Limited lamivudine and long-term hepatitis B immunoglobulin immunoprophylaxis for prevention of hepatitis B recurrence after liver transplantation

BACKGROUND: No consensus exists concerning dosage and duration of prophylactic hepatitis B immunoglobulin and lamivudine for prevention of hepatitis B recurrence after liver transplantation (LT). METHODS: Lamivudine was discontinued 12 months after LT, maintaining hepatitis B immunoglobulin prophylaxis in eight patients who received lamivudine treatment before LT. RESULTS: At LT, six patients were serum hepatitis B virus (HBV)-DNA negative, whereas two patients had low serum HBV-DNA levels. Hepatitis B surface (HBs) antigen and hepatitis B core antigen stained positively by immunohistochemistry in all hepatectomy specimens. All patients remained recurrence free during the 12 months on combination therapy with normal liver histological examination and negative HBs and HB core staining on biopsy specimens. No relapse occurred after lamivudine withdrawal during a median follow-up of 17.5 months (normal transaminases, negative serum HBs antigen, and HBV-DNA). CONCLUSIONS: Discontinuation of lamivudine 12 months after LT is feasible and safe even in patients with ongoing low viral replication at LT, providing adequate prophylaxis with hepatitis B immunoglobulins.     

Antiviral combination therapy for lamivudine‐resistant hepatitis B reinfection after liver transplantation

Abstract Development of resistance is a major issue in antiviral treatment of hepatitis B reinfection after liver transplantation. Antiviral combination therapy is discussed for therapy or prevention of this breakthrough of viral replication. Eight patients were enrolled into this retrospective analysis after liver transplantation for chronic hepatitis B infection. All had reinfection of the graft and breakthrough of HBV during consecutive famciclovir and lamivudine monotherapy. Subsequently a combination therapy with lamivudine and interferon‐α 2 a (group I, n = 4) or lamivudine and famciclovir (group II, n = 4) was initiated. Combination therapy was started 61 months (group I) and 25 months (group II) after liver transplantation. It markedly reduced the viral replication rate in all patients despite lamivudine resistance. In group I three of four patients and in group II two of four patients became HBV‐DNA negative. Two long‐term responders were observed in group I, and none in group II. No patient became HBsAg negative or lost HbeAg. Pretreatment elevated ALT and AST levels were significantly reduced. No severe complications, and especially no rejection episodes, occurred. Lamivudine in combination with other antiviral agents, especially interferon‐α, might be a therapeutic option for hepatitis B reinfection after liver transplantation. Suppression of virus replication to the point of undetectable values is possible even in patients with lamivudine‐resistant virus mutations.     

Results on preemptive or prophylactic treatment of lamivudine in HBsAg (+) renal allograft recipients: comparison with salvage treatment after hepatic dysfunction with HBV recurrence

BACKGROUND: Lamivudine has been reported to be able to stabilize liver enzyme and hepatitis B virus (HBV) replication with recurrent hepatitis that has been regarded as a frequent and major risk factor for hepatic dysfunction and chronic liver disease in renal transplant recipients. Because large number of hepatitis antigenemia patients among renal transplant patients experience recurrent hepatic dysfunction with HBV recurrence and permanent histological deterioration, preemptive or primary prophylactic use of lamivudine before transplantation may be more beneficial than a trial for the treatment of advanced hepatic dysfunction. METHODS: We conducted a double arm study to compare the efficacy of lamivudine between the preemptive (HBV DNA positive) or prophylactic (HBV DNA negative) trial for the maintenance of stable liver function (n=10) and the trial for the salvage of advanced hepatic dysfunction developed after renal transplantation (n=6) in hepatitis B viremia carrier renal transplant recipients. RESULTS: Hepatic dysfunction with recurrent HBV antigenemia developed in 11 of 36 (30.6%) hepatitis antigenemia patients with a mean duration of 8.4 months (range 5-19.4 months). In six patients treated with lamivudine after hepatic dysfunction from recurrent hepatitis B viremia, serum AST and ALT level normalized within 1 month and HBV-DNA disappeared in all cases. HBV-DNA, however, reappeared in three (50%) without any discontinuation of lamivudine. Liver biopsy revealed recurrent chronic active hepatitis with severe activity of fibrosis in four cases, cholestatic fibrosing hepatitis in one, and permanent cirrhotic change in one. In seven patients who had preemptive lamivudine treatment at 9, 6, 2, 2, 1, 0, 0 month before the transplantation, HBV-DNA had converted to negative with a mean follow up of 1.2 months (range 1-2 month) in all case. Three patients who had prophylactic trials with lamivudine have all remained HBV-DNA negative. The recurrence rate of HBV viremia in the preemptive or prophylactic lamivudine treated group is 10.0% (1/10), which is significantly lower than that (42.3%, 11/25) in the nonlamivudine-treated group. The re-recurrence rate of HBV viremia was significantly higher (3/6, 50.0%) in the reactive lamivudine treated group than in prophylactic or preemptive group (1/10, 10%). CONCLUSION: Although lamivudine treatment after hepatic dysfunction can be a sound conventional treatment modality, this preliminary study may suggest that preemptive or prophylactic trial of lamivudine before hepatic dysfunction might be a more effective strategy for prevention of permanent histological deterioration and recurrence of hepatitis B viremia.     

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.     

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.     

拉米夫定联合小剂量乙型肝炎免疫球蛋白预防肝移植术后乙型肝炎病毒复发

目的:初步探讨拉米夫定联合小剂量乙型肝炎免疫球蛋白预防肝移植术后乙型肝炎病毒(HBV)复发的疗效。方法:35例HBV相关疾病病人接受肝移植后使用拉米夫定联合小剂量乙型肝炎免疫球蛋白(HBIg)预防HBV复发,同时监测乙型肝炎血清标志物、血清HBV鄄DNA、YMDD区变异及肝活检组织乙型肝炎标记物免疫组化。结果:本组病例平均获随访557d,结果5例(14.3%)出现了HBV复发:复发病例中2例HBV鄄DNA阳性,无YMDD变异。病人术前HBeAg状态与肝移植术后HBV复发间无明显相关(P>0.05),而术前HBV鄄DNA阳性的病人术后HBV复发率显著增加(P<0.05)。结论:拉米夫啶联合小剂量HBIg预防肝移植术后HBV复发的近期疗效较为肯定。术前HBV鄄DNA状态是影响术后HBV复发的重要因素。     

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     

拉米夫定治疗肾移植术后乙型病毒性肝炎的临床观察

目的 :观察拉米夫定 (lamivudine)对肾移植术后乙型病毒性肝炎肝损害的保护作用。方法 :患有慢性乙型病毒性肝炎的肾移植受者为 4 6例 ,术后 12例出现HBV -DAN( )、转氨酶升高 ,在一般护肝治疗的同时给予拉米夫定 10 0mg/d以抑制病毒的复制。治疗中观察乙肝病毒指标及肝功能、血生化、血常规等变化。结果 :经过治疗后患者的病情改善转氨酶下降 ,并有 2例 (16 .7% )发生病毒血清转换率。治疗过程中无 1例发生肝功能衰竭。对移植肾功能无影响。结论 :应用拉米夫定可显著降低肾移植受者乙肝肝损害的发生 ,对肾移植后的乙肝有一定的治疗作用 ,而未发现对移植肾功能的损害。拉米夫定可用于有效治疗肾移植术后乙肝     

Lamivudine for treating active hepatitis B in renal transplant recipients: a case report

AIM: Chronic hepatitis B is still a matter of concern among renal transplantation patients and patients waiting for a renal transplant since it influences negatively morbidity and mortality. Morbidity and mortality are associated with HBV replication. Lamivudine is a new antiviral agent whose use has been advocated to treat HBV-infected liver transplanted patients. SUBJECT AND METHODS: Here we present our experience with an HBV-positive kidney-liver transplanted patient treated with lamivudine after transplantation. RESULTS: After lamivudine was started HBV-DNA became negative (chemiluminescence, Digene Hybrid Capture System, USA 1997) and ALT levels returned to normal. After eighteen months and after steroid pulses treatment for acute rejection, HBV-DNA became positive again, probably due to virus mutation. Lamivudine treatment was not withdrawn since it has been suggested that the mutant form might be less pathogenic than the wild one. To this extent, more than 10 months after, our patient is still in a good clinical general condition and still takes lamivudine 75 mg/day. No lamivudine-related side effects were recorded. CONCLUSIONS: Our case confirms that lamivudine is a safe and useful tool in treating renal transplant recipients with chronic hepatitis B.     

Efficacy of lamivudine therapy for advanced liver disease in patients with precore mutant hepatitis B virus infection awaiting liver transplantation

BACKGROUND: Orthotopic liver transplantation (OLT) for end-stage liver disease resulting from hepatitis B virus (HBV) infection is associated with a high rate of recurrence and reduced survival. Lamivudine is effective in inhibiting HBV replication in patients with chronic hepatitis. This study evaluated the impact of lamivudine on viral suppression, liver function, and disease severity in patients awaiting OLT with HBV e-minus strain infection. METHODS: Twenty-five patients received lamivudine (100 mg per day) from the day of listing for OLT. All patients were positive for serum HBV-DNA by polymerase chain reaction and all had a Child-Pugh score of 7 or higher. RESULTS: Patients were followed for 12+/-9 months (mean +/- SD). Eleven underwent OLT within 13 months of treatment initiation, one died after 10 months, and one dropped out after 3 months. After 3, 6, and 9 months, HBV-DNA by polymerase chain reaction was undetectable in 14 of 25, 14 of 20, and 13 of 15 patients, respectively. Two patients developed lamivudine resistance after 9 and 18 months of treatment, respectively, without liver decompensation. Comparing baseline to last visit data, a significant improvement in prothrombin activity (43+/-15% vs. 52+/-19%; P=0.0014), serum bilirubin (3.4+/-1.9 vs. 2.5+/-2.2 mg/dL; P=0.0007), serum albumin (3.3+/-0.3 vs. 3.6+/-0.5 g/dL; P=0.0278), presence of ascites (15/25 vs. 7/25; P=0.0047), and Child-Pugh score (9 vs. 8; P=0.0003) was observed. Because of liver function improvement, four patients were placed on low priority status for OLT (United Network of Organ Sharing 3) and 9 on inactive status (United Network of Organ Sharing 7). The overall probability of survival at 6 and 12 months was 100% and 90.9%, respectively. CONCLUSIONS: Lamivudine has an important role in patients with end-stage liver disease caused by HBV precore mutant strain. Not only does HBV-DNA suppression allow patients to be eligible for OLT, but the improvement of the patients' clinical status may delay the need for OLT in an era of organ shortage.     

Extension of transplantation free time by lamivudine in patients with hepatitis B-induced decompensated cirrhosis

BACKGROUND: Liver transplantation for hepatitis B virus (HBV)-induced cirrhosis carries a high risk of graft reinfection and poor prognosis. Active viral replication is considered a contraindication for transplantation in most centers. Lamivudine, a new nucleoside analog, is a potent inhibitor of HBV replication that has been used safely for pretransplantation suppression of HBV replication. METHODS: We report the pattern of response to lamivudine treatment in three consecutive patients with decompensated cirrhosis due to the replicative phase of chronic HBV infection. RESULTS: In addition to virological and biochemical response, impressive clinical improvement was noted in all three patients, with disappearance of the ascites and marked improvement of synthetic liver function tests. One patient converted to anti-hepatitis B surface and is free of symptoms 20 months after initiation of treatment. The other two patients experienced significant clinical improvement for 8 to 9 months and were removed from the waiting list for transplantation. However, progressive liver disease recurred in both patients--one underwent liver transplantation and the other is a candidate for the procedure. CONCLUSION: The administration of lamivudine for pretransplantation HBV suppression was associated with impressive clinical and biochemical improvement. Lamivudine may extend the transplantation free time in such patients. The mechanism of this desirable effect should be explored.     

Prevention of and Treatment for Hepatitis B Virus Infection After Liver Transplantation in the Nucleoside Analogues Era

Post-transplant prophylaxis with hepatitis B immune globulin (HBIG) has significantly reduced hepatitis B virus (HBV) recurrence rates, but it is rather ineffective in patients with pretransplant viremia. Moreover, long-term HBIG administration is very expensive and may be associated with emergence of escape HBV mutants. Lamivudine has been widely used in the management of HBV transplant patients. Pretransplant lamivudine lowers HBV viremia, decreasing the risk of post-transplant HBV recurrence, but to try and minimize development of resistant HBV strains, it should start within the last 6 months of the anticipated transplantation timing. Preemptive post-transplant lamivudine monotherapy is associated with progressively increasing HBV recurrence rates, but combined therapy with lamivudine and HBIG at relatively low dosage is currently the most effective approach in this setting, even in HBV-DNA-positive patients, who also receive lamivudine in the pretransplant period. The most frequent therapy for post-transplant HBV recurrence is lamivudine, but the increasing resistance rates represent a rather challenging problem. Adefovir dipivoxil and entecavir are currently the most promising agents for lamivudine-resistant HBV strains. All these advances in anti-HBV therapy have made HBV liver disease an indication for liver transplantation irrespective of viral replication status, a complete turn around from 10 years ago.     

Beneficial Effects of Short-Term Lamivudine Treatment for de novo Hepatitis B Virus Reactivation After Liver Transplantation

Clearance of hepatitis B surface antigen (HBsAg) by lamivudine is achieved in only a small proportion of patients with chronic hepatitis B virus (HBV) infection. We investigated the effect of lamivudine on de novo HBV reactivation after living-donor liver transplantation when the number of HBV was expected to be very small. Thirty-eight HBV-naive recipients who received liver grafts from antibodies to core antigen-positive donors receiving hepatitis B immunoglobulin (HBIG) were studied. HBsAg appeared in nine cases (23.7 %) despite receiving HBIG for 12-71 months (mean: 35.1 months) after transplantation. Lamivudine treatment was started in six recipients during the acute phase of HBV reactivation. Five of the six recipients achieved complete clearance of HBsAg in sera at a median of 4.6 months (ranging from 21 to 330 days) after lamivudine administration. Although lamivudine was stopped in four cases, all remained negative for HBsAg. Our findings suggested that short-term lamivudine treatment during acute phase of HBV reactivation could achieve complete clearance of HBsAg in a significant number of liver transplant recipients.     

肝移植术后乙型肝炎复发的预防和治疗

目的探讨拉米夫定联合低剂量乙型肝炎（乙肝）免疫球蛋白（HBIG）预防肝移植术后乙肝复发的效果及乙肝复发后的治疗。方法对2000年12月至2003年5月因乙肝相关性终末期肝病和（或）合并肝细胞癌于我院接受肝移植手术并经随访的11例患者进行回顾性分析。所有患者均接受拉米夫定联合低剂量HBIG预防乙肝复发方案。观察术后近期乙肝转阴情况、术后较远期乙肝复发情况以及乙肝复发后的治疗情况。结果（1）所有患者HBsAg、HBeAg、HBV-DNA均于术后1-4d转为阴性,术后1周所有患者对HBIG均有反应,HBsAb滴度水平逐渐上升;（2）所有患者于观察期内生存情况均良好,对患者HBsAb滴度水平定期进行监测结果示大部分患者HBsAb滴度水平与预期治疗水平基本符合;（3）1例患者于术后25个月乙肝复发,通过改用阿德弗韦并加大HBIG用量,基本得到控制。结论拉米夫定联合低剂量HBIG预防肝移植后乙肝复发疗效确切,而且可显著降低治疗费用。     

Liver transplantation in Asian patients with chronic hepatitis B using lamivudine prophylaxis

OBJECTIVE: To report the results of liver transplantation in 31 Asian patients with chronic hepatitis B using lamivudine prophylaxis in an open-label study. SUMMARY BACKGROUND DATA: Chronic hepatitis B is a prevalent cause of end-stage liver disease in Asia, but the results of liver transplantation in these patients are poor. METHODS: Thirty-one Asian patients with chronic hepatitis B underwent liver transplantation using lamivudine prophylaxis (100 mg daily). Twenty-three (74%) patients had detectable serum hepatitis B envelope antigen (n = 18) or hepatitis B virus DNA (n = 11) before treatment, and seven had associated hepatocellular carcinoma. Lamivudine was continued indefinitely after transplantation, and hepatitis B immune globulin was not used. RESULTS: The actuarial patient and graft survival rates were 84% and 81%, respectively. Five patients died of causes unrelated to hepatitis B, and 26 patients were alive at a median follow-up of 16 months (range 6-47) after transplantation. One (3.8%) patient developed recurrent hepatitis B resulting from viral breakthrough at week 53 and survived after retransplantation using adefovir and hepatitis B immune globulin treatment. The remaining 25 surviving patients had no biochemical or histologic evidence of recurrent hepatitis, and serum hepatitis B virus DNA remained negative by polymerase chain reaction. In six patients, hepatitis B surface antigen (HBsAg) persisted or reappeared in serum. Among 19 patients who became negative for HBsAg from 5 to 431 days after transplantation, 13 developed anti-HBsAb that lasted a median of 6 months (range 1-21). None of the seven patients with hepatocellular carcinoma developed recurrent tumor. CONCLUSIONS: Asian patients with chronic hepatitis B may achieve a good outcome after liver transplantation using lamivudine prophylaxis.     

Reactivation of hepatitis and lamivudine therapy in 11 HBsAg-positive renal allograft recipients: a single centre experience

BACKGROUND: In hepatitis B virus (HBV) surface antigen (HBsAg) (+) renal allograft recipients, the mortality associated with liver disease reaches 37-78%. An antiviral agent, lamivudine, has recently been reported to be safe and effective for preventing hepatic damage in these patients, although either resurgence of HBV-DNA levels after discontinuation or emerging resistant HBV mutants caused by long-term administration are still unsettled. METHODS: Between July 1976 and December 2003, 555 renal transplantations were performed in our centre. Of these, 11 patients who were HBsAg (+) at the time of transplantation (2.0%) were selected for this study. We investigated the incidence of hepatitis reactivation for three yr after transplantation and their clinical courses, including the efficacy of lamivudine therapy in seven of the 11 patients. RESULTS: Six episodes of hepatitis reactivation developed in five of the 11 patients (45.5%) within three yr after transplantation. Five episodes of six occurred within four months after transplantation. The patient who underwent the most severe reactivation needed intensive care including lamivudine administration and plasma exchange. Lamivudine caused no severe adverse effects and HBV-DNA levels dropped to under measurable levels within four months after lamivudine administration in all patients. Resistant HBV mutant emerged in only one patient, who had the longest lamivudine administration of 49 months. CONCLUSIONS: For HBsAg (+) renal allograft recipients, careful monitoring of HBV-DNA levels and timely administration of lamivudine could prevent hepatic damage caused by reactivation of hepatitis.     

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.     

拉米夫定对肝移植术后乙肝病毒再感染的预防作用

目的 探讨单一应用拉米夫定预防良性乙肝相关性肝病肝移植术后乙肝病毒再感染的疗效。方法 总结单一应用拉米夫定预防肝移植术后生存时间大于3个月的31例良性乙肝相关性终末期肝病患者的乙肝病毒再感染情况，同时检测肝移植手术前、后血清及肝穿刺组织乙肝表面标志物及HBVDNA的变化。结果 31例患者随访时间平均为38．2个月（3．2～70．2个月），随访期间死亡8例。乙肝病毒总的再感染率为19．4％（6／31），术后1、3、5年乙肝再感染率分别为7．1％（2／28）、16．0％（4／25）及26．1％（6／23），生存率分别为87．1％（27／31）、80．6％（25／31）及66．1％（20．5／31）。术前HBeAg和HBVDNA的清除率分别为54．5％（6／11）和50．0％（5／10）。术前HBVDNA和HBeAg阳性患者术后乙肝病毒再感染率高。结论 拉米夫定可以有效地预防良性乙肝相关性肝病患者肝移植术后乙肝病毒的再感染；术前应尽可能使HBVDNA和HBeAg转阴。     

Liver transplantation for chronic hepatitis B with lamivudine-resistant YMDD mutant using add-on adefovir dipivoxil plus lamivudine.

Lamivudine treatment in patients with chronic hepatitis B virus (HBV) infection may improve clinical state and suppress viral replication before liver transplantation. Emergence of lamivudine-resistant YMDD mutant is common. We report the results of liver transplantation in 16 patients with pretransplantation YMDD mutants after receiving lamivudine treatment for a median of 738 days (range, 400-1799 days). Adefovir dipivoxil (10 mg daily) was added on to lamivudine for a median of 20 days (range, 8-271 days) before (n = 11) or at (n = 5) liver transplantation, and the combination was continued indefinitely thereafter. Eight patients received additional intravenous hepatitis B immune globulin (HBIG) for a median of 24 months. Fifteen patients with known pre-adefovir HBV DNA levels had a median titer of 14,200 x 10(3) copies/mL (2 x 10(3) to 4,690,000 x 10(3) copies/mL), and 14 had HBV DNA >10(5) copies/mL. All but 1 patient remained positive for HBV DNA (by quantitative polymerase chain reaction [qPCR]) at the time of liver transplantation, and the titer was greater than10(5) copies/mL in 8 patients. The median follow-up after liver transplantation was 21.1 (range, 4.4-68.9) months. One patient (6%) died of an unrelated cause 12.2 months after transplantation, and 15 patients (94%) were alive with the original graft. All patients cleared HBV DNA and had no detectable HBV DNA by qPCR at the latest follow-up. Fourteen patients had cleared hepatitis B surface antigen (HBsAg), but 2 patients who received only adefovir dipivoxil and lamivudine without HBIG remained HBsAg positive after 7.7 and 9.5 months. Serum HBV DNA, however, was negative, and there was no biochemical or histological evidence of recurrence. Adefovir dipivoxil was well tolerated with no significant renal toxicity. In conclusion, a combination of add-on adefovir dipivoxil plus lamivudine therapy provides effective prophylaxis in patients with pretransplantation YMDD mutant that may be actively replicating. The cost effectiveness of additional passive immunoprophylaxis remains to be defined.     

Adherence to Lamivudine after an early withdrawal of hepatitis B immune globulin plays an important role in the long-term prevention of hepatitis B virus recurrence

Lamivudine combined with hepatitis B immune globulin (HBIg) is the standard of care for preventing the recurrence hepatitis B virus after liver transplant. To determine the risk of hepatitis B virus (HBV) recurrence after early withdrawal of HBIg in patients receiving lamivudine maintenance therapy, 20 patients receiving a course of HBIg and lamivudine after transplantation and long-term maintenance therapy with lamivudine and 9 patients receiving HBIg and lamivudine indefinitely were analyzed. The survival rate was 90% after a mean follow-up of 83 months. The HBV recurrence rate was 14% with a mean period of 91 months free from HBV recurrence. Both groups had similar HBV recurrence rates, 15% for the combination and 11% for lamivudine alone. Four patients, 3 of whom were noncompliant with therapy, experienced posttransplant HBV recurrence. Patients who adhere to long-term prophylaxis with lamivudine after early withdrawal of HBIg have a low risk of HBV recurrence, similar to those who receive combination prophylaxis.