肝移植后血清乙肝表面抗体的来源及临床意义

肝移植是终末期肝脏疾病最有效的治疗手段。乙肝高价免疫球蛋白(HBIG)是预防乙肝相关性肝脏疾病肝移植术后乙肝复发的主要药物之一，据信与拉米呋啶合用可取得令人满意的预防效果。我们在临床实践中发现未使用HBIG的乙肝相关性肝脏疾病肝移植后近期乙肝表面抗体总体阳性率     

肝移植术后乙型肝炎复发的回顾性分析

目的:回顾性分析肝移植术后乙型肝炎(乙肝)复发的发病及防治情况.方法:对我院1994年5月～2003年3月因乙肝相关性终末期肝病接受肝移植手术病人进行回顾性分析,调查其术前、术后乙肝相关检查及复发情况.结果:在351例病人中,围手术期(术后30 d以内)因感染、多脏器功能衰竭等各种原因而死亡的病人59例.生存>30 d的292例病人中有19例出现乙肝复发,乙肝复发率为6.51%(19/292),其中未使用任何预防措施的7例病人中,复发率为71.43%(5/7);单用拉米夫定的15例病人中,复发率为13.33%(2/15),拉米夫定联合低剂量乙肝免疫球蛋白(HBIG)的270例病人中,复发率为4.44%(12/270).3组病人复发率比较具有统计学差异(P<0.001).乙肝复发时间在0.3～66.6个月(中位值为6.1个月);复发后采取加用或改用阿德福韦(Adefovir)或恩替卡韦(Enticavir)等措施,疾病得到控制.结论:核苷类似物联合低剂量HBIG的应用能有效预防肝移植术后乙肝复发,及时发现及治疗可改善乙肝复发病人预后.定期监测术后长期生存病人的乙肝标记物及HBV-DNA十分重要.     

联合应用拉米呋定和乙肝免疫球蛋白预防肝移植术后乙肝复发的疗效观察

目的观察联合应用拉米呋定和小剂量乙肝免疫球蛋白预防肝移植术后乙肝复发的临床疗效。方法回顾性分析35例乙肝病毒（hepatitis B virus．HBV）相关终末期肝病患者行肝移植术后联合应用拉味夫定和小剂量乙肝免疫球蛋白的临床资料．观察此方案对预防肝移植术后乙肝病毒再感染的疗效。结果4例肝移植术后发生乙肝复发,复发率11％．其余31例病毒标志物均为阴性。结论联合应用拉米呋定和小剂量乙肝免疫球蛋白可以有效地预防乙肝病毒相关终末期肝病肝移植术后乙肝复发,小样本短期随访效果满意,有待于进一步大样本长期观察     

"大三阳"乙肝病人肝移植后抗HBV治疗远期效果分析

目的 通过长期观察大三阳乙肝病人肝移植后在LAM或(和)HBIG预防下其体内HBV标志物的变化.探讨乙肝复发的可能机制,为预防复发及个体化治疗寻找切人点.方法 ELISA、HBV-DNA荧光定量、免疫组化定期检测术前术后各期血清及其供肝活检组织,回顾性观察55例大三阳病人随访中HBV标志物的变化.结果 平均随访69.14个月,共12例乙肝再感染/复发,LAM+HBIG组乙肝复发比率为4.8%(2/42),而LAM组为76.9%(10/13)(P=0.000).联合组1、2、3、4年生存率分别为100%、97.1%、92.7%、92.7%;单用组1、2、3、4年生存率分别为76.9%、69.2%、53.8%、46.2%(P=0.000);前者2年内乙肝复发率<3%,后者1、2、3、4年复发率分别为16.1%、41.3%、66.4%、66.4%(P=0.000).结论 HBIG联合核苷(酸)类似物作为当前最佳的乙肝复发预防方案明显地降低了复发率,治疗依从性差及病毒的自身状态是中国肝移植后乙肝再感染/复发的主要原因.根据治疗过程中病毒自身状态的变化及时调整用药将有助于进一步减少术后乙肝复发.     

原发性肝癌术后HBV活跃复制者拉米呋啶治疗对肿瘤复发的影响

目的 探讨肝癌根治术后HBVDNA活跃复制病人应用拉米呋啶治疗对肿瘤复发的影响.方法 将41例原发性肝癌根治性切除术后血清HBVDNA＞105 copies/ml病人随机分2组:治疗组21例(手术切除+拉米呋啶),对照组20例(单纯手术切除);同期22例肝癌根治术后HBVDNA ＜500 opies/ml病人作阴性组.观察各组术后血清HBVDNA、ALT水平、e抗原表达、复发时间作统计学分析.结果 治疗组和对照组术后1年HBVDNA清除率为76.2%和15%(P＜0.01),e抗原转阴率为45.5%和22.2%(P＞0.05);治疗组、对照组、阴性组术后1年肝癌复发率分别为28.98%、50%、22.73%,治疗组显著低于对照组(P=0.022),与阴性组无差异(P=0.508);治疗组与对照组术后中位复发时间分别为20个月和11个月(P=0.043).结论 肝癌根治术后HBV活跃复制者应用拉米呋啶治疗可提高HBVDNA清除率,有助于延长肿瘤复发时间.     

乙肝病毒相关性肝病肝移植术后乙肝病毒再感染的防治

目的　探讨联合应用拉米呋啶、乙肝免疫球蛋白预防肝移植术后乙肝病毒再感染的疗效。方法　回顾性研究 6例乙肝病毒相关终末期肝病患者肝移植术后联合应用拉米呋啶、乙肝免疫球蛋白的临床资料 ,分析总结该方案对预防肝移植术后乙肝病毒再感染的疗效。结果　 1例于术后 3月内HBV DNA阳性 ,余 5例病毒检查阴性。结论　联合应用拉米呋啶、乙肝免疫球蛋白可有效预防乙肝病毒相关终末期肝病肝移植术后乙肝病毒再感染     

乙肝病毒相关性肝病肝移植术后乙肝病毒再感染的防治

目的 探讨联合应用拉米呋啶、乙肝免疫球蛋白预防肝移植术后乙肝病毒再感染的疗效。方法 回顾性研究6例乙肝病毒相关终末期肝病患者肝移植术后联合应用拉米呋啶、乙肝免疫球蛋白的临床资料，分析总结该方案对预防肝移植术后乙肝病毒再感染的疗效。结果 1例于术后3月内HBV-DNA阳性，余5例病毒检查阴性。结论 联合应用拉米呋啶、乙肝免疫球蛋白可有效预防乙肝病毒相关终末期肝病肝移植术后乙肝病毒再感染。     

拉米夫定及乙型肝炎免疫球蛋白预防肝移植后乙型肝炎复发的疗效观察

目的:研究单用拉米夫定或与乙型肝炎(乙肝)免疫球蛋白(HBIG)联合应用对乙肝相关肝病病人肝移植术后预防乙肝复发的效果。方法:应用酶联免疫试验(EIA)检测HBsAg、抗鄄HBs、HBeAg、抗鄄HBe及抗鄄HBc;用聚合酶链反应法(PCR)检测乙肝病毒(HBV)DNA。26例单用拉米夫定15例,联合应用拉米夫定和HBIG11例。结果:26例乙肝相关肝病病人于肝移植术后随访3～24个月,2例死亡,4例出现乙肝复发,其余20例病人HBsAg持续阴性。结论:肝移植是治疗乙肝终末期病人的有效方法,拉米夫定与HBIG联合应用可有效预防肝移植术后乙肝复发。     

恩替卡韦联合乙肝免疫球蛋白预防肝移植术后乙肝复发

肝移植是乙肝相关终末期肝病的最主要适应证,而肝移植术后乙肝复发则是影响肝移植受者长期生存的主要原因之一.文献报道,拉米夫定联合乙型肝炎免疫球蛋白(hepatitis B immuno globulin,HBIG)预防移植术后乙肝复发,其1年复发率为2.1%～13.5%,2年复发率为4.5%～15.2%[1-2].目前,用恩替卡韦联合HBIG预防肝移植后乙肝复发的文献报道较少.本文对我中心2007年1月至2009年4月采用恩替卡韦联合HBIG以及拉米夫定联合HBIG预防肝移植术后乙肝复发的104例临床资料进行了回顾性分析.     

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。     

肝移植术后乙肝复发的预防与处理

目的总结和探讨肝移植术后乙肝复发的预防与处理。方法回顾性分析253例乙肝相关性肝病行肝移植术患者乙肝防治方法、术后乙肝复发的处理。结果术后乙肝复发者7例,复发率2.76%。复发后分别采用加大乙肝免疫球蛋白(HB IG)剂量、改用恩替卡韦、加用贺维力等措施,2例HBsAg经治疗后转阴,2例HBsAg明显下降,总有效率57%。结论肝移植术后HB IG 拉米夫丁能有效预防肝移植术后乙肝复发,HB IG、恩替卡韦、贺维力能不同程度控制肝移植术后乙肝复发。     

Combination Low-Dose Hepatitis B Immune Globulin and Lamivudine Therapy Provides Effective Prophylaxis Against Posttransplantation Hepatitis B

Although antiviral prophylaxis with lamivudine monotherapy appears to reduce post–liver transplantation recurrence of hepatitis B virus (HBV) infection, breakthrough infections occur in at least 20% of the patients because of the development of drug resistance. Combined lamivudine and intravenous hepatitis B immune globulin (HBIG) therapy (10,000-IU doses) may reduce this risk, but its use is limited by cost (∼US $45,000/yr) and availability. We report the experience at liver transplant centers in Australia and New Zealand in which lamivudine has been used in combination with much lower doses of HBIG than used in conventional HBIG prophylaxis. Lamivudine, 100 mg/d, was administered to hepatitis B surface antigen (HBsAg)–positive candidates on listing for transplantation and was continued posttransplantation. HBIG, 400 or 800 IU, was administered intramuscularly (IM) daily for 1 week from transplantation and monthly thereafter. Thirty-seven HBsAg-positive patients underwent transplantation using this protocol. Thirty-six of these patients were HBV DNA positive by polymerase chain reaction (PCR) or hybridization assay. Thirty-four patients had chronic HBV, 2 patients had hepatitis B and C, and 1 patient had hepatitis B, C, and D. Five patients died within 1 month of transplantation and are not included in the analysis. Mean follow-up in the remaining 32 patients was 18.4 months (range, 5 to 45 months). Treatment was well tolerated, with no significant adverse events. Thirty-one of 32 patients were HBsAg negative, and all 32 patients were HBV DNA negative by PCR at latest follow-up. The cost of treatment was US $967 for lamivudine and between $2,290 and $4,480/yr for IM HBIG. Lamivudine and low-dose HBIG treatment prevents posttransplantation recurrence of hepatitis B and is likely to be more cost-effective than high-dose HBIG regimens.(Liver Transpl 2000;6:429-433.)     

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.     

An Efficacy and Cost-Effectiveness Analysis of Combination Hepatitis B Immune Globulin and Lamivudine to Prevent Recurrent Hepatitis B After Orthotopic Liver Transplantation Compared With Hepatitis B Immune Globulin Monotherapy

Orthotopic liver transplantation (OLT) for hepatitis B virus (HBV) infection was limited until recently by poor graft and patient outcomes caused by recurrent HBV. Long-term immunoprophylaxis with hepatitis B immune globulin (HBIG) dramatically improved post-OLT survival, but recurrent HBV still occurred in up to 36% of the recipients. More recently, combination HBIG and lamivudine has been shown to effectively prevent HBV recurrence in patients post-OLT. The aim of the current study is to determine long-term outcome and cost-effectiveness of using combination HBIG and lamivudine compared with HBIG monotherapy in patients who undergo OLT for HBV. A retrospective chart review identified 59 patients administered combination HBIG and lamivudine and 12 patients administered HBIG monotherapy as primary prophylaxis against recurrent HBV. Lamivudine, 150 mg/d, was administered orally indefinitely. HBIG was administered under a standard protocol (10,000 IU intravenously during the anhepatic phase, then 10,000 IU/d intravenously for 7 days, then 10,000 IU intravenously monthly) indefinitely. A decision-analysis model was developed to evaluate the potential economic impact of prophylaxis against HBV with combination therapy compared with monotherapy. Recurrent HBV was defined as the reappearance of hepatitis B surface antigen (HBsAg) after its initial disappearance post-OLT. In the combination-therapy group, no patient redeveloped serum HBsAg or HBV DNA during mean follow-ups of 459 and 416 days, respectively. In the monotherapy group, 3 patients (25%) had reappearance of HBsAg in serum during a mean follow-up of 663 days. Combination therapy resulted in a dominant, cost-effective strategy with an average cost-effectiveness ratio of $252,111/recurrence prevented compared with $362,570/recurrence prevented in the monotherapy strategy. Combination prophylaxis with HBIG and lamivudine is highly effective in preventing recurrent HBV, may protect against the emergence of resistant mutants, and is significantly more cost-effective than HBIG monotherapy with its associated rate of recurrent HBV. (Liver Transpl 2000;6:741-748.)     

Network meta-analysis on prophylactic regimens against recurrent hepatitis B virus infection after liver transplantation

Background

Previous meta-analyses of non-randomized studies suggested that the hepatitis B immunoglobulin (HBIG) and lamivudine (LAM) combination therapy was significantly better than HBIG or LAM alone in preventing hepatitis B virus (HBV) recurrence after transplantation. However, substantial evidences supporting the superiority of combination therapy are still insufficient. Therefore, we sought to conduct a multiple-treatment comparison to integrate current data which was based on randomized controlled trials (RCTs).

Methods

We searched electronic databases of PubMed, Embase and the Cochrane Library for eligible literatures. Pair-wise meta-analyses were to synthesize studies comparing the same pair of treatments. Appropriate networks for overall and 1-year recurrence rates were established. Bayesian algorithm was used in multiple-treatment comparisons to compare relative effects of all included regimens.

Results

Four RCTs on prophylaxis against HBV recurrence after liver transplantation, involving 162 participants, were included. HBIG mono-therapy, LAM mono-therapy and HBIG plus LAM showed no statistically difference in risk ratios (RRs) in terms of overall HBV recurrence rate in network meta-analysis. Nevertheless, HBIG mono-therapy had potential advantage compared with combination of HBIG and LAM in 1-year HBV recurrence rate [RR 0.00, 95% confidence interval (CI): 0.00 to 0.91] while the rest comparisons revealed no significance. The cumulative probabilities of treatments associated with the highest recurrence were (overall HBV recurrence rate, 1-year HBV recurrence rate): HBIG (18%, 1%), LAM (32%, 42%) and HBIG plus LAM (50%, 57%).

Conclusions

This network meta-analysis based on data from RCTs showed no significant differences among HBIG mono-therapy, LAM mono-therapy, combination of HBIG and LAM in overall HBV recurrence rate after liver transplantation. Further well designed and large-scale RCTs are warranted to clarify these issues.     

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.     

Recurrence of hepatitis B is associated with cumulative corticosteroid dose and chemotherapy against hepatocellular carcinoma recurrence after liver transplantation.

The incidence of hepatitis B (HB) recurrence after a liver transplantation has been reduced by prophylaxis with hepatitis B immunoglobulin (HBIG) and lamivudine. However, the long-term incidence of recurrence is <10%, and the factors associated with HB recurrence are unclear. This study analyzed the factors associated with HB recurrence in 203 recipients who underwent liver transplantation for HB in 3 major centers in Korea over 4 years. Eighty-five patients (41.9%) had a hepatocellular carcinoma (HCC). Preoperative active virus replicators with the HBeAg(+) (46.8%) and/or hepatitis B virus DNA(+) (39.4%) were observed in 136 patients (67.0%). The HB prophylaxis consisted of either HBIG monotherapy (n = 95, HBIG group) or combination therapy with lamivudine (n = 108, combination group). HB recurrence was defined as the appearance of the HBsAg. The follow-up period was 28.3 +/- 13.1 months (mean +/- SD). HB recurred in 21 patients (10.3%) after transplantation. The time from transplantation to recurrence was 16.3 +/- 9.4 months. Pre-LT DNA positivity was more prevalent in HBIG group (55.8%) than in the combination group (39.8%) (P = 0.015). However, the incidence of HB recurrence was similar in the HBIG (6.3%) and combination group (13.8%), as well as between the active replicators (12.5%) and nonreplicators (4.1%) (P < 0.05). There was a far higher incidence of HB recurrence in patients receiving corticosteroid pulse therapy (21.0% vs. 7.9%), patients who experienced HCC recurrence (31.3% vs. 8.6%), and patients receiving chemotherapy to prevent HCC recurrence (25.0% vs. 4.4%) (P < 0.05). The cumulative corticosteroid dose was higher in patients who experienced recurrence of HB (P = 0.002). Multivariable analysis confirmed the effect of the cumulative corticosteroid dose and chemotherapy to be risk factors. Liver transplantation for HB is safe, with low recurrence rates if adequate prophylaxis is used. However, the cumulative corticosteroid dose and the chemotherapy used for HCC were risk factors for HB recurrence, so careful monitoring for HB recurrence is needed in these patients.     

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.     

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.