Prevention of hepatocellular carcinoma in patients with chronic hepatitis B

Patients with chronic hepatitis B are at significant risk for hepatocellular carcinoma(HCC). Globally,over half a million people each year are diagnosed with HCC,with marked geographical variations. Despite overwhelming evidence for a causal role of hepatitis B virus(HBV) infection in the development of HCC and a well-established relationship between high baseline hepatitis B viral load and cumulative risk of HCC,the molecular basis for this association has not been fully elucidated. In addition,a beneficial role for antiviral therapy in preventing the development of HCC has been difficult to establish. This review examines the biological and molecular mechanisms of HBV-related hepatocarcinogenesis,recent results on the effect of modern nucleos(t)ides on the rate of HCC development in high risk HBV cohorts and the potential mechanisms by which long-term antiviral therapy with potent inhibitors of HBV replication might reduce the risk of HCC in patients with chronic hepatitis B. Although evidence from randomized controlled trials shows the favourable effects of antiviral agentsin achieving profound and durable suppression of HBV DNA levels while improving liver function and histology,robust evidence of other long-term clinical outcomes,such as prevention of HCC,are limited.     

Current and future directions for treating hepatitis B virus infection

Hepatitis B virus(HBV) persistently infects approximately 350 million people, and approximately 600000 liverrelated deaths are observed per year worldwide. HBV infection is also one of the major risk factors for hepatocellular carcinoma(HCC). The persistence of serum hepatitis B e antigen(HBe Ag) and high level of serum HBV DNA are thought to reflect a high HBV replication status in hepatocytes, causing cirrhosis, HCC and liver-related deaths. It has been reported that antiviral therapy, such as peginterferon and nucleos(t)ide analogues(NUCs), could suppress liver-related death by inhibiting the HBV DNA levels and inducing seroconversion from HBe Ag to antibody to HBe antigen. Currently, peginterferon is widely used, but there are also several disadvantages in the use of peginterferon, such as various adverse events, the administration route and duration. It is difficult to predict the effects of treatment and interferon is contraindicated for the patients with advanced fibrosis of the liver and cirrhosis. With respect to NUCs, entecavir and tenofovir disoproxil fumarate are current the first-choice drugs. NUCs can be administered orally, and their anti-viral effects are stronger than that of peginterferon. However, because cessation of NUC administration leads to high levels of viral replication and causes severe hepatitis, they must be administered for a long time. On the other hand, the use of both interferon and NUCs cannot eliminate covalently closed circular DNA of HBV. In this review, we evaluate the natural course of chronic HBV infection and then provide an outline of these representative drugs, such as peginterferon, entecavir and tenofovir disoproxil fumarate.     

核苷(酸)类似物治疗慢性乙型肝炎存在的问题与对策

目前用于慢性乙型肝炎抗病毒治疗的药物主要有干扰素或聚乙二醇化干扰紊及核苷（酸）类似物两类，其中核苷（酸）类似物具有高效、低毒、使用方便等优点，在临床应用范围广泛。已批准用于乙型肝炎抗病毒治疗的核苷（酸）类似物有拉米夫定、阿德福韦酯和恩替卡韦；此外正在进行临床试验和开发的还有特比夫定、依曲他滨和克拉夫定等。随着新的核苷（酸）类似物不断问世及治疗方案的优化，其疗效已得到肯定。但核苷（酸）类似物抗乙型肝炎病毒（HBV）治疗开始容易，治疗过程中医师会面临众多难题：如疗程难以确定；停药难，可能出现停药反弹，不停药也难，继续治疗部分患者有出现耐药的可能；一旦出现耐药（基因型耐药或者表型耐药），在什么时机加用或改用其它药物治疗等。这些是任何现有核苷类药物都无法回避的问题。作为有责任和合格的肝病专科医师，在确定使用核苷（酸）类似物治疗后，需与患者进行充分和必要的沟通，将这些有关核苷（酸）类似物的重要信息告知患者。本文对核苷（酸）类似物治疗慢性乙型肝炎中常见的几个主要问题进行讨论。     

Cost of treating chronic hepatitis B: Comparison of current treatment guidelines

AIM: To compare program costs of chronic hepatitis B (CHB) screening and treatment using Australian and other published CHB treatment guidelines.METHODS: Economic modeling demonstrated that in Australia a strategy of hepatocellular cancer (HCC) prevention in patients with CHB is more cost-effective than current standard care, or HCC screening. Based upon this model, we developed the B positive program to optimize CHB management of Australians born in countries of high CHB prevalence. We estimated CHB program costs using the B positive program algorithm and compared them to estimated costs of using the CHB treatment guidelines published by the Asian-Pacific, American and European Associations for the Study of Liver Disease (APASL, AASLD, EASL) and those suggested by an independent United States hepatology panel. We used a Markov model that factored in the costs of CHB screening and treatment, individualized by viral load and alanine aminotransferase levels, and calculated the relative costs of program components. Costs were discounted by 5% and calculated in Australian dollars (AUD).RESULTS: Using the B positive algorithm, total program costs amount to 13 979 224 AUD, or 9634 AUD per patient. The least costly strategy is based upon using the AASLD guidelines, which would cost 34% less than our B positive algorithm. Using the EASL and the United States Expert Group guidelines would increase program costs by 46%. The largest expenditure relates to the cost of drug treatment (66.9% of total program costs). The contribution of CHB surveillance (20.2%) and HCC screening and surveillance (6.6%) is small - and together they represent only approximately a quarter of the total program costs.CONCLUSION: The significant cost variations in CHB screening and treatment using different guidelines are relevant for clinicians and policy makers involved in designing population-based disease control programs.     

乙型肝炎病毒相关性肾炎治疗研究进展

乙型肝炎病毒相关性肾炎（HBV-GN）是我国常见的继发性肾小球肾炎，多见于儿童和年青人。自发现乙型肝炎病毒感染与肾小球肾炎相关已有30余年，但 HBV-GN 的治疗至今仍存在较大的争议。本文重点介绍该领域的研究进展。     

Anti-viral therapy to reduce recurrence and improve survival in hepatitis B virus-related hepatocellular carcinoma

Hepatocellular carcinoma(HCC)is the most common malignancy and the third leading cause of cancer death worldwide.Chronic infection with hepatitis B virus(HBV)and hepatitis C virus accounts for approximately75%-80%of HCC cases worldwide.In particular,chronic HBV infection is a predominant risk factor for HCC in Asia and Africa.Hepatic resection and radiofrequency ablation are increasingly used for the curative treatment of HCC,and good local control can be achieved.However,the high rate of recurrence is a major obstacle to improving prognosis.A high viral load of HBV DNA is the most important correctable risk factor for recurrence.Furthermore,interferon and/or nucleotide analogues may decrease HBV DNA.Therefore,these drugs may decrease recurrence.In this article,treatment strategies for HBV-related HCC are described in order to reduce recurrence and improve survival.     

Antiviral therapies for hepatitis B virus-related hepatocellular carcinoma

Chronic hepatitis B virus(HBV) infection is a critical risk factor for the carcinogenesis and progression of hepatocellular carcinoma(HCC). It promotes HCC development by inducing liver fibrogenesis, genetic and epigenetic alterations, and the expression of active viral-coded proteins. Effective antiviral treatments inhibit the replication of HBV, reduce serum viral load and accelerate hepatitis B e antigen serum conversion. Timely initiation of antiviral treatment is not only essential for preventing the incidence of HCC in chronic hepatitis B patients, but also important for reducing HBV reactivation, improving liver function, reducing or delaying HCC recurrence, and prolonging overall survival of HBV-related HCC patients after curative and palliative therapies. The selection of antiviral drugs, monitoring of indicators such as HBV DNA and hepatitis B surface antigen, and timely rescue treatment when necessary, are essential in antiviral therapies for HBVrelated HCC.     

慢性乙型肝炎防治指南

慢性乙型肝炎是我国常见的慢性传染病之一，严重危害人 民健康。为进一步规范慢性乙型肝炎的预防、诊断和治疗，中 华医学会肝病学分会和中华医学会感染病学分会组织国内有关 专家，在参考国内外最新研究成果的基础上，按照循证医学的 原则，制订了《慢性乙型肝炎防治指南》(以下简称《指南》)。 其中推荐的意见所依据的证据共分为3个级别5个等次，文中 以括号内斜体罗马数字表示。     

Key role of hepatitis B virus mutation in chronic hepatitis B development to hepatocellular carcinoma

Chronic hepatitis B virus (HBV) infection is a major risk factor for hepatocellular carcinoma (HCC). The HBV mutations, which include point mutation, deletion, insertion and truncation mutation of HBV gene in 4 open reading frames (S, C, P, X), are closely associated with HCC pathogenesis. Some mutations accumulated during chronic HBV infection could be regarded as a biomarker to predict the occurrence of HCC. The detection of the mutations in clinical practice could be helpful for defining better preventive and therapeutic strategies and, moreover, predicting the progression of liver disease.     

乙肝病毒特异性转移因子治疗慢性乙型肝炎的临床研究

目的　评价乙肝病毒特异性转移因子治疗慢性乙型肝炎的临床疗效。方法　选择慢性乙型肝炎 86例 ,随机分为两组。对照组 40例 ,应用常规保肝降酶疗法 ;研究组 46例 ,在保肝降酶疗法的基础上加用乙肝病毒特异性转移因子。结果　研究组HBeAg及HBVDNA的阴转率显著高于对照组 (P <0 0 5 ) ,抗 HBe阳转率亦显著高于对照组 (P <0 0 1)。结论　乙肝病毒特异性转移因子用于治疗慢性乙型肝炎 ,可以改善患者的乙肝病毒病原学指标。     

Natural regression of fibrosis in chronic hepatitis B

The fibrosis of liver cirrhosis was considered to be irreversible before the anti-viral drugs showed that it is reversible when they lead to continuous suppression of viral replication and inflammation. However, several reports previously showed that fibrosis of type B liver cirrhosis was almost completely absorbed after the natural remission of chronic inflammation. This phenomenon might not be limited to exceptional patients, but rather occur commonly, considering the dynamic clinical features of chronic hepatitis B (CHB), where inactive carrier stage normally follows aggravation of hepatitis and progression of fibrosis at the time of HBeAg seroconversion. Thus, fibrosis levels of CHB as a hepatocellular carcinoma (HCC)-surveillance marker, particularly those of the inactive stage, could be underestimated, because some of them might have been (pre)cirrhotic in the past and recovered with the natural regression of fibrosis. We argue that cirrhosis-induced HCC mechanisms, rather than direct action of viral genome, may be more common than generally considered in CHB patients. This may have some impact on reconsidering the surveillance rationale for HCC in CHB, from where advanced HCCs tended to be missed. In addition, a molecular marker to assess the cancer-prone characteristics of the liver will definitely be needed to resolve the issue.     

血浆置换治疗246例慢性乙型重型肝炎疗效分析

目的 研究血浆置换治疗慢性乙型重型肝炎的临床疗效及影响因素。方法 对246例慢性乙型重型肝炎患者进行血浆置换治疗，观察血浆置换治疗对其病死率及生化指标改变的影响，研究置换的血浆量、置换次数及治疗时机对治疗效果的影响。结果 血浆置换治疗慢性重型肝炎能明显降低病死率，并能显著改善各种血清生化指标，增加血浆置换量和次数能提高治疗效果，慢性乙型重型肝炎早期采用血浆置换疗效明显好于中期及晚期患者。结论 血浆置换治疗慢性乙型重型肝炎有肯定的治疗效果，选择适当血浆置换量、置换次数及治疗时机有助于提高治疗效果。     

氧化苦参碱治疗慢性乙型肝炎的随机双盲对照多中心研究

目的 观察氧化苦参碱胶囊治疗慢性乙型肝炎的疗效及安全性。方法 进行多中心、随机、双盲、安慰剂对照设计的临床试验，选择慢性乙型肝炎患者144例，随机分为氧化苦参碱胶囊组72例和空白对照组72例完成52周治疗并随访12周。治疗前后及停药12周后观察患者临床症状、肝功能、血清乙型肝炎病毒(HBV)标志物和不良反应等。结果 所有入组患者中脱落和不符合入选标准剔除共14例，故共有130例患者纳入疗效统计，其中氧化苦参碱胶囊组65例，空白对照组65例。氧化苦参碱胶囊组治疗慢性乙型肝炎52周其HBVDNA和乙型肝炎e抗原(HBeAg)阴转率分别为43．08％(28／65)和33．33％(20／60)，丙氨酸氨基转移酶(ALT)复常率为70．77％(46／65)；空白对照组HBV DNA和HBeAg阴转率分别为12．31％(8／65)和3．33％(2／60)，ALT复常率为39．68％(25／63)。治疗后完全反应率．部分反应率和无反应率胶囊组分别为23．08％(15／65)，58．46％(38／65)和18．46％(12／65);而对照组分别为3．08％(2／65)、44．62％(29／65)和52．31％(34／65)。两组间比较胶囊组均明显高于对照组(QCMH=21．02，P=0．001)。氧化苦参碱胶囊组治疗慢性乙型肝炎停药12周后其HBV DNA和HBeAg阴转率分别为41．54％(27／65)和23．33％(14／60)，ALT复常率为60．00％(39／65);空白对照组HBV DNA和HBeAg阴转率分别为3．08％(2／65)和1．67％(1／60)，ALT复常率为31．75％(20／63)。完全反应率、部分反应率和无反应率胶囊组分别为21．54％(14／65)、47．69％(31／65)和30．77％(20／65)，而对照组分别为0，41．54％(27／65)和58．46％(38／65)，两组间比较胶囊组均明显高于对照组(QCMH=15．22，P=0．001)。氧化苦参碱胶囊组有5例(7．69％)发生不良反应，空白对照组有4例(6．15％)发生不良反应，主要表现为恶心、乏力、皮疹、上腹不适和口苦，均为轻，中度，无严重不良反应发生，不良反应发生率两组间比较差异无显著性。结论 氧化苦参碱胶囊是治疗慢性乙型肝炎有效，安全的药物。     

慢性乙型肝炎患者幽门螺杆菌感染的调查分析

目的探讨慢性乙型肝炎患者幽门螺杆菌(H.pylori)的感染情况及其临床意义。方法将167例慢性乙型肝炎患者分为肝炎组、肝硬化组、肝癌组,研究H.pylori感染状况与76例健康对照者的关系,并进一步分析H.pylori感染与肝功能、临床并发症的关系。结果慢性乙型肝炎患者H.pylori感染率为64.1%,明显高于健康对照组34.2%(P<0.01)。其中肝硬化组71.8%和肝癌组75.0%又高于肝炎组51.5%(P<0.05)。H.pylori阳性患者肝性脑病、上消化道出血及ALT水平高于H.pylori阴性患者(P<0.05),H.pylori阳性和H.pylori阴性患者的腹水并发症及TBIL差异无统计学意义(P>0.05)。结论慢性乙型肝炎患者H.pylori感染率显著增加,且H.pylori感染可能加重肝病病程。     

Subclinical proximal tubulopathy in hepatitis B: The roles of nucleot(s)ide analogue treatment and the hepatitis B virus

BACKGROUNDThe recommended monitoring tools for evaluating nucleot(s)ide analogue renal toxicity, such as estimated glomerular filtration rate (eGFR) and phosphatemia, are late markers of proximal tubulopathy. Multiple early markers are available, but no consensus exists on their use.AIMTo determine the 24 mo prevalence of subclinical proximal tubulopathy (SPT), as defined with early biomarkers, in treated vs untreated hepatitis B virus (HBV)-monoinfected patients.METHODSA prospective, non-randomized, multicenter study of HBV-monoinfected patients with a low number of renal comorbidities was conducted. The patients were separated into three groups: Naïve, starting entecavir (ETV) treatment, or starting tenofovir disoproxil (TDF) treatment. Data on the early markers of SPT, the eGFR and phosphatemia, were collected quarterly. SPT was defined as a maximal tubular reabsorption of phosphate/eGFR below 0.8 mmoL/L and/or uric acid fractional excretion above 10%. The prevalence and cumulative incidence of SPT at month 24 (M24) were calculated. Quantitative data were analyzed using analyses of variance or Kruskal-Wallis tests, whereas chi-squared or Fisher’s exact tests were used to analyze qualitative data. Multivariate analyses were used to adjust for any potential confounding factors.RESULTSOf the 196 patients analyzed, 138 (84 naïve, 28 starting ETV, and 26 starting TDF) had no SPT at inclusion. At M24, the prevalence of SPT was not statistically different between naïve and either treated group (21.1% vs 30.7%, P < 0.42 and 50.0% vs 30.7%, P = 0.32 for ETV and TDF, respectively); no patient had an eGFR lower than 50 mL/min/1.73 m² or phosphatemia less than 0.48 mmoL/L. In the multivariate analysis, no explanatory variables were identified after adjustment. The cumulative incidence of SPT over 24 mo (25.5%, 13.3%, and 52.9% in the naïve, ETV, and TDF groups, respectively) tended to be higher in the TDF group vs the naïve group (hazard ratio: 2.283, P = 0.05). SPT-free survival at M24 was 57.6%, 68.8%, and 23.5% for the naïve, ETV, and TDF groups, respectively. The median survival time without SPT, evaluated only in the TDF group, was 5.9 mo.CONCLUSIONThe prevalence and incidence of SPT was higher in TDF-treated patients compared to naïve patients. SPT in the naïve population suggests that HBV can induce renal tubular toxicity.     

Prediction models of hepatocellular carcinoma development in chronic hepatitis B patients

Chronic hepatitis B virus(HBV) infection is a major cause of cirrhosis and hepatocellular carcinoma(HCC). Applying the same strategies for antiviral therapy and HCC surveillance to all chronic hepatitis B(CHB) patients would be a burden worldwide. To properly manage CHB patients, it is necessary to identify and classify the risk for HCC development in such patients. Several HCC risk scores based on risk factors such as cirrhosis, age, male gender, and high viral load have been used, and have negative predictive values of ≥ 95%. Most of these have been derived from, and internally validated in, treatment-na?ve Asian CHB patients. Herein, we summarized various HCC prediction models, including IPM(Individual Prediction Model), CU-HCC(Chinese University-HCC), GAG-HCC(Guide with Age, Gender, HBV DNA, Core Promoter Mutations and Cirrhosis-HCC), NGM-HCC(NomogramHCC), REACH-B(Risk Estimation for Hepatocellular Carcinoma in Chronic Hepatitis B), and Page-B score. To develop a noninvasive test of liver fibrosis, we also introduced a new scoring system that uses liver stiffness values from transient elastography, including an LSM(Liver Stiffness Measurement)-based model, LSM-HCC, and mR EACH-B(modified REACH-B).     

Latent hepatitis B is a risk factor for hepatocellular carcinoma in patients with chronic hepatitis C

AIM:To study the potential association between hepatocellular carcinoma(HCC)in patients with chronic hepatitis C(CHC),cirrhosis and latent hepatitis B(LHB)infection,defined as the absence of detectable serum hepatitis B surface antigen(HBsAg)and the presence of hepatitis B core antibody(HBcAb).METHODS:This retrospective analysis is comprised of 185 cirrhotic patients with HCC who were hepatitis C virus antibody(HCV Ab)(+)and HBsAg(-)at Wayne State University between 1999 and 2008.From these,108 patients had HCV polymerase chain reaction confirmation of viremia while the remaining(77)were considered to have CHC on the basis of a positive HCV Ab and the absence of any other cause of liver disease.Controls were drawn from our institutional database from the same time period and consisted of 356 HBsAg(-)age,race and gender matched patients with HCV RNA-confirmed CHC and without evidence of HCC.A subgroup of controls included 118matched patients with liver cirrhosis.χ2test and t test were used for data analysis.RESULTS:Seventy-seven percent of patients in all3 groups were African Americans.Patients with HCC had a significantly higher body mass index(P=0.03),a higher rate of co-infection with human immunodeficiency virus(HIV)(P=0.05)and a higher prevalence of alcohol abuse(P=0.03)than the controls.More patients with HCC had LHB than controls(78%vs39%,P=0.01).Sixty three percent of patients with HCC were both hepatitis B surface antigen(HBsAb)(-)and HBcAb(+)compared to 23%of controls(P<0.01).When compared to cirrhotic controls,the frequency of HBcAb(+)remained higher in patients with HCC(78%vs 45%,P=0.02).Patients with HCC were more likely to be both HBsAb(-)and HBcAb(+)than the cirrhotic controls(63%vs 28%,P=0.01).Although not statistically significant,100%of CHC and HIV coinfected patients with HCC(n=11)were HBcAb(+)when compared to controls(44%;n=9).CONCLUSION:These data suggest that LHB occurs at a significantly increased frequency in patients with CHC and HCC than in patients with CHC without HCC.