慢性乙型肝炎患者肝组织 HBV cccDNA含量与血清 HBV 标志物和病毒载量的相关性

乙型肝炎病毒共价闭合环状 DNA （ HBV cccDNA）是嗜肝病毒持续感染和HBV复制的突出标志,也是评价HBV感染状态及治疗效果最客观、敏感的指标。监测肝脏内 HBV cccDNA的含量对于病情判断、疗效和预后评估均具有重要意义。本研究通过检测拉米夫定初治后患者肝组织内HBV cccDNA 的含量及血清 HBsAg、HBeAg、HBV DNA等水平,探讨肝组织内HBV cccDNA的含量与HBV血清学标志物和病毒载量的相关性。     

血清乙型肝炎病毒DNA定量对乙型肝炎病毒相关性肾炎的影响

目的回顾性研究血清乙型肝炎病毒DNA（HBV-DNA）定量与乙型肝炎病毒相关性肾炎（HBV-GN）临床表现、肾脏病理演变及预后的相关性。方法根据HBV-DNA复制程度,将41例HBV-GN患者分为3组,分别测定患者的24小时尿蛋白定量、血浆白蛋白、胆固醇、甘油三酯及肌酐;检验其中35例膜性肾病病理分期与病毒DNA复制高低相关性以及病毒复制水平与治疗总有效率的相关性。结果①随着血清HBV-DNA定量的增加,患者的尿蛋白定量升高,血浆白蛋白降低,胆固醇及甘油三酯升高,差别具有统计学意义（p〈0.05）;血肌酐水平随着血清HBV-DNA定量的增加也升高,但差别无统计学意义。②随着血清HBV-DNA定量增加,35例膜性肾病患者的肾脏病理病变逐渐加重,DNA定量水平与病理变化之间存在相关性（p〈0.05）。③随着血清HBV-DNA定量增加,HBV-GN患者治疗的总有效率降低,差别具有统计学意义（p〈0.05）。结论随着血清HBV-DNA定量增加,HBV-GN患者的临床表现及肾脏病理表现加重,治疗的总有效率降低,其变化存在相关性。     

乙型肝炎后肝硬化肝移植乙型肝炎病毒再感染检测

目的探讨乙型肝炎病毒（HBV）DNA、YMDD变异及血清标志物在乙型肝炎肝硬化患者肝移植后HBV再感染检测的临床意义。方法定量聚合酶链反应（PCR）检测HBV DNA；HBV PCR产物限制性片段长度多态性分析检测YMDD变异；酶联免疫检测HBV血清标志物；分析乙型肝炎患者肝移植后YMDD变异、HBV DNA及血清标志物检测结果。结果乙型肝炎肝硬化患者肝移植术后HBV再感染率为8．9％（17／189）；YMDD变异病例达HBV再感染病例58．8％（10／17）；HBV DNA定量检测有较高的灵敏度，能早期诊断HBV的再感染，有利于临床治疗；对HBV DNA阴性但HBsAg阳性病例，PreS1和HBeAg血清标志物可用于病毒复制的补充检测。结论乙型肝炎肝硬化患者肝移植后预防乙型肝炎复发应采用HBV DNA、YMDD变异及血清标志物联合检测。     

乙型肝炎病毒前-S1抗原研究进展

乙型病毒性肝炎在我国发病率高,其快速诊断和治疗是临床研究的重要课题。随着医学的发展,对乙型肝炎病毒（HBV）感染的认识逐渐加深。过去临床筛查以HBV表面标志物为主,部分有条件的医院加查HBV DNA定量,从而对HBV是否复制、传染性及临床预后等进行监测。但由于HBV血清学指标在病程不同时期转换模式多样,     

原发性肝癌患者血清HBV DNA含量的测定

HBV感染与肝细胞癌的发生密切相关,血清HBV DNA是HBV复制活动最直接和可靠的标志,可以反映病变活动程度及不同临床演变过程。本文采用免疫荧光定量PCR检测186例原发性肝癌患者的血清HBV DNA含量,综合分析其与HBV血清学标志物的关系,并比较HCC肝炎活动期与静止期患者血清HBV DNA水平及与血清甲胎蛋白（AFP）的关系,为HCC的发病机制、诊断及治疗提供理论依据。     

血清 HBV DNA 定量与 HBV 相关性肾炎患者临床病理特征及预后的相关性

目的：探讨HBV相关性肾炎（ HBV-GN）患者血清HBV DNA复制水平与临床病理特征及预后的相关性。方法选取2009年1月至2012年10月在青岛大学附属医院接受治疗的HBV-GN患者102例。采用荧光定量聚合酶链反应法测定所有患者血清HBV DNA载量,并依此将患者分为HBV DNA低度复制组（ HBV DNA＜103拷贝／mL）、HBV DNA中度复制组（103拷贝／mL≤HBV DNA≤105拷贝／mL）和HBV DNA高度复制组（ HBV DNA﹥105拷贝／mL）。所有患者行肾脏穿刺活检,明确病理类型,并进行肾脏组织中HBV相关抗原（ HBsAg、HBcAg及HBeAg）的免疫荧光定量检测。所有患者均接受拉米夫定（100 mg／d）联合阿德福韦酯（10 mg／d）治疗,随访观察18个月,并对各组患者治疗前后的肾功能和生化免疫学指标进行比较。采用One-way ANOVA单因素方差分析比较不同HBV DNA复制水平的患者肾功能、生化免疫学指标、肾脏组织中HBV相关抗原沉积的差异,并采用Spearman相关分析法分析血清HBV DNA水平与肾脏病理分期的相关性。结果102例患者中, HBV DNA低度复制组20例,HBV DNA中度复制组51例,HBV DNA高度复制组31例。随着血清HBV DNA复制水平的增高,患者24 h尿蛋白定量、胆固醇及三酰甘油呈现不同程度的增加（ F＝34.64,40.10和31.72,P＜0.01）,血浆白蛋白降低（F＝24.04,P ＜0.01）;肾脏组织中 HBV 抗原（HBsAg、HBcAg及HBeAg）免疫复合物的沉积增加（F＝41.49,15.64和10.41,P＜0.01）。对78例膜性肾病（MN）患者分析发现,随着血清HBV DNA复制的增加,HBV-MN患者病理分期加重（r＝0.38, P＜0.01）。抗病毒治疗后,各组24 h尿蛋白排泄量较治疗前均显著下降（ t＝7.86,19.28和16.74, P＜0.01）;补体C3较治疗前上升,但与治疗前比较差异无统计学意义（t＝1.05,1.04和1.94,P＞0.05）;血肌酐较治疗前无明显变化（ t＝0.14,0.52和0.57,P＞0.05）。治?     

肝移植后乙型肝炎病毒再感染的检测

目的 检测乙型肝炎所致的终末期肝病患者肝移植前、后血清乙型肝炎病毒（HBV）DNA的含量，探讨HBV再感染的检测方法。方法 采用荧光定量聚合酶链反应（FQPCR）技术检测275例乙型肝炎所致终末期肝病患者肝移植前以及肝移植后1周、1个月、3个月的血清HBVDNA含量，同时采用酶联免疫吸附试验（ELISA法）检测HBV标志物。结果 275例血清标本中，术前乙型肝炎表面抗原（HBsAg）、乙型肝炎核心抗体（抗-HBc）均为阳性；HBsAg、乙型肝炎e抗原（HBeAg）及抗-HBc阳性者的血清HBVDNA均为阳性；HBsAg、乙型肝炎e抗体（抗-HBe）及抗-HBc阳性者73．8％的血清HBV DNA阳性；HBsAg及抗-HBc阳性者67．6％的血清HBVDNA阳性。术后1周患者的HBsAg及HBVDNA均为阴性。术后1个月，69例HBsAg转为阳性，其中48例（69．6％）HBVDNA为阳性。术后3个月，137例HBsAg为阳性，其中104例（75．9％）HBVDNA为阳性。结论 乙型肝炎所致的终末期肝病患者肝移植后HBV的再感染率较高，应用FQPCR检测HBVDNA含量能更准确地反映体内HBV的复制情况，可与HBV标志物检测互补。     

慢性乙型肝炎患者肝细胞HBV ccc DNA与血清HBV DNA及肝纤维化程度的相关性

目的探讨慢性乙型肝炎（CHB）患者肝细胞HBV ccc DNA含量与血清HBV DNA、肝组织纤维化程度的相关性及在抗病毒治疗中的临床意义。方法对48例未接受抗病毒治疗CHB患者（A组）和6例经聚乙二醇化干扰素α-2a规律抗病毒治疗48周CHB患者（B组）进行肝组织活检以检测肝纤维化分期,并应用real time-PCR检测肝细胞HBV ccc DNA含量。分析A组患者肝细胞HBV ccc DNA与肝纤维化程度以及两组患者肝细胞HBV ccc DNA与血清HBV DNA相关性,分析B组患者HBV ccc DNA变化。结果肝细胞cccDNA及血清DNA水平均与肝组织纤维化程度呈负相关,但HBV ccc DNA相关性更强（r=-0.465,P=0.008）。肝细胞HBV ccc DNA与血清HBV DNA不存在相关性（r =0.057, P =0.418）。B组患者肝细胞HBV ccc DNA较对照组（自A组中选取性别、年龄及HBV DNA无差异患者共12例）显著下降,其中3例患者血清HBV DNA载量低于检测下限,但肝细胞仍可检出HBV ccc DNA。结论肝细胞HBV ccc DNA与肝纤维程度呈负相关,而血清HBV DNA水平不能反映肝内病毒复制的程度。CHB患者抗病毒治疗需要长期进行才可能完全清除肝细胞内HBV ccc DNA。     

血清及精浆中乙型肝炎病毒的存在情况对精子质量的影响

目的 探讨血清及精浆中乙型肝炎病毒存在的情况与精子参数、形态学及精子DNA完整性等精子质量的相关性。方法 收集2016年1月至2021年12月在温州医科大学附属第一医院生殖医学中心就诊男性的精液标本,采用微粒子酶免疫分析法检测血清乙肝标志物滴度、荧光定量PCR技术检测血清和精浆中HBV-DNA拷贝水平,同时所有精液标本进行精液参数、精子形态学及精子DNA碎片指数(DFI)分析。根据HBV病毒检测情况将患者分为4组：A组(HBsAg阴性,n=1 122)、B组(血清HBsAg阳性,而HBeAg、HBV-DNA和精浆HBV-DNA拷贝数均阴性,n=460)、C组(血清HBsAg、HBeAg和HBV-DNA拷贝均阳性,而精浆HBV-DNA拷贝阴性,n=81)和D组(血清HBsAg、HBeAg和HBV-DNA拷贝均阳性,且精浆HBV-DNA拷贝阳性,n=112),比较各组之间的基本资料、肝功能及精子质量的差异。结果 根据纳排标准纳入2 063例患者,HBV感染者(HBsAg阳性检出者)占45.6%(941/2 063),最终纳入分组分析的患者共1 775例。与未感染者(A组)相比,HBV感染者...     

肾炎患者糖皮质激素和免疫抑制剂应用中乙肝病毒感染的处理

目的：观察肾炎合并慢性乙肝病毒（hepatitis B virus HBV）感染患者糖皮质激素或糖皮质激素加免疫抑制剂治疗中乙肝病毒复制情况、抗病毒治疗对策以及原发病的缓解情况。方法：HBV DNA阴性组在糖皮质激素、免疫抑制剂治疗前先不加用抗乙肝病毒药物,随访中如出现HBV DNA转阳性再加用拉米夫定100mg/d;HBV DNA阳性组在糖皮质激素、免疫抑制剂治疗前1周开始口服拉米夫定100mg/d;拉米夫定治疗失效者换用恩替卡韦1mg/d治疗。两组患者定期随访肝肾功能、尿常规、24h尿蛋白定量、HBV DNA、HBV病毒变异情况。结果：HBV DNA阴性组8/12例出现HBV DNA转阳性,予拉米夫定100mg/d治疗后,6例HBV DNA转阴,2例下降;HBV DNA阳性组9例HBV DNA滴度逐步下降,但12月后3例出现病毒变异,改用恩替卡韦治疗后HBV DNA重新转阴。结论：肾炎合并慢性乙肝患者,应用糖皮质激素和免疫抑制剂治疗风险大,无论治疗前HBV DNA是否复制表达,都应积极进行抗病毒治疗,并严密监测肝功能和HBV DNA。     

慢性乙型肝炎患者病毒e系统状态与肝纤维化关系的研究

目的:观察慢性乙型肝炎患者乙型肝炎病毒e系统状态和复制指标在肝纤维化发生过程中的变化及其与血清纤维化标志的关系,探讨它们在肝纤维化发生过程中的作用及其可能的临床意义.方法:188例慢性乙型肝炎患者根据肝纤维化程度分为S0～S4期等5组,分别用定量PCR及放免法检测患者血清中HBV-DNA及肝纤维化标志透明质酸、Ⅳ型胶原、Ⅲ型前胶原和层粘连蛋白的含量;HBeAg和抗-HBe采用酶联免疫吸附法(ELISA)检测,并观察其在不同肝病理纤维化分期时的变化.结果:随着肝纤维化程度加重,血清HBV-DNA含量逐渐升高,从S1期开始显著增加(P＜0.01);而HBeAg阳性率逐渐降低,S3、S4期较S0显著减少(P＜0.05和P＜0.01);抗-HBe阳性率呈相反的变化趋势,在S3和S4期的阳性率明显高于S0期(P＜0.05和P＜0.01).血清HBV-DNA( )HBeAg( )组血清纤维化标志最低,HBV-DNA(-)抗-HBe( )组最高,两者差异有显著性(P＜0.01).结论:HBV复制和e系统状态的改变与肝纤维化程度密切相关,肝内病毒复制标志与血清纤维化标志联合检测,对于判断肝纤维化程度和指导抗病毒治疗有重要的价值.     

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.     

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。     

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     

Long-term results of famciclovir for recurrent or de novo hepatitis B virus infection after liver transplantation

Since the introduction of famciclovir in the treatment of hepatitis B virus (HBV) infection after liver transplantation, promising results have been published. In this study, the long-term efficacy and safety of famciclovir were assessed. Twenty-four patients with recurrent hepatitis B and 6 patients with de novo infection after liver transplantation were enrolled in an open prospective trial. Patients received oral famciclovir, 500 mg three times daily. Serum HBV-DNA, viral serology, and liver enzymes were measured sequentially; liver histology was taken before and during treatment in 12 patients. In the reinfected patients, 17 patients initially responded well to treatment, with a mean decrease of HBV-DNA of 82%, 5 patients became HBV-DNA negative. The drug was effective for 1-51 months (mean 16 months), then viral replication increased again in 13 out of 17 patients. One patient did not respond to treatment. Six out of 24 patients already had severe cirrhosis at the time of enrollment and died shortly afterwards, due to the HBV infection. The 6 patients with de novo infection all had a decline of HBV-DNA for 2-42 months (mean 14 months); 1 patient converted to HBV-DNA negative. Five out of 6 patients experienced a viral breakthrough later on. No severe side-effects were observed. Therefore, famciclovir is effective in certain HBV-infected patients after orthotopic liver transplantation (OLT), but in the long term, most of the patients relapse.     

Improved clinical outcomes with liver transplantation for hepatitis B-induced chronic liver failure using passive immunization.

OBJECTIVE: The goals were to summarize the results of liver transplantation for chronic hepatitis B disease (HBV) at the University of Virginia, correlate pretransplant viral markers with posttransplant hepatitis B immunoglobulin (HBIg) requirements, and identify the relation between viral protein in the liver and clinical reinfection. SUMMARY BACKGROUND DATA: Liver transplantation is an accepted treatment for end-stage liver disease from chronic HBV infection, although lifelong antiviral treatment (with HBIg or antiviral agents) is still necessary. Patients with evidence of active viral replication (detectable serum HBV-DNA or e antigen) at the time of transplant have a higher rate of allograft infection. Whether clinically stable patients receiving HBIg immunoprophylaxis have detectable viral products in their grafts remains unknown. METHODS: Forty-four transplants performed for HBV disease at the University of Virginia since March 1990 were reviewed. Most patients underwent aggressive passive immunoprophylaxis with HBIg to maintain serum HBV surface antibody (HBsAb) levels > or =500 IU/l for the first 6 months after the transplant, and > or =150 IU/l thereafter. Patients had viral markers quantified, underwent pharmacokinetic analysis of HBsAb levels to adjust dosing, and were biopsied routinely every 3 to 6 months and when indicated. RESULTS: Forty-four transplants were performed in 39 patients. Actual 1-year and 3-year graft survival was 95% and 81%, respectively, and 1-year and 3-year patient survival was 98% and 96%, respectively. After the adoption of indefinite HBIg prophylaxis, nine grafts became infected (all in recipients positive for HBV e antigen). Three occurred within 8 weeks of transplantation and were associated with a short HBsAb half-life and a wild-type virus. Six occurred >8 months after the transplant, and most of these were associated with viral mutation. Quantification of pretransplant markers was an overall poor predictor of HBIg requirements after the transplant. Immunohistochemistry demonstrated transient low-level expression of core protein in the liver in 23% of patients without serum or clinical evidence of recurrent hepatitis. CONCLUSIONS: An excellent outcome is possible after liver transplantation for chronic HBV disease using HBIg dosed by pharmacokinetic parameters. Currently, quantification of pretransplant serum markers of the HBV antigen load does not predict the intensity of posttransplant treatment required for good clinical outcomes. Because HBV is not eradicated from the patient, some form of indefinite antiviral therapy continues to be warranted.     

化学发光技术检测乙肝前S1蛋白的临床价值

目的：采用化学发光技术检测乙肝前s1蛋白（pre-S1）和乙肝两对半，探讨乙肝pre-S1作为反映乙肝病毒感染、复制、传染性及肝细胞损伤指标的临床意义。方法：采用化学发光技术检测337例乙肝表面抗原阳性患者的血清乙肝两对半和pre-S1，比较不同乙肝两对半模式患者pre-S1的阳性率。结果：乙肝表面抗原的S／CO值高低与pre—s1有关，乙肝表面抗原S／CO值越高，pre—s1的阳性率越高，不同两对半模式pre-S1阳性率不同，其中以“大三阳”EHBsAg（＋）／HBeAg（＋）／HBcAb（＋）]的阳性率最高（93．3％）。乙肝e抗原与pre—s1结果差异有显著性（P〈0．01）。结论：化学发光技术检测前S蛋白能较早以及较准确地反映乙肝病毒复制的情况，对于条件不适合做乙肝病毒DNA的实验室，pre—s1是乙肝两对半的补充。     

Clinical and virological effects during two years of ongoing adefovir dipivoxil in the treatment of lamivudine-resistant chronic hepatitis B infection

OBJECTIVE: Our aim was to evaluate the efficacy and safety of adding adefovir to lamivudine therapy for hepatitis B virus (HBV)-infected patients resistant to Ramivudine. PATIENTS AND METHODS: Among 17 studied patients, 7 had chronic active HBV infection and 10 were posttransplant with HBV infection (9 with de novo HBV). They received lamivudine plus adefovir therapy for 2 years. We assessed reductions in serum HBV-DNA and alanine aminotransferase (ALT) levels, loss of HBeAg (in HBeAg+ cases), and HBsAg clearance. RESULTS: A virological response, as defined by HBV-DNA below the cut off by hybridization, was observed in 12 (70.6%) patients and loss of HBeAg in 4 (44.4%) of the 9 initially HBeAg-positive cases. A biochemical response, defined as a decreased serum ALT to the normal range, occurred in 4 (26.7%) patients. Median serum creatinine increased in 3 of 15 (20%) patients, excluding those on hemodialysis. There were two noteworthy cases of sustained HBsAg seroconversion with adefovir (11.8%): one patient with de novo HBV infection posttransplantation and positive hepatitis C virus-RNA serology, and one patient with decompensated HBV cirrhosis in whom viral replication ceased, making him eligible for transplantation. CONCLUSIONS: Currently, adefovir is an effective rescue therapy that broadens the existing range of options for patients with lamivudine-resistant chronic hepatitis B infection, particularly those with decompensated cirrhosis awaiting a liver graft, and those with recurrent posttransplantation HBV. The relatively small biochemical response seen in these patients may be attributable to the high prevalence of concomitant hepatitis C virus infection (41%).     

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.     

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.