拉米夫定预防乙型肝炎病毒再激活的临床分析

目的探讨使用免疫抑制剂和（或）细胞毒性化疗药物的乙型肝炎病毒（HBV）感染者HBV再激活的发生率及其抗病毒治疗的疗效。方法预防组33例患者在接受免疫抑制剂和（或）细胞毒性化疗药物治疗前予拉米夫定（LAM）100mg／d并持续至治疗结束后6个月,对照组39例未接受预防治疗,观察两组患者HBV再激活的发生率和临床表现。统计学分析采用两种属性独立性χ2检验,进行危险比评估。结果预防组HBV再激活发生率为12．12％（4／33）,对照组为76．92％（30／39）,预防组HBV再激活发生率低于对照组,χ2=10．35,P=0．001,差异有统计学意义;对照组HBV再激活后患者死亡率、肝炎发生率高于预防组,差异有统计学意义;两组药物性肝损伤、重型肝炎的发病率差异无统计学意义,对照组中有9例进展为重型肝炎,均死亡。结论使用免疫抑制剂和（或）细胞毒性化疗药物的HBV感染者预防性使用LAM可以有效防止HBV再激活,降低病死率。所有需要使用免疫抑制剂和（或）化疗药物的患者在用药前须进行常规HBV筛查。     

拉米夫定与干扰素联合治疗慢性乙型病毒性肝炎的疗效观察

目的观察拉米夫定(3-TC)与干扰素(IFN)联合与单用治疗慢性乙型病毒性肝炎(CHB)的疗效。方法以2种药物分别单用或联合应用,治疗130例CHB患者,观察治疗前后各自临床症状、ALT、病毒标志物水平的变化。结果治疗结束时联合用药组HBV-DNA阴转率为81.6％(62/76),HBeAg阴转率为38.2％(26/68),抗-HBe阳转率为25％(17/68);单用3TC组HBV-DNA阴转率为70.8％(17/24),HBeAg阴转率为10％(2/10),抗-HBe阳转率为5％(1/20);单用IFN组HBV-DNA阴转率为33.3％(10/30),HBeAg阴转率为40％(12/30),抗-HBe阳转率为10％(3/30)。各组患者ALT水平于12周以后均正常。肝炎临床症状改善,应用IFN者副作用稍多,但多数患者可以耐受治疗。结论联合用药组综合疗效优于单独用药组。     

免疫检查点抑制剂抗肿瘤治疗与HBV再激活的关系

近年来,免疫检查点抑制剂(ICI)单药和联合治疗在从实体瘤到淋巴瘤等多种恶性肿瘤中取得了广泛的疗效,并且成为了多种癌症的标准化和系统化治疗模式。然而,在HBV感染的恶性肿瘤患者中,ICI应用的安全性研究尚不多见。有早期研究陆续报道在临床中ICI抗肿瘤治疗所致的HBV再激活。本文通过回顾已有文献,对近年来ICI在慢性病毒感染的癌症患者中的临床试验及应用进展进行综述,阐明这类特殊群体应用ICI的有效性及安全性,以期为临床用药提供一定参考。     

2014年美国胃肠病学会指南:免疫抑制剂治疗过程中HBV再激活的预防及治疗

<正>本指南旨在转述美国胃肠病学会(AGA)关于免疫抑制应用患者HBV再激活的预防及治疗策略,由临床实践和质量管理委员会(美国临床实践指南委员会)编制,并得到AGA理事会授权。本指南是由AGA参考一份已发表指南的相关流程制订的[1]。简而言之,本指南中包括了对推荐等级的评估、制订与评价方法(GRADE)[2]以及医学研究机构的最佳临床实践[3]。按照GRADE方法的要求,准备及收集指南相关的文献资料,     

应用免疫抑制剂或化疗药物的慢性乙肝患者HBV再激活及其治疗

乙型肝炎病毒(HBV)感染呈全球分布,全世界约20亿人曾感染HBV,慢性HBV感染者约3.5亿.中国是HBV高流行区,慢性HBV携带者约1.2亿,占全世界的1/3.在这部分人群中,部分患者因合并其他疾病而需运用免疫抑制剂或化疗药物,由于其免疫功能状态的改变,可能导致HBV再激活,从而引起肝功能受损甚至发生暴发性肝衰竭而威胁生命.     

拉米夫定与干扰素联合治疗慢性乙型病毒性肝炎的疗？…

目的：观察拉米夫定（３－ＴＣ）与干扰素（ＩＦＮ）联合与单用治疗慢性乙型病毒性肝炎（ＣＨＢ）的疗效。方法：以２种药物分别单和或联合应用,治疗１３０例ＣＨＢ患者,观察治疗前后各自临床症状,ＡＬＴ、病毒标志物水平的变化。     

拉米夫定治疗慢性乙型肝炎耐药性的基础与临床研究

拉米夫定(lamivudine)是核苷类似物,对乙型肝炎病毒(HBV)的复制有很好的抑制作用．其主要抗病毒机制是抑制HBV多聚酶的逆转录酶活性,有效阻止病毒核酸的复制合成．拉米夫定因其具有迅速抑制HBV复制,降低病毒载量,促进HBeAg血清转换,改善肝组织炎症坏死病变,延缓肝纤维化进程作用,以及良好的耐受性、安全性和服用方便等特点,已广泛应用于临床．虽然总体上不良反应发生率较低,但是在临床继续应用的几年后遇到了越来越多的治疗问题,尤其是拉米夫定治疗慢性乙型肝炎的耐药性问题．现对拉米夫定治疗慢性乙型肝炎的作用机制、耐药性产生及发生机制、HBV产生耐药性的分子病毒学基础、YMDD变异株的生物学特性及YMDD变异对病情的影响等作了系统全面的阐述,并就预防和处理耐药性问题提出了应对策略,对拉米夫定联合用药等问题作了回顾与展望．     

拉米夫定对免疫受损HBsAg携带者HBV再激活预防和治疗

目的观察拉米夫定对免疫受损宿主HBV再激活的预防和治疗作用。方法将HBsAg阳性免疫受损宿主分为两组：拉米夫定预防组和对照组；预防组在使用免疫抑制剂或细胞毒性化疗之前2～3周开始使用拉米夫定0．1g口服1次／d，进行预防性治疗，对照组在宿主出现HBV再激活表现时开始用相同剂量进行治疗，分别于拉米夫定治疗后或免疫抑制治疗开始后2周、4周、6周、12周、24周检测肝功、HBVM及HBV病毒定量。结果拉米夫定预防组在使用免疫抑制剂或细胞毒性药物过程中或结束后，18．5％（3／16）出现HBV再激活表现；对照组53％（7／13）出现HBV再激活，拉米夫定治疗后71．4％（5／7）病毒转阴，肝功恢复正常，其中2例死于暴发性肝衰竭。结论早期应用拉米夫定可有效预防及治疗免疫受损宿主HBV再激活。     

拉米夫定防治化疗或应用免疫抑制剂患者的乙型肝炎再活动

HBsAg阳性患者应用免疫抑制剂或细胞毒性药物治疗期间或之后有21％～53％发生不同程度的乙型肝炎再活动,死亡率达4％～41％。拉米夫定可有效防治化疗或应用免疫抑制剂患者的乙型肝炎再活动。     

免疫抑制疗法相关的HBV再激活及其预防

乙型肝炎病毒再激活(HBVr)可导致肝功能衰竭,甚至死亡,从而加重疾病负担。近年来,与免疫抑制剂和免疫调节剂相关的HBVr及其预防和治疗已成为研究热点。新型免疫抑制剂和免疫调节剂的陆续研发并获批用于临床,为恶性肿瘤、风湿病等免疫介导的疾病提供了更加完善的治疗方案,极大提高了患者的生存率和生活质量。由于此类药物通过抑制机体免疫反应发挥疗效,在治疗原发病的同时增加了HBVr风险。因此,需要进一步评估各类免疫抑制剂和免疫调节剂的HBVr风险,并提前干预,避免不良事件发生。     

应用细胞毒药物或免疫抑制剂治疗时应重视预防乙型肝炎的发作

根据2006年全国人群乙型肝炎血清流行病学调查结果显示,我国1～59岁人群中HBsAg携带率已从1992年的9.75%降至7.18%,下降了26.36%.其中1～4岁人群HBsAg携带率最低,为0.96%;5～14岁人群为2.42%;15～59岁人群HBsAg携带率最高,达8.57%.按目前HBsAg携带率推算,我国仍然有HBsAg携带者约9300万人.     

Prevention and management of drug resistant hepatitis B virus infections

In the past decade, broadened therapeutic options of oral direct antiviral agents for the treatment of chronic hepatitis B infection include: Lamivudine, Adefovir Dipivoxil, Telbivudine, Entecavir and Tenofovir Disoproxil Fumarate. These direct oral antiviral agents effectively suppress the replication of the virus and reduce the risk of potential liver-related complications. However, prolonged use of these nucleos(t)ide analogues has been associated with drug resistance that compromises the initial clinical benefits. Moreover, the oncogenic risk of mutations due to prolonged nucleos(t)ide analogue therapy needs to be further investigated by in vitro and in vivo studies. In the current era of potent nucleotide analogues, new data are emerging, we are still facing the pool of patients who have developed resistance to the prior generation of nucleos(t)ide analogues. This paper aims to focus on incidence of antiviral drug resistance and virological breakthrough, prudent selection of initial therapy, on-treatment monitoring for drug resistance and revise treatment strategies for patients with resistant virus.     

Prevention and management of hepatitis B virus reactivation in cancer patients

Hepatitis B virus (HBV) reactivation during immunosuppressive therapy is common in patients with solid tumor or hematological malignancies. It is associated with significant morbidity and mortality due to hepatitis flare and/or hepatic decompensation. These consequences arising from HBV reactivation are, however, largely preventable. Routine screening for HBV serologic status is recommended for all cancer patients undergoing chemotherapy or biologics. By recognizing different serological patterns (which represent either overt or occult HBV infection) and the types of immunosuppressive therapies prescribed, a risk-adapted approach can be established. Prophylactic therapy with nucleos(t)ide analogues (prior to or concomitantly with the commencement of immunosuppressive therapies) is more effective than pre-emptive therapy (starting antiviral when HBV DNA level is rising) in high-risk individuals. Entecavir has been proven to be more effective than lamivudine according to recent studies. Close monitoring of serum HBV level is the preferred strategy in low-risk patients. However, the optimal interval of DNA monitoring and the duration of therapy remain unknown.     

Efficacy of hepatitis B virus (HBV) vaccination in treating lamivudine-resistant HBV reactivation following hepatitis B surface antigen seroconversion.

BACKGROUND: HBsAg vaccination might help to control HBV replication following nucleos(t)ide analog therapy. We tested HBsAg vaccine in a patient who developed lamivudine resistance. PATIENT AND RESULTS: An HBeAg negative HBV chronically-infected patient developed HBsAg seroconversion after 3 years of treatment by lamivudine. However, the control of HBV replication was transient and HBV DNA could be detected in the serum one year after lamivudine was stopped. Concurrently, the anti-HBs antibodies (HBsAb) titre had decreased from more than 100 IU/L to 23 IU/L. Due to the presence of rtM204V resistance mutation, lamivudine was not reintroduced and the patient was treated by HBsAg vaccination. After three injections, HBV DNA was no more detectable and the HBsAb titre reached more than 200 IU/L. CONCLUSION: This observation suggests that a regular follow up of patients presenting HBsAg seroconversion following lamivudine therapy is necessary. In these patients, a low titre of HBsAb may not prevent from lamivudine-resistant HBV reactivation. Evaluation of HBsAg vaccination to maintain HBsAb at a high titre in these patients deserves further studies.     

免疫抑制剂致乙肝病毒再激活的临床分析

目的 探讨需要使用免疫抑制剂的乙肝病毒（HBV）感染者使用免疫抑制剂后乙肝病毒再激活的发生及其抗病毒治疗的收益.方法 收集我院近3年收治的46例使用免疫抑制剂患者的临床资料,并分析其免疫抑制剂类型、肝脏损害程度及抗病毒治疗情况.结果 出现乙肝再激活17例（37.0%）,发生重症肝炎6例（13.0%）.接受拉米夫定预防性抗病毒治疗的患者有80%HBV DNA下降,乙肝再激活后再行抗病毒治疗的7例患者中,2例死于肝衰竭.未作抗病毒治疗的患者中有10例（47.6%）乙肝病毒再激活.结论 所有需要使用免疫抑制剂的患者在用药前需要进行常规的HBV筛查,对存在HBV感染的患者需要考虑到HBV再激活.使用强烈的免疫抑制剂、糖皮质激素以及低龄、男性患者容易发生乙肝再激活.对具有高危因素的患者需要及时使用抗病毒药物,抗病毒药物的使用可以降低病毒再激活的风险.     

乙型肝炎病毒基因型、YMDD变异与拉米夫定治疗后HBV DNA反弹关系的研究

目的探讨HBV基因型、YMDD变异与拉米夫定抗病毒治疗后HBV DNA反弹的关系。方法应用多引物对巢式PCR法、PCR-序列分析法检测拉米夫定治疗的27例乙型肝炎患者和19例从未用过抗病毒治疗的患者HBV基因型和P区（YMDD）的突变位点。结果在27例HBV DNA反弹的患者中，13例（48．15％）检出YMDD变异，而对照人群无YMDD变异（P〈0．05）。YMDD变异的位点为rtM204V／I（C区）±rtL180M（B区）；在治疗组YMDD变异的患者中，B、C基因型构成比（46．15％和59．26％）与对照组（53．85％和68．42％）比较无显著性差异（P〉0．05）。结论YMDD变异是拉米夫定治疗后出现耐药导致HBV DNA反弹的主要原因；YMDD变异的常见位点依然为rtM204V／I（C区）±rtL180M（B区）；YMDD变异在B、C基因型病人中无差别。     

Role of lamivudine in the reactivation of hepatitis B virus infection in immunodepressed patients.

INTRODUCTION: hepatitis B virus (HBV) reactivation in immunocompromised states is a well-known event that may be a serious problem in endemic areas of infection. Presently, the investigation of hepatitis B status has been recommended prior to receiving cytotoxic treatment. Lamivudine has been used in the reactivation of HBV in immunocompromised states. We report our corresponding data for lamivudine in the treatment of HBV reactivation after intensive chemotherapy in patients with lymphoma and after kidney transplantation. CLINICAL OBSERVATION: we present two cases of HBV reactivation after chemotherapy for lymphoma and two cases after cadaveric renal transplantation treated with lamivudine (100-150 mg/day). RESULTS: we observed a prompt clinical improvement in all patients after lamivudine treatment. Furthermore, laboratory data showed a rapid biochemical and antiviral response. However, the response in lymphoma patients was quicker than in patients who had post-transplantation reactivation of HBV. Therapy was well tolerated and no relevant side effects appeared during follow-up (twenty four months). The HBV remained negative in three cases. CONCLUSION: lamivudine is effective and safe in the treatment of HBV reactivation in immunodepressed patients. Lamivudine therapy should be considered for the treatment of HBV reactivation in patients with prior hepatitis B or chronic hepatitis B with inactive viral replication.     

Delayed hepatitis B virus reactivation after cessation of preemptive lamivudine in lymphoma patients treated with rituximab plus CHOP

Preemptive lamivudine in lymphoma patients undergoing intensive chemotherapy can effectively prevent chemotherapy-related HBV reactivation. Nevertheless, the safety profile after withdrawal of lamivudine and the impact of rituximab-containing chemotherapy on HBV reactivation has not been defined. To illustrate the necessity of prolonged surveillance after cessation of preemptive lamivudine in lymphoma patients treated with rituximab and chemotherapy, four patients with B-cell NHL carrying HBV received rituximab plus CHOP. Preemptive lamivudine therapy was administered 1 week before chemotherapy until 4 weeks after completion of chemotherapy. Serial serum alanine aminotransferase (ALT), total bilirubin, and HBV-DNA levels were prospectively monitored in three patients. The fourth patient was closely monitored for ALT. The HBV DNA was checked after development of clinical overt hepatitis. The peripheral blood CD20⁺ B-lymphocyte counts were analyzed periodically in two patients. All of the three patients studied prospectively had virological relapses with surgence of HBV DNA 6–8 months after completion of rituximab-plus-CHOP (R+CHOP) therapy. Two of the three patients had biochemical relapses and one of them developed severe hepatitis. Sequencing for HBV polymerase gene in these patients failed to show evident emergence of lamivudine-resistant mutations. The fourth patient developed a hepatitis flare-up 6 months after completion of chemotherapy. The CD20⁺ lymphocytes were totally depleted when HBV DNA started to increase. Delayed HBV reactivation can occur in lymphoma patients receiving R+CHOP after withdrawal of preemptive lamivudine. More protracted lamivudine therapy may be an alternative to close monitoring following chemotherapy, and further studies are needed to define optimal duration of lamivudine therapy.     

Prevention of hepatitis B reactivation with lamivudine in hepatitis B virus carriers with hematologic malignancies treated with chemotherapy--a prospective case series

Administration of immunosuppressive treatment in hepatitis B virus carriers with malignancies is associated with the risk of hepatitis B reactivation. This complication is more frequent in patients with hematologic malignancies because administration of corticosteroids, the mainstay of treatment of these patients, is an independent risk factor for hepatitis B reactivation. When lamivudine is given prior to chemotherapy, it prevents the viral replication during the immunosuppression period; therefore, it might reduce the risk of hepatitis B exacerbation. We performed a prospective study to assess the efficacy of prophylactic administration of lamivudine in this setting. Ten hepatitis B virus carriers with hematologic malignancies were included in this study; seven were HBsAg positive, and three had isolated antiHBc and detectable HBV-DNA levels. Nine patients were given corticosteroids after the administration of lamivudine. Lamivudine was given per os at a dose of 100 mg once daily. In four patients that had not been previously treated with chemotherapy, lamivudine was started 19 days (median) (range, 0-35 days) prior to the onset of chemotherapy. The administration of lamivudine has not stopped since in any of our patients. After a median follow-up of 15 months (range 6-38 months), no hepatitis B reactivation was observed. HBV-DNA levels were decreased in all 6 patients who had detectable HBV-DNA at baseline. Lamivudine was well tolerated. Chemotherapy regimens were administered as planned, and their effectiveness was not compromised by lamivudine. In conclusion, prophylactic administration of lamivudine should be considered as a means of reducing the frequency of hepatitis B reactivation in hepatitis B virus carriers with hematologic malignancies who are being treated with chemotherapy.