核苷类似物抗乙型肝炎病毒耐药相关问题

近年来崛起的抗HBV核苷类似物(NA)所产生的耐药问题,已引起临床医生高度关注。本文从病毒耐药概念,各种NA引起的HBV聚合酶逆转录结构域变异位点,耐药类型,耐药产生的后果,耐药监测及耐药对策进行讨论。     

核苷类药物对HBV复制的抑制机制和HBV对核苷类药物的耐药机制

乙型肝炎病毒(HBV)仍然是全世界面临的对人类危害最大的病原体之一.核苷(酸)类似物药物可以有效抑制HBV的复制,目前已成为治疗HBV感染的首选药物.患者长期用药会导致对耐核苷(酸)类似物的HBV突变体的选择,影响药物的继续使用.本文参考近年来国内外有关研究进展,对核苷(酸)类似物的作用机制和HBV对其的耐药机制作一综述.     

核苷(酸)类似物耐药相关位点分析

目的:分析慢性乙型肝炎患者HBV逆转录酶基因与核苷(酸)类似物耐药相关位点的变异情况与临床耐药的关系。方法:分析不同核苷(酸)类似物的耐药相关突变情况及不同核苷(酸)类似物耐药的突变形式。结果:拉米夫定耐药突变中以M204V/I最常见,可伴随L180M突变,阿德福韦耐药中以N236T±A181位碱基替换为主;恩替卡韦耐药突变发生在拉米夫定耐药基础上;替比夫定的耐药突变为M204I;替诺福韦的变异位点以194位碱基替换为主(rtA194T)。结论:检测HBV逆转录酶基因多位点耐药相关突变,有助于临床及时发现乙型肝炎患者是否存在HBV耐药,从而合理进行抗病毒治疗。     

慢性乙型肝炎长期核苷(酸)类似物治疗过程中HBV储存库的变化规律研究

目的 探究慢性乙型肝炎(CHB)长期核苷(酸)类似物(NA)治疗过程中乙型肝炎病毒(HBV储存库的变化规律。方法 将HBV-脱氧核糖核酸(DNA)低于检测下限>1年、长期服用核苷(酸)类似物治疗的初始为乙型肝炎E抗原(HBeAg)阳性和HBeAg阴性的CHB患者各20例作为研究对象,于纳入后0(基线)、6、12、18个月采集血清标本,通过分析血清中HBV-核糖核酸(RNA)的含量和准种,确定HBV储存库的活动水平和变化规律,分析HBV-RNA评价病毒储存库的意义。结果 对患者0(基线)、6、12、18个月进行HBV、前基因组(pgRNA)和乙型肝炎表面抗原(HBsAg)定量结果发现, HBV、pgRNA和HBsAg不服从正态分布, CHB患者长期核苷(酸)类似物治疗过程中, HBV水平出现逐渐降低的变化规律。对HBV-RNA定量后与对应时期的各病毒学指标进行相关性分析发现, HBV-RNA与pgRNA、HBsAg呈正相关(r=0.64、0.96, P<0.01)。结论 CHB长期核苷(酸)类似物治疗过程中HBVRNA水平出现逐渐降低的变化规律,且与HBsAg呈现出高度相关性...     

核苷(酸)类似物治疗慢性乙型肝炎早期病毒抑制与长期疗效的关系

有效的抗病毒治疗是治疗慢性乙型肝炎的关键.临床上大多数接受核苷(酸)类似物治疗的患者难以通过短期治疗实现持久应答,需要接受长期治疗,但长期应用中有药物耐药风险.研究表明,抗病毒治疗疗效评价最重要的预测指标除HBVDNA基线水平和ALT水平外,还包括治疗最初6个月时或治疗后更早期血清HBV DNA下降的水平.同时抗病毒治疗早期病毒抑制情况和耐药的发生密切相关.早期HBV DNA的水平的监测可以指导治疗过程中方案的调整.本文对近来有关口服核苷(酸)类似物治疗慢性乙型肝炎早期病毒抑制与疗效及耐药发生率的关系做一综述.     

恩替卡韦治疗对阿德福韦酯耐药的慢性乙型肝炎疗效分析

<正>乙型肝炎病毒(HBV)慢性感染是困扰全球的公共性健康问题之一。目前抗HBV药物主要有两类:干扰素和核苷类似物药物治疗,而核苷类似物药物由于口服方便、疗效显著已经被广泛应用[1],但长期接受核苷类似物治疗后,逐年增高的耐药风险和耐药现象,已经成为影响临床决策的重要因素。本研究选用恩替卡韦联合阿德福韦酯治疗阿德福韦酯耐药后的慢性乙型肝炎患者,并对这两种治疗方案的疗效进行比较。1资料与方法     

抗乙型肝炎病毒核苷类似物耐药机制的研究进展

核苷类似物是目前临床上治疗乙型肝炎的重要抗病毒药物,然而由于长期用药,很容易产生耐药性,药物疗效不是很理想。本文就目前抗乙型肝炎病毒(HBV)核苷类似物进行比较并分析其耐药机制。     

乙型肝炎病毒的耐药和耐药管理

抗病毒治疗是慢性乙型肝炎(以下简称乙肝)最根本的治疗方法,目前公认有效的抗乙型肝炎病毒(HBV)药物主要包括干扰素(IFN)类和核苷(酸)类似物.自1998年拉米夫定在全球上市以来,迄今已有拉米夫定(LAM)、阿德福韦酯(ADV)、恩替卡韦(ETV)和替比夫定(LdT)共4种核苷(酸)类似物获国家食品药品监督管理局(SFDA)批准用于抗HBV治疗.相对于干扰素,口服核苷(酸)类似物治疗具有方便有效的优点,但该类药物只有长期治疗才有望实现持久应答,使得HBV产生耐药性的风险大大增加.     

乙型肝炎病毒拉米夫定耐药的监测

随着抗HBV核苷类似物的临床应用，如何组织和开展核苷类似物HBV耐药性监测计划并指导各级医院和国家的抗HBV耐药监测的规范和管理，正确认识核苷类似物的耐药性，这些问题已成为临床医师关注的焦点，研究HBV耐药性对治疗效果的影响可能有重要的临床价值/     

乙型肝炎病毒对核苷(酸)类似物耐药的研究进展

在过去10余年里,口服核苷（酸）类似物的应用使慢性乙型肝炎的治疗取得很大进展。长期核苷（酸）类似物治疗的主要缺陷是乙型肝炎病毒（HBV）耐药性的产生,后者可致所获得的疗效丢失,有时可导致肝炎活动、甚至死亡。本文主要介绍HBV耐药的发生机制、相关定义、发生率、处理及预防策略等。     

Recommendations and potential future options in the treatment of hepatitis B

The natural history of chronic hepatitis B should be clearly defined before appropriate recommendations for treatment can be advocated. In patients who acquire the disease in early life, the complications of chronic hepatitis B continue to occur as a result of prolonged insidious damage to the liver, even in the low viraemic phase. Treatment that ends with hepatitis B e antigen seroconversion with hepatitis B virus DNA levels just below 10(5) copies/ml may not be sufficient. Patients with mild elevation of alanine aminotransferase levels are already at considerable risk of developing complications. Treatment strategy should aim at maximal and prolonged viral suppression to the lowest possible hepatitis B virus DNA levels. Nucleotide/nucleoside analogues will become the mainstay of treatment. Future treatment strategic plans should target maximising antiviral potency and minimising the chance of drug resistance.     

Review article: hepatitis B and liver transplantation

Liver transplantation is an excellent treatment for hepatitis B virus infected patients who have acute or chronic liver failure and/or primary liver cancer. Advances in antiviral prophylaxis prevent clinically significant graft re-infection for the majority of patients. Graft and patient survival has improved significantly during the past decade, and results of transplantation for hepatitis B virus are now superior to those achieved for most other indications. In particular, the availability of lamivudine and adefovir have transformed outcome. The addition of lamivudine to passive immunoprophylaxis with hepatitis B virus immunoglobulin prevents re-infection in most cases. Adefovir should be added to this combination when the patient develops lamivudine resistance before transplantation. The significance of serum hepatitis B virus DNA positivity in the absence of circulating hepatitis B surface antigen is uncertain. Hepatitis B virus infection of the graft can be observed when prophylaxis is inadequate, when the donor liver contains latent hepatitis B virus infection (so-called de novo infection from the hepatitis B virus core antibody positive donor), and when the donor is exposed to third party infection (sexual or nosocomial transmission). Established hepatitis B virus graft infection is a good indication for combination nucleoside analogue therapy. Combination therapy can achieve sustained suppression of viral replication, and hepatitis B e antigen and hepatitis B surface antigen clearance can also be observed.     

抗乙型肝炎病毒新药——阿德福韦酯的研究进展

阿德福韦酯(adefovir)是新一代核苷类抗病毒药物,能够有效抑制逆转录病毒、嗜肝病毒和疱疹病毒等各种病毒的复制和表达。实验研究表明阿德福韦酯不仅对野生HBV有效,对拉米夫定耐药的HBV病毒株也有显著的抑制作用,提示其能够作为拉米夫定耐药病毒感染的补充、替代产品,成为解决乙型肝炎病毒核苷类似物耐药问题的有效办法。阿德福韦酯有望成为联合治疗乙型肝炎的药物之一,可用于两种或多种药物的联合或序贯应用等方式治疗慢性乙型肝炎或HBV／HIV-1的合并感染。本文主要从阿德福韦酯的作用机制、药效毒理、临床药物动力学、体内抗病毒作用、耐药监测、临床用药的安全性等作一总结。     

Novel treatment options for hepatitis B virus infection

Chronic hepatitis B virus (HBV) infection affects between 350 and 400 million people globally. Interferon-alpha, lamivudine and adefovir (Hepsera) are approved for the treatment of chronic hepatitis B; however, the use of interferon-alpha is limited. Lamivudine and adefovir have excellent antiviral activity and oral bioavailability, although viral rebound after cessation of therapy and development of resistance after long-term therapy with lamivudine are major clinical limitations. Adefovir has proven to be effective against lamivudine-resistant strains in vitro and in vivo. The various steps of HBV replication provide opportunities for new antiviral drugs to interact with the virus. Recent developments, including new antivirals that interfere with viral DNA replication, hold promise for the future. Sustained reduction in viral load and improved treatment of chronic HBV infection could, in future, be achieved by the development of new drugs with different mechanisms of action and resistance profiles, and with combination therapy involving two or more nucleosides with or without immunomodulators.     

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.     

Adefovir dipivoxil added to ongoing lamivudine therapy in patients with lamivudine-resistant hepatitis B e antigen-negative chronic hepatitis B

BACKGROUND: Long-term treatment with lamivudine is required to control viral replication in patients with hepatitis B e antigen-negative chronic hepatitis B, but is associated with a high rate of viral resistance. The role of adefovir dipivoxil in these patients has not been definitively evaluated. AIM: To address the role of adefovir in the management of patients with lamivudine-resistant hepatitis B e antigen-negative chronic hepatitis B. METHODS: Patients were assigned to receive adefovir 10 mg once daily plus ongoing lamivudine 100 mg once daily for 52 weeks. The primary end point was reduction in serum hepatitis B virus DNA level (hepatitis B virus DNA response). Secondary end points included the proportion of patients with undetectable hepatitis B virus DNA at week 52 (complete virological response) and the percentage of patients with normalization of alanine transferase level at week 52 (biochemical response). RESULTS: A total of 49 consecutive patients were enrolled in this study. After 52 weeks of treatment, all patients had an hepatitis B virus DNA response and 57.1% had complete virological response. Biochemical response occurred in 75.6% of patients. CONCLUSIONS: Administration of adefovir in patients with lamivudine-resistant chronic hepatitis B results in significant suppression of viral replication. Nevertheless, continuous therapy will probably be needed in order to maintain remission in these patients.     

Occult hepatitis B virus infection in dialysis patients: a multicentre survey

BACKGROUND: The epidemiology and clinical significance of occult hepatitis B virus infection (serum hepatitis B surface antigen-negative patients with detectable hepatitis B virus viraemia in serum) remains controversial with only limited information about its prevalence in patients on long-term dialysis. AIM: To address the epidemiology of occult HBV infection in a large cohort of dialysis patients. METHODS: We screened a large cohort (n = 585) of Italian chronic dialysis patients; from this population, a group of hepatitis B virus surface antigen seronegative patients (n = 213) was tested by Amplicor hepatitis B virus Monitor Test to detect hepatitis B virus viraemia (hepatitis B virus-DNA) in serum. RESULTS: Occult hepatitis B virus infection was absent (zero of 213 = 0%). Persistent hepatitis B virus surface antigen carriage was less frequent than anti-hepatitis B virus core antibody (anti-hepatitis B core antigen) seropositive status in this study group [1.88% (11 of 585) vs. 36% (216 of 585), P = 0.0001]. No dialysis patients seropositive for anti-hepatitis B core antibody in serum (zero of 123 = 0%) had detectable hepatitis B virus-DNA by polymerase chain reaction technology. No significant association between abnormal biochemical liver tests and serum anti-hepatitis B core antibody was noted in our population. Nominal logistic regression analysis demonstrated an independent and significant relationship between anti-HCV antibody and anti-hepatitis B virus core antibody in serum (Wald chi-square 16.06, P = 0.0001). The rate of seropositive patients for anti-hepatitis B virus core antibody was higher among study patients than controls with normal renal function [36.9% (216 of 585) vs. 21.4% (59 of 275), P = 0.0001]; this difference partially persisted after correction for demographic parameters, and viral markers. CONCLUSION: In conclusion, occult hepatitis B virus was absent in our study group. Anti-hepatitis B core antibody was significantly related to presence of anti-HCV antibody supporting shared modes of transmission. Clinical studies based on molecular biology techniques provided with higher sensitivity are planned.     

2462例农民工乙型肝炎感染情况调查与分析

目的了解农民工乙型肝炎感染情况,探索特殊人群乙型肝炎的传播与流行的防治策略。方法对本地区2462例农民工健康体检中乙型肝炎五项的检查结果进行回顾性分析。结果农民工乙型肝炎感染率较高,高达11.66%,超过我国平均感染率;但获取保护性抗体抗-HBs的人群比例也较高,高达74.05%。结论本地农民工乙型肝炎感染率较高,通过加强卫生宣传、体检监测、预防接种、提高机体免疫力能过有效控制乙型肝炎的传播与流行。     

A point mutation in influenza B neuraminidase confers resistance to peramivir and loss of slow binding

The influenza neuraminidase (NA) inhibitors peramivir, oseltamivir, and zanamivir are potent inhibitors of NAs from both influenza A and B strains. In general, these inhibitors are slow, tight binders of NA, exhibiting time-dependent inhibition. A mutant of influenza virus B/Yamagata/16/88 which was resistant to peramivir was generated by passage of the virus in tissue culture, in the presence of increasing concentrations (0.1-120 microM over 15 passages) of the compound. Whereas the wild type (WT) virus was inhibited by peramivir with an EC(50) value of 0.10 microM, virus isolated at passages 3 and 15 displayed EC(50) values of 10 and >50 microM, respectively. Passage 3 virus contained 3 hemagglutinin (HA) mutations, but no NA mutation. Passage 15 (P15R) virus contained an additional 3 HA mutations, plus the NA mutation His273Tyr. The mechanism of inhibition of WT and P15R NA by peramivir was examined in enzyme assays. The WT and P15R NAs displayed IC(50) values of 8.4+/-0.4 and 127+/-16 nM, respectively, for peramivir. Peramivir inhibited the WT enzyme in a time-dependent fashion, with a K(i) value of 0.066+/-0.002nM. In contrast, the P15R enzyme did not display the property of slow binding and was inhibited competitively with a K(i) value of 4.69+/-0.44nM. Molecular modeling suggested that His273 was relatively distant from peramivir (>5A) in the NA active site, but that Tyr273 introduced a repulsive interaction between the enzyme and inhibitor, which may have been responsible for peramivir resistance.     

Lamivudine treatment for fulminant hepatic failure due to acute exacerbation of chronic hepatitis B infection

BACKGROUND: Exacerbation of chronic hepatitis B infection can lead to fulminant hepatic failure with a mortality of up to 90%. AIM: To evaluate the efficacy of lamivudine in the treatment of this subgroup of patients. METHODS: Twenty-four patients with exacerbation of chronic hepatitis B infection and fulminant hepatic failure were treated with lamivudine, 100 mg daily. Hepatitis A, C, D and human immunodeficiency virus co-infections and hepatocellular carcinoma were excluded. RESULTS: The median age was 53 years (range, 24-77 years) with a male predominance of 20:4. Seventeen patients were hepatitis B e antigen positive. Mean hepatitis B virus DNA was 2079 Meq/mL. Eight patients (33%) survived (group A). Thirteen patients died and three patients received liver transplantation (67%) (group B). Baseline laboratory results were comparable between the two groups, including serum albumin, bilirubin, alanine aminotransferase, prothrombin time and creatinine. Group B patients had significantly more comorbid illnesses at baseline and more complications, including sepsis and renal failure, compared with group A patients. Six out of eight survivors (75%) had full hepatitis B e antigen seroconversion, but this was not sustained in four patients. CONCLUSIONS: Lamivudine may be useful in treating patients with fulminant hepatic failure due to exacerbation of chronic hepatitis B. Hepatitis B e antigen seroconversion was less durable in this subgroup of patients and long-term therapy may be required.