化疗相关乙肝病毒再激活的诊治现状

全球近1／3的人口感染过乙肝,多数分布在许多亚洲国家中。我国是乙肝大国,我国现有的慢性乙肝病毒感染者约9300万人。化学治疗是肿瘤综合治疗中的一项重要手段,随着人口寿命增加和癌症发病率逐年增长,癌症患者接受化疗治疗后,乙肝病毒再激活已经成为癌症化疗中不可忽视的问题。再激活可能导致严重肝损害,迫使患者推迟化疗甚至死于肝衰竭。化疗病人乙肝病毒再激活能够被核苷（酸）类药物有效地预防,但预防及治疗的最佳策略仍在研究中。     

拉米夫定预防免疫抑制剂诱导乙型肝炎病毒再激活的临床研究

目的研究慢性HBV感染者接受免疫抑制剂时使用拉米夫定防治HBV再激活的重要性和必要性。方法选择患有自身免疫性疾病、肿瘤需进行细胞毒性药物化学治疗或免疫抑制剂治疗的慢性HBV感染者为研究对象。对照组：组内所有患者在接受免疫抑制剂治疗之前未接受核苷类似物预防性抗病毒治疗。预防组：在使用免疫抑制剂或细胞毒性药物化学治疗前应用拉米夫定治疗,观察HBV再激活的情况和临床表现。用χ2检验比较两组的再激活率。结果两组病例在随访期间再激活率比较,差异有统计学意义（χ2=19.41,P〈0.001）。结论 HBV感染者使用免疫抑制剂时,会诱发HBV感染再激活,肝炎活动甚至肝功能失代偿。使用拉米夫定能有效预防免疫抑制剂诱导的HBV感染再激活和肝脏炎症再活动,并且有良好的安全性。     

抗肿瘤药物与乙肝再激活风险的研究进展

乙肝再激活（HBV-R）是指宿主免疫和病毒复制之间的平衡被打破,乙型肝炎病毒（HBV）携带者从隐性感染状态转变为显性感染状态,或导致的显性感染状态急性加重。HBV-R的发生可影响抗肿瘤治疗疗效甚至对患者生命带来威胁。通过综述各类抗肿瘤药物相关HBV-R的国内外研究进展,期望为临床实践中抗肿瘤药物相关HBV-R的风险分层评估及其防治管理提供参考。     

真菌产生的新核苷转运抑制剂增强药物的抗肿瘤活性

从南极土壤中分离的一株真菌所产生的抗生素C3368-B(CB)有较强的核苷转运抑制活性。CB显著抑制艾氏腹水癌(EAC)细胞的胸苷和尿苷转运,IC₅₀分别为7.5和9.6μmol·L^-1。用克隆生成法测定,CB在本身无明显细胞毒性剂量下,能显著增强氨甲蝶呤(MTX)、5-氟脲嘧啶(5FU)和丝裂霉素C(MMC)等抗癌药物对人口腔鳞癌KB细胞和人肝癌BEL-7402细胞的杀伤。生长抑制法结果显示,CB还能部分逆转小鼠白血病L1210/MDR细胞对长春新碱(VCR)和放线菌素D(ACD)的抗药性。结果提示新核苷转运抑制剂CB可能应用于肿瘤联合化疗的前景。     

使用免疫抑制剂的肾病患者抗乙肝的治疗分析

目的调查分析广州市某医院长期使用免疫抑制剂治疗的患者对应用核苷类似物抗病毒的情况,以指导临床合理用药。方法收集2005～2010年间肾内科患有自身免疫性疾病和结缔组织疾病所致的肾损伤及肾移植术后合并HBV感染患者52例,A组33例使用免疫抑制剂同时服用核苷类似物,B组19例使用免疫抑制剂即已出现HBV再激活后,及时加用核苷类似物;并且分析病例资料、HBV-DNA水平和肝酶(ALT)及治疗期间用药情况。结果 A组中HBV再激活3例(9.1%),其中有2例重型肝炎,有1例肝硬化;B组HBV再激活3例(15.8%),其中3例肝硬化,无死亡病例。因此A组HBV发生率低于B组(P<0.05)。总体上讲,A组疗效优于B组。结论乙肝患者在使用免疫抑制剂前服用核苷类似物进行抗HBV治疗可有效降低HBV再激活概率。若已接受免疫抑制剂治疗,及时加用核苷类似物进行抗HBV治疗,仍可在很大程度上减少HBV再激活的概率。     

全腹腔镜和传统开腹肝癌切除术对乙型肝炎病毒再激活的影响

目的研究全腹腔镜和传统开腹肝癌切除术对乙型肝炎病毒(HBV)再激活的影响。方法对158例行肝癌切除手术治疗的患者资料进行回顾分析,其中行全腹腔镜手术者102例,开腹手术者56例,依据术后HBV再激活情况,分析影响HBV再激活危险因素。结果 20例患者发生术后HBV再激活,Logistic单因素和多因素分析显示,手术方式[OR值(95%CI)为3.217(1.325,8.624),P=0.012]和抗病毒治疗[OR值(95%CI)0.351(0.115,0.749),P=0.025]是影响术后HBV再激活的独立危险因素;全腹腔镜组、开腹组HBV再激活率分别为8.5%和27.3%,差异有统计学意义(P<0.05);全腹腔镜组肿瘤大小、手术时间、术中失血量、术中输血例数均显著小于或短于传统开腹组,差异具有统计学意义(P<0.05);HBV再激活患者中抗病毒治疗者11例,抗病毒治疗的HBV表面抗原阳性率和高HBV-DNA拷贝量例数显著高于未抗病毒治疗,差异具有统计学意义(P<0.01)。结论手术方式和抗病毒治疗是影响术后HBV再激活的独立危险因素,传统开腹肝癌切除术过程手术时间的延长、术中失血量的增多和输血均会增加HBV再激活风险,选择腹腔镜手术和术前抗病毒治疗可降低HBV术后再激活风险。     

紫杉醇联合铂类方案化疗致卵巢癌乙型肝炎病毒再激活9例并文献复习

目的探讨紫杉醇联合铂类方案化疗对卵巢癌患者乙型肝炎病毒（HBV）再激活的机制及临床表现、治疗方法。方法回顾性分析我院2005年6月～2008年12月期间,采用紫杉醇联合铂类方案治疗卵巢癌合并HBV携带出现HBV再激活9例,并进行有关文献复习。结果9例携带HBV的卵巢癌患者化疗后均出现肝功能损害,符合HBV再激活诊断标准,诊断为HBV再激活,发生的时间为化疗2～4个疗程。9例HBV再激活后均接受了拉米夫定抗病毒治疗,2例化疗延期,5例终止化疗,2例死亡,抗病毒治疗效果不佳。结论紫杉醇联合铂类方案化疗可导致携带HBV的卵巢癌患者HBV再激活,其原因可能与该方案中紫杉醇和铂类均为细胞毒性药物,同时还与在使用紫杉醇过程中为预防过敏反应使用大剂量激素预处理有关。     

一例免疫检查点抑制剂治疗后HBV再激活患者的药学监护

目的 为临床药师参与原发性肝癌免疫检查点抑制剂治疗后HBV再激活患者的药学分析和监护提供经验和参考。方法 回顾性分析临床药师参与的1例原发性肝癌患者免疫治疗后出现免疫相关不良反应,对症治疗后出现HBV再激活进而肝衰竭的整个治疗及监护过程。结果 分析患者HBV再激活及肝衰竭的原因,并分析HBV感染者是否可以使用免疫治疗、发生HBV再激活后的治疗方法、以及肝衰竭的治疗方法。结论 临床药师需培养药学与临床相结合的独立思维能力、解决罕见问题的能力,确保治疗的安全性及有效性。     

丹酚酸A抑制核苷转运并增强化疗药物的抗肿瘤作用丹酚酸A抑制核苷转运并增强化疗药物的抗肿瘤作用

目的观察丹酚酸A(SAA)的抑制核苷转运活性及其抗肿瘤作用。方法用3H-TdR和3H-UR转运测定法,克隆生成测定法以及小鼠移植性肉瘤180模型。结果SAA抑制艾氏腹水癌细胞的胸苷和尿苷的转运,其IC₅₀分别为18.1和17.1 μmol·L^-1。SAA能明显增强5-FU、丝裂霉素C、MTX对KB细胞、肝癌BEL-7402细胞的细胞毒性。体内试验,SAA 200 mg·kg^-1和5-FU 10 mg·kg^-1单独使用的抑瘤率分别为41%和27%;SAA和5-FU联合使用的抑瘤率为63%(CDI=0.86)。结论SAA有抑制肿瘤细胞核苷转运的活性,可增强5-氟尿嘧啶等药物的抗肿瘤作用,有可能用于肿瘤联合化疗。     

用核苷(酸)类似物治疗乙肝患者致病情加重42例临床分析

目的:分析核苷(酸)类似物治疗乙肝患者后病情加重的可能原因。方法:对42例用核苷(酸)类似物抗病毒治疗后病情加重的乙肝患者的资料进行回顾性分析。结果:予乙肝患者抗病毒治疗2周时谷丙转氨酶(ALT)、总胆红素(TBIL)在治疗2,4,6周较治疗前明显上升,差异具统计学意义(P<0.05);反之,凝血酶原活动度(PTA)在治疗2,4周,前白蛋白(PAB)在治疗2,4周时较治疗前均明显下降,差异具统计学意义(P<0.05),而白蛋白(ALB)值变化不大;HBV-DNA定量,治疗后4周即明显下降,差异具统计学意义(t=12.55,P<0.01),其中13例低于检测值,治疗8周时34例低于检测值,12周时HBV-DNA定量均低于检测值。结论:42例患者抗病毒治疗后,HBV-DNA定量下降明显,肝功能指标未改善,尚有恶化趋势,主要表现在予抗病毒治疗后2～4周间,包括黄疸加深,ALT升高,PAB和PTA下降,伴有乏力及消化道等不良反应症状,部分患者出现顽固性腹水,甚至死亡;应用核苷(酸)类似物治疗乙肝患者时应重视其早期病情的变化,以避免肝脏失代偿的发生。     

The main hepatitis B virus (HBV) mutants resistant to nucleoside analogs are susceptible in vitro to non-nucleoside inhibitors of HBV replication

Long-term treatment of chronic hepatitis B with nucleos(t)ide analogs can lead to the emergence of HBV resistant mutants of the polymerase gene. The development of drugs with a different mode of action is warranted to prevent antiviral drug resistance. Only a few non-nucleosidic molecules belonging to the family of phenylpropenamides (AT-61 & AT-130) and heteroaryldihydropyrimidines (BAY41-4109) can prevent RNA encapsidation or destabilize nucleocapsids, respectively. The sensitivity of the main nucleos(t)ide analog- resistant mutants to these inhibitors was evaluated in vitro. HepG2 stable cell lines permanently expressing wild type (WT) HBV or the main HBV mutants resistant to lamivudine and/or adefovir (rtL180M + rtM204V, rtV173L + rtL180M + rtM204V, rtM204I, rtL180M + rtM204I, rtN236T, rtA181V, rtA181V + rtN236T, rtA181T, rtA181T + rtN236T) were treated with AT-61, AT-130 or BAY-41 4109. Analysis of intracellular encapsidated viral DNA showed that all mutants were almost as sensitive to these molecules as WT HBV; indeed, the fold-resistance ranged between 0.7 and 2.3. Furthermore, the effect of a combination of either AT-61 or AT-130 with BAY41-4109, and the combination of these compounds with tenofovir was studied on wild type HBV as well as on a lamivudine and an adefovir-resistant mutant (rtL180M + M204V and rtN236T, respectively). These combinations of compounds resulted in inhibition of viral replication but showed slight antagonistic effects on the three HBV species. Based on this in vitro study, BAY-41 4109, AT-61 and AT-130 molecules that interfere with capsid morphogenesis are active against the main lamivudine- and adefovir-resistant mutants. These results suggest that targeting nucleocapsid functions may represent an interesting approach to the development of novel HBV inhibitors to prevent and combat drug resistance.     

Does hepatitis B virus therapy reduce the risk of hepatocellular carcinoma?

Introduction: Liver cancer is one of the most common cancers. Hepatocellular carcinoma (HCC) represents > 90% of primary liver cancers and is a major global health problem today. Chronic hepatitis B virus (HBV) infection is associated with more than half of HCCs.

Areas covered: Long-term therapy with nucleos(t)ide analogues (NUCs) improves outcomes in HBV-infected patients by slowing the progression of liver disease. It is associated with improvements in histological and clinical outcomes, improved patient survival, reduced need for liver transplantation and improved liver function in patients with decompensated liver disease. This review highlights the results of previous studies conducted on HCC prevention with long-term NUC therapy. Studies include the use of all available drugs in different clinical scenarios, and the comparison between treated and untreated patients.

Expert opinion: NUCs have been studied extensively in HCC prevention. A comprehensive review of the literature has shown that they can be safely and effectively used for this purpose. Despite some discrepancies between studies, most of the evidence favors using NUC therapy for HCC prevention.     

Recent advances in the treatment of chronic hepatitis B

Introduction: At present, two strategies exist for the treatment of chronic hepatitis B (CHB): i) standard or pegylated interferon alpha (IFN) with mainly immune modulatory effects; and ii) nucleos(t)ide analogues (NA) with direct antiviral effects. The optimal treatment for an individual patient remains controversial.

Areas covered: The treatment efficacy and prediction of response to antiviral agents for chronic hepatitis B are reviewed and discussed.

Expert opinion: The rates of hepatitis B e antigen (HBeAg) and hepatitis B surface antigen (HBsAg) loss or seroconversion are continuously increasing in CHB patients after stopping a finite course of IFN, whereas long-term NA therapy is usually required to improve the adverse outcomes of CHB. Lower baseline HBV DNA level is a strong predictor for both sustained viral suppression and HBeAg seroconversion in patients receiving IFN-based as well as NAs therapy. In addition, HBeAg-positive patients with genotype A or B infection have better responses to IFN-based therapy than those with genotypes C or D infection. Furthermore, on-treatment predictors such as declines of serum HBV DNA, HBsAg and HBeAg levels may be helpful in making decisions of subsequent therapy. Regarding the association of host genetic factors with responses to antiviral therapy, current evidence is limited.     

扶正化瘀制剂抗肝纤维化和治疗慢性肝病的临床疗效

本文介绍扶正化瘀制剂（胶囊/片剂）抗肝纤维化和肝硬化,联合抗乙型肝炎病毒核苷（酸）类似物治疗慢性乙型肝炎及其肝硬化,联合其他药物治疗原发性胆汁性肝硬化和非酒精性脂肪性肝炎,以及治疗肝硬化相关的门静脉高压和代谢障碍等的临床疗效,并介绍扶正化瘀片在美国进行的用于抗慢性丙型肝炎肝纤维化的Ⅱ期临床试验情况。     

Long-term safety and tolerability of entecavir in patients with chronic hepatitis B in the rollover study ETV-901

Objective: To review long-term safety data from the rollover study ETV-901, focusing on adverse events (AEs) with a potential nucleos(t)ide association.

Methods: The open-label study ETV-901 (AI463901) assessed the safety of entecavir in chronic hepatitis B patients who received entecavir, lamivudine or adefovir monotherapy in previous entecavir Phase II/III studies. Long-term cumulative safety results are based on reported AEs, regardless of causal relationship.

Results: Median exposure to entecavir in study ETV-901 was 184 weeks. Commonly reported AEs (≥ 10%) were upper respiratory tract infection, headache and nasopharyngitis. Most AEs were mild to moderate; 203 (19%) patients reported grade 3 – 4 AEs, with 45 (4%) considered related to entecavir. There were 14 (1%) discontinuations due to AEs. On-treatment alanine aminotransferase (ALT) flares were reported in 32 (3%) patients and were associated with a reduction in hepatitis B virus DNA of more than 2 log₁₀ copies/ml in 25/32 patients. AEs potentially associated with nucleos(t)ide analogs were infrequent, the most common being myalgia (n = 54; 5%) and neuropathy-related AEs (hypoparesthesia and hyperparesthesia, polyneuropathy; n = 42; 4%).

Conclusions: Long-term administration of entecavir was associated with low rates of serious AEs, discontinuations due to AEs and ALT flares. AEs potentially associated with nucleos(t)ide use occurred at low rates.     

非核苷类抗乙型肝炎病毒药物的研究进展

目前美国FDA批准的抗乙型肝炎病毒（HBV）药物分为两类：免疫调节剂和核苷类似物。但免疫调节剂的副作用和核苷类似物耐药性病毒株的出现使得慢性乙型肝炎的临床治疗仍然面临着巨大的挑战。因而，非核苷类抗HBV药物的研究引起广泛关注。本文按照不同的结构和作用机制对此类药物的研究进展做一综述。     

Reactivation of hepatitis B virus with rituximab

Rituximab has become a useful drug for the treatment of non-Hodgkin’s lymphoma (NHL) and such autoimmune diseases as idiopathic thrombocytopenic purpura and rheumatoid arthritis. When combined with cytotoxic agents, rituximab showed synergistic effects for the treatment of NHL. In such treatment, hepatitis B virus (HBV) reactivation is a crucial complication when patients are treated with immunosuppressive or chemotherapeutic agents. Despite its treatment efficacy, several studies have pointed out unusual viral infections after its administration that resulted in fatal hepatitis due to HBV reactivation. In the cases at the authors’ institute, the authors analysed the kinetics of HBV antibodies, HBV-reactivation timing, and the prophylactic efficacy of lamivudine. The authors reviewed their cases and the previous literature to clarify the characteristics of HBV-reactivated patients who were administered rituximab.