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.     

Hepatitis B Prophylaxis Using Lamivudine and Individualized Low-dose Hepatitis B Immunoglobulin in Living Donor Liver Transplantation

Background

Currently, most available experience concerning prophylaxis against hepatitis B virus (HBV) recurrence after living donor liver transplantation (LDLT) is limited to studies of small size and short follow-up. The objective of this study was to evaluate the efficacy of a prophylactic regimen using lamivudine and individualized low-dose intramuscular hepatitis B immunoglobulin (HBIG) in LDLT.

Methods

We used a database of adult-to-adult right-lobe LDLT procedures performed from June 2002 to April 2012 at our center for HBV-related end-stage liver diseases. Patients were divided into 3 groups: group A, HBV-related decompensated liver cirrhosis; group B, fulminant hepatitis B; and group C, hepatocellular carcinoma (HCC).

Results

During a mean follow-up of 38.3 ± 28.9 months, 8 of 165 (4.8%) recipients developed HBV recurrences. The mean time for HBV reinfection was 15.8 + 11.0 months after transplantation. The overall 1-, 3-, and 5-year HBV recurrence rates were 3%, 7%, and 8.2%, respectively. Both patients with fulminant hepatitis B or HCC seemed to have higher rates of HBV recurrence than those with decompensated liver cirrhosis, albeit not significantly. The independent predictor of HBV recurrence was high HBV DNA level (≥10⁵ copies/mL) at LDLT.

Conclusions

Lamivudine and individualized low-dose intramuscular HBIG provides effective prophylaxis against HBV recurrence after LDLT. Pre-LDLT HBV DNA of ≥ 10⁵ copies/mL was associated with HBV recurrence.     

核苷类似物联合HBIG干预下肝移植后HBV再感染的危险因素及预后分析

目的 探讨肝移植术后在核苷类似物联合低剂量乙肝免疫球蛋白(HBIG)的干预下乙型肝炎病毒(HBV)再感染的危险因素及其预后.方法 回顾性分析340例因HBV相关性终末期肝病行肝移植患者的临床资料.所有患者术前即开始给予核苷类似物控制病情,术中和术后均给予核苷类似物联合低剂量HBIG的预防方案.术后对患者进行定期随访,监测患者的HBV再感染发生率、存活率及预后.记录患者性别、年龄、原发病、术前2周HBV DNA水平、HbeAg水平、YMDD变异以及术后免疫抑制剂和核苷类似物使用情况等指标进行单因素分析,将P<0.1的变量纳入COX多因素回归分析,筛选出影响术后HBV再感染的危险因素.结果 340例患者术后发生HBV再感染33例,再感染率为9.7%,再感染时间为术后(8.4±13.2)个月(2～49个月),术后1、3、5年再感染率分别为7.0%、10%、13%.33例患者HBV再感染后均停用HBIG,并调整核苷类似物的用量,除3例HBV DNA定量为3 log10～5 log10拷贝/ml外,其余均控制在3 log10拷贝/ml以下.340例患者术后1、3、5年存活率分别为89%、83%和82%,其中HBV再感染者分别为94%,87%,81%,未再感染者分别为89%,82%,82%,Log-rank检验显示HBV再感染对患者长期存活率无明显影响(P=0.828).经COX多因素回归分析表明,原发病为原发性肝癌(P=0.035)、HBVDNA定量>5 log10拷贝/ml(P<0.001)是发生HBV再感染的危险因素.进一步分层分析显示,原发性肝癌复发后HBV再感染发生率显著高于未复发者,分别为27.9%和8.7%(P=0.001).结论 原发病为原发性肝癌及术前HBV DNA>5 log10拷贝/ml是影响HBV再感染的高危因素.在核苷类似物联合HBIG预防方案的干预下,HBV再感染对预后影响不大.     

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.     

High Viremia,Prolonged Lamivudine Therapy and Recurrent Hepatocellular Carcinoma Predict Posttransplant Hepatitis B Recurrence†

Hepatitis B virus (HBV) recurrence following orthotopic liver transplantation (OLT) is generally preventable by prophylaxis with hepatitis B immunoglobulin (HBIG) and lamivudine (LAM). However, HBV recurrence sometimes develops despite prophylaxis. This study assessed posttransplant outcomes and identified predictors of HBV recurrence. We analyzed the outcomes of 209 consecutive patients positive for hepatitis B surface antigen who underwent OLT, who received either combination prophylaxis with HBIG and LAM (89.0%) or HBIG monoprophylaxis (11.0%). The median follow‐up was 36.8 months (range, 1.0–84.4). Posttransplant HBV recurrence occurred in 22 patients (10.5%), including 13 patients with drug‐resistant mutations. HBV recurrence was observed in six patients after hepatocellular carcinoma (HCC) recurrence. Independent predictors of HBV recurrence were recurrent HCC (p < 0.001), LAM therapy >1.5 years (p = 0.001) and high HBV DNA titers (≥10⁵ copies/mL) at OLT (p = 0.036). In conclusion, high viremia at OLT and prolonged exposure to LAM should be further stressed as main predictors of HBV recurrence.     

Prophylaxis of hepatitis B virus recurrence after liver transplantation in carriers of lamivudine-resistant mutants.

The combination of lamivudine and hepatitis B immunoglobulin (HBIG) reduces the risk of hepatitis B virus (HBV) recurrence after liver transplantation (LT). However, the efficacy of this strategy and the need for combined therapy with adefovir dipivoxil (ADV) in patients who select lamivudine-resistant strains (YMDD) before surgery is still unknown. Twenty-two patients treated with lamivudine (LAM) who underwent LT after YMDD-mutant selection were studied. In 13 patients, YMDD mutants were associated with an HBV DNA breakthrough greater than 5 log10 (group A: phenotypic resistance), and 11 were treated with ADV to decrease viral load before LT. In the remaining 9 patients who did not experience the viral breakthrough, YMDD mutants were detected only retrospectively in sera stored at the time of LT (group B: genotypic resistance). During 35 months of post-LT follow-up, none of the 11 patients of group A treated with ADV before and after surgery (in addition to HBIG and LAM) had HBV recurrence, and neither did any of the 7 subjects of group B treated with LAM before and after transplantation (in addition to HBIG). HBV recurred in 2 patients of group A (untreated with ADV before surgery and transplanted with an HBV DNA exceeding 5 log10) and in 2 subjects of group B (who spontaneously stopped HBIG after surgery). In carriers of YMDD mutants, the risk of post-LT HBV recurrence is low, provided that preemptive and prophylactic ADV (in addition to LAM and HBIG) treatment is used in highly viremic patients and prophylactic LAM (or ADV) and HBIG therapy is continued in low viremic patients.     

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     

Impact of Virologic Breakthrough and HBIG Regimen on Hepatitis B Recurrence After Liver Transplantation

The availability of hepatitis B immune globulin (HBIG) and several oral antiviral therapies has reduced but not eliminated hepatitis B virus (HBV) recurrence. We aimed to determine the rate of HBV recurrence after orthotopic liver transplantation (OLT) in relation to virologic breakthrough pre‐OLT and HBIG regimens post‐OLT. Data from the NIH HBV‐OLT database were analyzed. A total of 183 patients transplanted between 2001 and 2007 followed for a median of 42 months (range 1–81) post‐OLT were studied. At transplant, 29% were hepatitis B e antigen (HBeAg) (+), 38.5% had HBV DNA > 5 log₁₀ copies/mL, 74% were receiving antiviral therapy. Twenty‐five patients experienced virologic breakthrough before OLT. Post‐OLT, 26%, 22%, 40% and 12% of patients received intravenous (IV) high‐dose, IV low‐dose, intramuscular low‐dose and a finite duration of HBIG, respectively as maintenance prophylaxis. All but two patients also received antiviral therapy. Cumulative rates of HBV recurrence at 1 and 5 years were 3% and 9%, respectively. Multivariate analysis showed that listing HBeAg status and HBV DNA level at OLT were the only factors associated with HBV recurrence. In conclusion, low rates of HBV recurrence can be accomplished with all the HBIG regimens used when combined with antiviral therapy including patients with breakthrough pre‐OLT as long as rescue therapy is administered pre‐ and post‐OLT.     

Outcomes of hepatitis B virus recurrence after liver transplantation

The introduction of high doses of hepatitis B immune globulin (HBIG) and lamivudine for liver transplantation (OLT) prophylaxis has reduced the risk of hepatitis B recurrence and improved the survival of patients transplanted for hepatitis B virus (HBV)-related liver disease. But, posttransplant prophylaxis strategies to treat the recurrence of HBV have not yet been standardized. We analyzed 23 patients with HBV recurrence among 340 HBV-associated liver transplants performed from September 1996 to April 2004 (6.7%). Nine patients underwent deceased donor OLT and 14, living donor OLT. Mean follow-up was 37 months. Seroconversion after recurrence was observed in 6 of 23 patients (26%). Mean time to HBV recurrence tended to be shorter among the seroconversion (+) patients compared to seroconversion (-) patients (10 months vs 19.7 months; P = .062). Seroconversion rate after HBIG and lamivudine combination therapy for patients with HBV recurrence was 37.5% and time to seroconversion after HBV recurrence was 1.7 months. Seroconversion was best achieved when the pretransplant HBV DNA level was high and HBeAg was positive. Also, seroconversion rate was increased when HBV DNA level was low and the alanine transferase level high at the time of recurrence and when the time to recurrence after transplantation was short. Seroconversion after HBV recurrence, which was observed in 26%, may be increased in selected cases. Accordingly, aggressive treatment should be undertaken after HBV recurrence.     

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.     

Recurrence-free long-term survival after liver transplantation for hepatitis B using interferon-alpha pretransplant and hepatitis B immune globulin posttransplant.

OBJECTIVE: The authors determined whether pretransplant reduction of hepatitis B virus (HBV) load using alpha-interferon-2b (IFN) and passive immunoprophylaxis using hepatitis B immunoglobulin (HBIg) posttransplantation can prevent HBV recurrence in patients undergoing liver transplantation (LT) for HBV cirrhosis. SUMMARY BACKGROUND DATA: Liver transplantation in patients with HBV cirrhosis is associated with a high rate of recurrence and reduced survival. In patients with evidence of replicating virus (HBV-DNA or hepatitis B e antigen [HBeAg]-positive serum or both), recurrence is nearly universal. Passive immunoprophylaxis with HBIg alone is not effective in preventing HBV recurrence posttransplant, especially in patients with evidence of active viral replication pretransplant. Higher doses of HBIg posttransplant has reduced recurrence rates to 30% to 50%. Lamivudine, a nucleoside analogue that has shown early promise, also is associated with significant HBV recurrence. The authors report a reliable method of preventing viral recurrence in patients even with evidence for active HBV replication pretransplant. METHODS: Pretransplant patients with evidence of replicating HBV were given IFN starting at 1 million IU 3 times per week subcutaneously. This dose was increased to 2 and then 3 million IU 3 times per week when patient's side effects permitted and was maintained until the patient underwent a LT. All patients were tested every 4 weeks for hepatitis B surface antigen (HBsAg), HBeAg, and HBV-DNA. When patients became negative for HBeAg and HBV-DNA, they were listed for LT. Patients that were only HBsAg positive were listed immediately and received a LT without prior IFN treatment. Post-LT, all patients began receiving HBIg 2000 IU (10 mL) daily from days 1 to 20 and then weekly for the first 2 years. After 2 years, all patients received 2000 IU (10 mL) monthly. Additional HBIg immunoprophylaxis was given during intense immunosuppression for rejection. Posttransplant serum was tested for HBsAg, HBeAg, and HBV-DNA in all patients 1 week, 1 month, and every 3 months thereafter. Liver biopsies were done at least yearly and when liver enzymes were abnormal and were always tested for HBsAg and HBcAg by immunoperoxidase. RESULTS: Thirteen patients with decompensated HBV cirrhosis were transplanted. Pretransplant, eight patients had evidence of active viral replication at the initial assessment (HBeAg or HBV-DNA-positive serum or both). All eight were successfully treated with IFN (median duration, 24 weeks; range, 8-53) and converted to a negative status before transplantation. Side effects from IFN were minimal and well tolerated, except in one patient who required 6 million IU to convert to a nonreplicating status. The five patients that were only HBsAg positive were not treated with IFN pretransplant. After surgery, HBIg given as described achieved consistently serum levels greater than 1000 IU/L. Twelve of the 13 patients are alive with normal liver function and without serologic evidence of HBV recurrence at a median follow-up of 32 months (range, 9-56 months). None have evidence of HBV recurrence as measured by serum HBsAg/HBeAg/HBV-DNA at recent follow-up. The sera of the seven longest survivors has tested negative for HBV-DNA using the polymerase chain reaction method. In addition, a liver biopsy was obtained in six of these patients, the results of which also tested negative for HBV-DNA using polymerase chain reaction. Liver biopsy specimens have been negative for the presence of HBsAg and HBcAg by immunoperoxidase staining in all 12 patients. CONCLUSION: A reduction of viral load pretransplant with IFN and posttransplant HBIg prevents recurrence of hepatitis B and permits LT for HBV cirrhosis, even in patients with evidence of replicating virus. The IFN pretransplant was well tolerated, and the small frequent dosing of HBIg posttransplant did not cause side effects while achieving serum levels > 1000 IU/L.     

Genotype prevalence, viral load and outcome of hepatitis B virus precore mutant infection in stable patients and in patients after liver transplantation

OBJECTIVE: The precore mutant is detectable in most Israeli patients with persistent hepatitis B virus (HBV) infection. The aim of this study was to determine the prevalence of HBV genotypes, viral load and outcome of precore mutant infection in stable patients and in patients after liver transplantation. METHODS: The prevalence of HBV genotype and viral load were investigated in 81 patients with HBV precore mutant infection. Of these, 50 patients (40 males, 10 females; mean age 43.4 +/- 11.0 yr) underwent liver transplantation and were serum HBV DNA-negative by hybridization at the time of transplantation. Patients received long-term HBV immunoprophylaxis and immunosuppression, and lamivudine in cases of graft HBV recurrence. The remaining 31 patients were stable, with serum anti-HBe-positivity. Genotypes were tested by restriction fragment length polymorphism of an S gene amplicon. Precore mutations were studied with an INNO-LiPA probe assay. RESULTS: Follow-up was 46.6 +/- 37.7 months. Most of the transplanted group was of Middle Eastern origin (53.6%); the remainder were from Eastern Europe (21.4%), Western Europe and the USA (10.8%), Africa (7.1%), and Asia (7.1%). In the transplanted group, the pre-transplant HBV genotype D was the most prevalent (96%), while genotype A was found in only 4%. Eleven patients (22%) developed recurrent HBV infection post-transplantation. There were no differences in genotype distribution between patients with graft reinfection or lamivudine resistance and patients without recurrence. Mean viral load at recurrence was 148.4 x 10(6) +/- 60.4 x 10(6) copies/mL. The stable group had a similar origin and HBV genotype prevalence, but a lower mean viral load of 12.4 x 10(6) +/- 29.4 x 10(6) copies/mL (p = 0.007). The prevalence of mutations at the precore region and codon 28 was similar in both groups. CONCLUSIONS: The chronic precore mutant HBV-infected patients were characterized as follows: (i) genotype D was the most frequent genotype, (ii) the HBV genotype distribution was similar in patients with stable infection and after liver transplantation, (iii) viral load at recurrence was significantly higher than in stable infection, and (iv) HBV genotype was unrelated to the development of recurrence or lamivudine resistance in the tested population.     

Antiviral treatment for hepatitis B virus recurrence following liver transplantation

The purpose of this study was to identify the factors associated with the recurrence of hepatitis B virus (HBV) following liver transplantation (LT) for HBV‐related disease and to recognize the outcome of treatment for HBV recurrence with oral nucleos(t)ide analogues. Six hundred and sixty‐seven LTs were performed for HBsAg‐positive adult patients in our institute from 1996 to 2010. HBV prophylaxis was performed by hepatitis B immunoglobulin (HBIG) monotherapy or HBIG and entecavir combination therapy. There were 63 cases (11.4%) of HBV recurrences during a median follow‐up of 51 months. The median time to HBV recurrence was 22 months. A preoperative HBV DNA load of more than 10⁵ IU/mL, HBIG monotherapy, and hepatocellular carcinoma in the explant liver were independent risk factors for HBV recurrence following LT in multivariate analysis. Patient survival at 10 yr was 54.2% for HBV‐recurrent patients. Among patients with HBV recurrence, HBsAg seroclearance was achieved in 13 patients (20.6%), but HBsAg seroclearance did not affect survival in these patients after the recurrence of HBV (p = 0.28). The recurrence of HBV led to graft failure in six cases. HBV recurrence should be prevented by strict management of pre‐transplant HBV viremia and an effective post‐transplant HBV prophylaxis.     

Lamivudine therapy in patients undergoing liver transplantation for hepatitis B virus precore mutant-associated infection: high resistance rates in treatment of recurrence but universal prevention if used as prophylaxis with very low dose hepatitis B immune globulin.

Recurrent hepatitis B virus (HBV) infection remains a major cause of morbidity and mortality after liver transplantation. Recently, antiviral therapy, such as lamivudine, has become available for prophylaxis against HBV reactivation posttransplantation and for the treatment of HBV recurrent disease. We report our initial experience with lamivudine therapy in patients with precore mutant-associated HBV infection undergoing liver transplantation (n = 29). Outcomes were compared in three patient groups: group 1, precore mutant HBV infection not receiving lamivudine (n = 10); group 2, recurrent precore mutant HBV infection posttransplantation subsequently treated with lamivudine (n = 10); and group 3, HBV precore mutant patients undergoing liver transplantation and receiving lamivudine and low-dose hepatitis B immune globulin (HBIG) from the time of transplantation (n = 9). In group 1, HBV recurred in 9 of 10 patients, with subsequent graft loss in all 9 patients. In group 2, all patients developed HBV recurrence at a mean of 7.3 months posttransplantation and started lamivudine therapy at a median of 16 months posttransplantation. Follow-up on lamivudine therapy was for a median of 11 months. Six of these 10 patients developed mutations in the HBV polymerase gene associated with lamivudine resistance. There were two liver failure-related deaths in this group. In group 3 patients, there was one death from graft-versus-host disease. The remaining 8 patients have been followed up for a mean of 15.6 months posttransplantation, and all remain hepatitis B surface antigen negative and HBV DNA negative. In conclusion, lamivudine therapy in association with low-dose HBIG is effective in preventing HBV reactivation posttransplantation. Rescue therapy with lamivudine in patients with HBV recurrence is only moderately effective, with a 60% lamivudine resistance rate in patients treated for longer than 6 months.     

Low risk of hepatitis B virus recurrence after withdrawal of long-term hepatitis B immunoglobulin in patients receiving maintenance nucleos(t)ide analogue therapy.

Hepatitis B virus (HBV) recurrence rates of 0-16% had been reported in patients maintained on nucleoside analogues (NA) after hepatitis B immunoglobulin (HBIG) discontinuation after orthotopic liver transplantation (OLT). However, follow-up in most studies was short. We aimed to determine the long-term risk of HBV recurrence using this strategy. All HBV patients who received > or =7 doses of intravenous HBIG after OLT, with no HBV recurrence while receiving HBIG, and who eventually discontinued HBIG and were maintained on NA, were included. HBV recurrence was defined as HBsAg-positive or HBV DNA > or =5 log copies/mL on 2 consecutive occasions. Twenty-one patients met the inclusion criteria. Immediate post-OLT prophylaxis was combination HBIG and NA in 15 patients, whereas 6 patients received HBIG monotherapy for 62-109 months before NA was added. HBIG was discontinued a median of 26 (range, 0.2-121) months after OLT. Median follow-up post-HBIG discontinuation was 40 (range, 5-51) months. Only 1 patient, who had 12 months of HBIG and was noncompliant to NA therapy, had HBV recurrence, 34 months after HBIG discontinuation. One patient had HBV DNA of 3.3 log copies/mL 47 and 48 months after HBIG discontinuation but remained HBsAg-negative. Lamivudine-resistant mutations were detected in both patients. Probability of HBV recurrence was 0% and 9% at 2 and 4 years after HBIG discontinuation. Three patients had 1-2 episodes of transiently detectable HBV DNA. All were HBV DNA and HBsAg negative on repeated tests over a period of 2-36 months. Maintenance therapy with NA after discontinuation of long-term HBIG therapy is associated with a low risk of HBV recurrence after OLT in compliant HBV patients.     

乙肝肝移植受体术后骨髓CD34+细胞和PBMCs内乙肝病毒DNA的同步检测

目的 肝移植术后乙肝复发严重影响预后,HBV感染的病毒来源值得研究.采用PCR技术可检测到术后病人外周血单个核细胞(PBMCs)中HBV DNA的存在,然而PBMCs的寿命有限,其中的病毒来源仍不清楚.该研究对此问题做了初步的探索.方法 采集13例乙肝肝移植术后受体外周血和骨髓标本,运用Ficoll密度梯度离心法结合免疫磁性分离法(MACS)分别从外周血和骨髓标本中分离出PBMCs和骨髓来源CD34+细胞即造血干祖细胞,利用实时荧光定量PCR法检测细胞中的HBV DNA,同时检测血清HBV标志物和血清HBV DNA.结果 13例病人术前血清HBV DNA阳性8例,阴性5例.术后平均37个月的随访期内(16～77个月)血清中HBV DNA,HBsAg和HBeAg检测结果全为阴性;13例PBMCs中均检测到HBV DNA的存在,阳性率为100%.PBMCs中DNA含量对数平均值为3.40±0.85;13例骨髓来源CD34+细胞中都检测到HBV DNA的存在.阳性率也是100%.CD34+细胞中DNA含量对数平均值为3.30±0.58.病人PBMCs和CD34'细胞内DNA含量对数值均数差异无统计学意义(P>0.05).同一病人PBMCs与CD34+细胞HBV DNA同时为阳性.术前血清HBV DNA检测阳性和阴性病人的PBMC内DNA含量对数值均数差异无统计学意义(P＞0.05);术前血清HBV DNA检测阳性和阴性病人的CD34+细胞内DNA含量对数值均数差异也无统计学意义(P＞0.05).结论 现有预防措施下,乙肝肝移植受体虽然外周血清中不能检测到HBV DNA和HBV抗原成分的存在,但术后骨髓CD34+细胞和PBMCs中皆长期存在HBV DNA.含有HBV DNA的骨髓来源CD34+细胞可能是含有HBV DNA的PBMCs的来源,也可能是肝移植术后PMBCs内HBV DNA长期存在的原因,及以后导致HBV复发的潜在危险因素.然而,现在尚无有效方法可以完全清除这些残存病毒,术后长期的抗病毒药物预防措施是必要的.     

Antiviral prophylaxis and recurrence of hepatocellular carcinoma following liver transplantation in patients with hepatitis B

BACKGROUND: Orthotopic liver transplantation (OLT) is a viable treatment option for patients with hepatitis B (HBV) and concomitant hepatocellular carcinoma (HCC). However, cancer recurrence following transplantation approaches 20%. This study sought to identify the clinical and pathological factors associated with post-OLT survival. METHODS: Univariate and multivariate analyses considered the following variables: combination viral prophylaxis, HBV recurrence, tumor stage, vascular invasion, distribution, nodularity, pre- and post-OLT tumor size, pre-OLT alpha-fetoprotein (AFP), Milan and UCSF criteria, and Asian race. RESULTS: Cumulatively, HCC recurrence-free survival was 77%, 62%, and 53% at 1, 3, and 5 years, respectively, and was significantly better in patients who were free of viral recurrence post-OLT. Similarly, patients treated with combination prophylaxis had a significantly lower mortality than those who were not. CONCLUSIONS: Multivariate analysis revealed that AFP>500 ng/mL, presence of vascular invasion by explant, HBV recurrence, and combination prophylaxis were independent predictors of HCC recurrence-free survival.     

Virologic and Clinical Outcomes of Hepatitis B Virus Infection in HIV‐HBV Coinfected Transplant Recipients

Liver transplantation (LT) is the treatment of choice for end‐stage liver disease, but is controversial in patients with human immunodeficiency virus (HIV) infection. Using a prospective cohort of HIV‐hepatitis B virus (HBV) coinfected patients transplanted between 2001–2007; outcomes including survival and HBV clinical recurrence were determined. Twenty‐two coinfected patients underwent LT; 45% had detectable HBV DNA pre‐LT and 72% were receiving anti‐HBV drugs with efficacy against lamivudine‐resistant HBV. Post‐LT, all patients received hepatitis B immune globulin (HBIG) plus nucleos(t)ide analogues and remained HBsAg negative without clinical evidence of HBV recurrence, with a median follow‐up 3.5 years. Low‐level HBV viremia (median 108 IU/mL, range 9–789) was intermittently detected in 7/13 but not associated with HBsAg detection or ALT elevation. Compared with 20 HBV monoinfected patients on similar HBV prophylaxis and median follow‐up of 4.0 years, patient and graft survival were similar: 100% versus 85% in HBV mono‐ versus coinfected patients (p = 0.08, log rank test). LT is effective for HIV‐HBV coinfected patients with complications of cirrhosis, including those who are HBV DNA positive at the time of LT. Combination HBIG and antivirals is effective as prophylaxis with no clinical evidence of HBV recurrence but low‐level HBV DNA is detectable in ～50% of recipients.     

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.     

慢性病毒性乙型和丙型肝炎的肝移植

肝移植是治疗终末期肝脏疾病病人的最有效手段。不幸的是,慢性病毒性肝炎病人肝移植术后的结果并不像其他肝脏疾病那样理想,其主要原因是移植肝脏肝炎复发率高,最终导致移植肝脏功能衰竭,甚至受体死亡。因此,世界上许多器官移植中心对这类病人实施原位肝移植,进行重新考虑和评价。目前预防乙型肝炎再感染的措施主要集中在那些具有较低再感染机会的乙型肝炎病人,特别是那些缺乏启动并激活ＨＢＶ复制因素的病人。最近的实验研究