudine-resistant mutant.     

Lamivudine as first- and second-line treatment of hepatitis B infection after liver transplantation

Lamivudine and famciclovir have expanded therapeutical options for HBV infection after liver transplantation. First studies confirm good antiviral effects of both, but at present the major problem seems to be a rapid resistance formation in immunosuppressed patients. Thirty-four adult patients with HBV recurrence despite passive immunoprophylaxis and seven with de novo infection after orthotopic liver transplantation (OLT) were treated with 100–150 mg lamivudine daily. Patients were either treated directly after infection (n = 14) or after breakthrough of viral replication during an initial famciclovir therapy (n = 27). All patients except two responded to treatment with a reduction of serum HBV-DNA of over 50 %. Thirty-one patients (76 %) turned HBV-DNA-negative during lamivudine therapy. Viral breakthrough was observed in 14 of these patients after 4–13 months of treatment. A total of17 patients (40 %) remained HBV-DNA-negative for more than 12 months. Only nine patients eliminated HBsAg, of which four had and an HDV coinfection. None of the HBeAg-positive patients converted to anti-HBe. Most patients showed a prompt and significant reduction of aspartate aminotransferase (ALAT) levels. No severe complications occurred. Therefore, a safe and effective therapy of HBV infection after transplantation is possible with lamivudine. Viral replication is suppressed even in patients who revealed breakthrough during famciclovir therapy. Resistance formation as a major drawback occurred in one third of the patients within the first year of treatment. Received: 5 May 1999 Revised: 16 December 1999 Accepted: 26 April 2000     

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.     

肝移植患者乙型肝炎病毒再感染的防治

目的 预防和早期诊断肝移植患者术后乙型肝炎病毒（ＨＢＶ）再感染和乙型肝炎（乙肝）的复发,以及探讨肝炎复发后的进一步治疗。方法 肝移植患者术后常规采用拉米夫定预防ＨＢＶ再感染,同时监测肝功能、乙型肝炎血清标记物、血清ＨＢＶ－ＤＮＡ、肝活检组织乙型肝炎标记物免疫组化。结果 ４例患者出现ＨＢＶ再感染,其中２例表现为复发的乙型肝炎,经治疗后,２例复发的乙肝患者１例继续发展成为慢必 症肝炎,１例好转。结论     

Lamivudine for hepatitis B in liver transplantation: a single-center experience

BACKGROUND: Liver transplantation for hepatitis B virus (HBV) has been associated with a high rate of reinfection and graft failure. Lamivudine, a potent inhibitor of HBV replication, has been shown to prevent viral recurrence after transplantation. METHODS: The effectiveness of lamivudine monotherapy for the management of HBV recurrence after liver transplantation was assessed. Lamivudine was used in three patient groups: (1) patients started before transplantation and continued after transplantation (n = 13); (2) patients treated after transplantation (n = 15); and (3) patients with de novo hepatitis B after transplantation (n = 4). RESULTS: Median follow-up on lamivudine was 24 months. Active viral replication (HBV-DNA+) was seen in 17 (53%) of 32 at treatment initiation. All lost HBV-DNA at a mean of 2.4+/-1.6 months after lamivudine initiation. Twenty-six (81%) patients remain free of viral recurrence. Six (19%) patients have evidence of breakthrough infection with the YMDD mutant of HBV, two of whom progressed to graft failure. All four patients in group 1 who developed breakthrough had evidence of hepatitis B surface antigen expression in the explanted liver by immunohistochemistry despite being serum HBV-DNA negative before transplantation. No difference was observed among the three groups in DNA clearance or breakthrough rates. CONCLUSIONS: Lamivudine achieves viral DNA clearance in almost all patients. Expression of viral antigens in the liver seems to identify patients at risk of developing HBV-DNA recurrence. Disease-free survival of 81% at 22 months is similar to data with hepatitis B immunoglobulin therapy. Given the safe clinical profile and high efficacy in the prevention of disease recurrence, lamivudine will favorably change the outlook of liver transplantation for HBV.     

Management of hepatitis B virus infection in liver transplant recipients: prospects and challenges

Although survival of liver transplantation for patients with hepatitis B infection is comparable to uninfected transplant recipients, prevention of hepatitis B virus (HBV) reinfection remains an important goal. In this article, several aspects of the hepatitis B reinfection and its management will be examined. Approximately 50% of the treatment failures that occur with hepatitis B immune globulin (HBIg) prophylaxis are due to mutations in the 'a' determinant of the HBV. In patients without mutations, failure of HBIg therapy may relate to the frequency and dose of HBIg, the type and amount of immunosuppression, and the pre-transplant replication status. Antiviral therapy with lamivudine and famciclovir has been used successfully to treat patients who have failed HBIg treatment and as monotherapies for liver transplant recipients. Combining antiviral and immunomodulatory therapies appears efficacious, at least in the short term. New developments related to immunotherapy predict three potential trends in future use: 1) i.v. formulated HBIg, 2) monoclonal antibodies, or 3) hepatitis B immune plasma. In conclusion, there are an increasing number of therapeutic options for the management of patients undergoing liver transplantation for hepatitis B infection. Continued improvement in patient outcomes requires further understanding of each therapeutic agent and the specific patient characteristics that may influence efficacy.     

Disappearance of hepatitis B virus core deletion mutants and successful combined kidney/liver transplantation in a patient treated with lamivudine

Hepatitis B virus (HBV) core deletion variants with enhanced viral replication are associated with rapid deterioration of liver function in renal allograft recipients. Antiviral agents such as famciclovir and lamivudine offer new treatment strategies for these patients. Appearance, accumulation and persistence of HBV core deletion mutants were closely monitored in a kidney transplant recipient with liver cirrhosis before and after initiation of antiviral treatment. Under treatment with famciclovir HBV DNA concentration decreased by 50 %, HBV mutants persisted. After replacement of famciclovir by lamivudine HBV replication was reduced below the detection limit. Lamivudine was well tolerated and liver function improved. After successful combined kidney/liver transplantation the patient became HBsAg and HBV DNA (detected by PCR) negative under continuous hyperimmune globulin and lamivudine treatment. Antiviral therapy with lamivudine may be useful in treatment of progressive liver disease associated with HBV core deletion mutants in renal allograft recipients and may enable successful liver transplantation. Received: 12 June 1998 Received after revision: 16 October 1998 Accepted: 10 November 1998     

121例重型乙型肝炎肝移植术后乙型肝炎病毒再感染的防治

目的 探讨重型乙型肝炎肝移植术后乙型肝炎病毒(hepatitis B virus,HBV)再感染的防治.方法 回顾性分析了121例重型乙型肝炎患者,移植前后给予抗病毒药物预防乙型肝炎病毒再感染,拉米夫定 乙肝免疫球蛋白(HBIg)114例,阿德福韦 拉米夫定 HBIg 4例,恩替卡韦 HBIg 3例,观察临床症状、血清HBsAg、血清HBeAg、血清HBV DNA及肝活检免疫组织化学检测等指标.结果 用拉米夫定 HBIg预防的114例患者中,有4例出现再感染,表现为血清HBsAg阳性,肝活检免疫组织化学检测有HBsAg表达,其中3例经治疗后HBsAg转阴.用阿德福韦 拉米夫定 HBIg或恩替卡韦 HBIg预防的7例中,血清学和肝活检免疫组织化学检测均无HBsAg表达.结论 拉米夫定 HBIg、拉米夫定 阿德福韦 HBIg或恩替卡韦 HBIg的联合应用以及合理使用免疫抑制剂可以有效预防重型乙型肝炎患者移植术后乙型肝炎病毒的再感染.     

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。     

肝移植术后预防乙型肝炎病毒再感染的策略

目的探讨预防肝移植术后乙型肝炎病毒（HBV）再感染的综合策略.方法对术前存在HBV感染的130例肝移植患者进行前瞻性研究,采用肌肉注射剂型乙型肝炎免疫球蛋白（IMHBIg）联合口服拉米夫定（lamivudine）作为预防术后HBV再感染的治疗方案;术后监测HBV再感染的情况.结果在130例患者中,128例术后HBsAg转为阴性,检测血清HBsAb呈阳性.平均随访12.2个月,8例出现HBV再感染,再感染率为6.3%;术前HBeAg阳性者再感染率为14.3%,阴性者4.0%,两组间差异有统计学意义（P＜0.05）;术后第一天HBsAg阳性者再感染率为21.1%,阴性者3.7%,两组间差异有统计学意义（P＜0.05）.结论拉米夫定联合肌肉注射剂型的人乙型肝炎免疫球蛋白可有效预防肝移植术后HBV再感染;术前血清HBeAg阳性以及术后第一天HBsAg者是术后HBV复发的高危因素.     

重型乙型肝炎肝移植术后乙型肝炎病毒再感染的防治

目的探讨重型乙型肝炎肝移植术后乙型肝炎病毒(HBV)再感染的防治。方法回顾性分析了73例重型乙型肝炎患者,移植前后给予抗病毒药物预防乙型肝炎病毒再感染,拉米夫定 乙肝免疫球蛋白(HBIG)71例,阿德夫韦 拉米夫定 乙肝免疫球蛋白2例,观察临床表现、血清HBSAg、血清HBeAg、血清HBV DNA及肝活检免疫组织化学检测等指标。结果应用拉米夫定 HBIG预防的71例中,有2例再感染,血清HBSAg为阳性,肝活检免疫组织化学检测有HBSAg表达,其中1例血清HBV DNA阳性,另1例经治疗后HBSAg又转阴。用阿德夫韦 拉米夫定 HBIG预防的2例中,血清学和肝活检免疫组织化学检测均无HBSAg表达。结论拉米夫定 HBIG或拉米夫定 阿德夫韦 HBIG联合应用以及合理的使用免疫抑制剂可以有效预防重型乙型肝炎患者移植术后乙型肝炎病毒的再感染。     

Treatment of hepatitis B reinfection after liver transplantation

Patients with chronic replicative hepatitis B virus (HBV) infection who undergo orthotopic liver transplantation (OLT) in the absence of prophylactic antiviral therapy have a high risk of graft reinfection. Serial monitoring of serum HBV DNA and HBV sequence analysis, especially of the polymerase and the "a" epitope of the surface antigen, may be a requisite diagnostic tool in order to provide optimal therapeutic management for inhibition of viral replication before and after OLT. Combination therapy with hepatitis B immunoglobulin (HBIG) and lamivudine has been widely adopted as an effective prophylactic treatment regimen against recurrent HBV disease. The major issue of concern has been the development of lamivudine resistance due to the emergence of mutations in the YMDD motif of the HBV DNA polymerase gene. Among newer antivirals, adefovir dipivoxil and entecavir have been demonstrated to be effective against both wild-type and lamivudine resistant mutants. Due to the availability of antiviral drugs, outcome of patient and graft survival has dramatically improved and has become similar or even better as compared to patients with non-HBV-related liver diseases.     

Prevention of hepatitis B virus reinfection after orthotopic liver transplantation

OBJECTIVE: We discuss the prevention of hepatitis B virus reinfection following orthotopic liver transplantation. METHODS: Sixty-eight cases of chronic fulminant hepatitis B, the end stage of liver cirrhosis and liver carcinoma complicated with HBV cirrhosis, were given antiviral drugs pre- and posttransplantation to prevent hepatitis B virus reinfection. Lamivudine was administered to two cases and lamivudine + HBIG to 63 cases. Adefovir + HBIG was administered to three cases. The serum HBV, HBV DNA, liver biopsy immunohistochemistry and clinical examinations were performed. RESULTS: One of two cases given lamivudine developed reinfection with serum HBSAg, HbeAb, HBcAb, HBV DNA, and positive and liver biopsy immunohistochemistry showing HBSAg phenotype. Two of the 63 cases given lamivudine + HBIG developed reinfection with serum HBSAg, HBeAb, HBcAb positive and liver biopsy immunohistochemistry showing HBSAg phenotype. The serum HBV DNA was positive in one of the two cases. Three cases given adefovir developed no reinfection with HBV. CONCLUSION: Orthotopic liver transplantation is an effective treatment for HBV infection; lamivudine + HBIG or adefovir + HBIG prevent hepatitis B virus reinfection.     

Five-year follow-up of a hepatitis B virus-positive recipient of hepatitis B surface antigen-positive living donor liver graft.

The shortage of cadaveric donor organs has led to the use of living donors and marginal cadaveric donors. To date, there have been only 2 reports on the use of hepatitis B surface antigen (HBsAg)-positive liver grafts. Here we describe the 5-yr posttransplantation sequence of a hepatitis B virus (HBV)-positive recipient who received an HBsAg-positive living donor liver graft. A 43-yr-old HBV-positive patient with hepatorenal syndrome received a living donor liver graft in October 2000 from a 27-yr-old HBsAg-positive carrier with no clinical evidence of HBV infection other than the serologic markers. The recipient recovered slowly after liver transplantation (LT). Recipient serum HBsAg was continuously positive despite anti-HBV therapy with high-dose hepatitis B immunoglobulin (HBIG) and lamivudine. The patient was also treated with famciclovir and interferon; to date, a final regimen of lamivudine and adefovir has kept liver function stable for 20 months. The recipient has lived for 64 months after transplantation. The donor has not revealed any clinical evidence of active hepatitis during follow-up. In conclusion, our result implicates that a recipient of liver graft from an HBsAg-positive carrier may survive for a long period following antiviral therapy with lamivudine and adefovir. Considering this living donor case and previously reported cases, the use of an HBsAg-positive cadaveric liver graft may deserve attention when no other donor is available.     

173例肝移植术后乙型肝炎病毒再感染防治经验回顾

目的 探讨原位肝移植术后乙型肝炎病毒再感染的预防。方法 回顾性分析了173例乙肝相关性肝病病人，移植前后给予抗病毒药物预防乙型肝炎病毒再感染，拉米呋啶2例，拉米呋啶＋乙肝免疫球蛋白（HBIg）166例，阿德福韦＋HBIg5例，观察临床表现、血清HBV、HBVDNA及肝活检免疫组织化学检测等指标。结果 应用拉米呋啶预防的2例病人，有1例再感染，其血清HBsAg、HBeAb、HBcAb和HBVDNA均阳性，肝活检免疫组织化学检测有HBsAg表达。用拉米呋啶＋HBIg预防的166例中，有3例再感染，血清均HBsAg、HBeAb和HBcAb阳性，肝活检免疫组织化学检测有HBsAg表达，其中1例血清HBVDNA阳性，有1例经治疗后HBsAg又转阴。用阿德福韦＋拉米呋啶＋HBIg预防的5例中，血清学和肝活检免疫组织化学检测均无HBsAg表达。结论 原位肝移植术是治疗HBV相关性终末期肝病的有效手段，拉米呋啶＋HBIg或拉米呋啶＋阿德福韦＋HBIg联合应用可以有效预防乙型肝炎病毒的再感染。     

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。     

肝移植术后预防乙型肝炎病毒再感染281例的分析

目的分析乙型肝炎病毒(HBV)相关性肝病肝移植术后HBV再感染的原因及防治经验。方法回顾性分析281例HBV相关性肝病,移植前后给予抗病毒药物拉米夫定 人乙肝免疫球蛋白(HBIg)预防HBV再感染,其中9例为拉米夫定 阿德夫韦 HBIg,观察临床表现、血清HBV标志物、HBV DNA及肝活检免疫组织化学检测等指标。结果用拉米夫定 HBIg预防的272例中,有7例再感染,血清HBsAg、HBeAb和HBcAb阳性,肝活检免疫组织化学检测有HBsAg表达,其中2例血清HBV DNA阳性,4例经治疗后HBsAg又转阴。用拉米夫定 阿德夫韦 HBIg预防的9例中,血清学和肝活检免疫组织化学检测无HBsAg表达。结论拉米夫定 HBIg或拉米夫定 阿德夫韦 HBIg联合应用,可以有效预防HBV相关性肝病肝移植后HBV的再感染。