Chronic hepatitis B--who should be treated?

Hepatitis B virus (HBV) can cause both acute and chronic infection and is an important human pathogen, with an estimated 350 million individuals chronically infected worldwide. HBV carriers are at risk for the development of cirrhosis and hepatocellular carcinoma (HCC), and patients with chronic infection require life-long monitoring. Effective hepatitis B antiviral treatment is important given the significant associated global morbidity and mortality from liver-related complications. The goals of treatment are to achieve sustained suppression of HBV replication and remission of liver disease. In the past decade, great progress has been made in the treatment of chronic HBV infection. Interferon alfa, longer-acting pegylated interferon, and nucleos(t)ide analogs such as lamivudine, adefovir dipivoxil, and entecavir are currently available for treatment of HBV infection. Effective treatment decisions require an understanding of the natural history of hepatitis B and the range of treatment options. This review includes criteria for determining when and how to most effectively intervene with antiviral therapy for chronically infected patients.     

Sulfamoylbenzamide Derivatives Inhibit the Assembly of Hepatitis B Virus Nucleocapsids

Chronic hepatitis B virus (HBV) infection, a serious public health problem leading to cirrhosis and hepatocellular carcinoma, is currently treated with either pegylated alpha interferon (pegIFN-α) or one of the five nucleos(t)ide analogue viral DNA polymerase inhibitors. However, neither pegIFN-α nor nucleos(t)ide analogues are capable of reliably curing the viral infection. In order to develop novel antiviral drugs against HBV, we established a cell-based screening assay by using an immortalized mouse hepatocyte-derived stable cell line supporting a high level of HBV replication in a tetracycline-inducible manner. Screening of a library consisting of 26,900 small molecules led to the discovery of a series of sulfamoylbenzamide (SBA) derivatives that significantly reduced the amount of cytoplasmic HBV DNA. Structure-activity relationship studies have thus far identified a group of fluorine-substituted SBAs with submicromolar antiviral activity against HBV in human hepatoma cells. Mechanistic analyses reveal that the compounds dose dependently inhibit the formation of pregenomic RNA (pgRNA)-containing nucleocapsids of HBV but not other animal hepadnaviruses, such as woodchuck hepatitis virus (WHV) and duck hepatitis B virus (DHBV). Moreover, heterologous genetic complementation studies of capsid protein, DNA polymerase, and pgRNA between HBV and WHV suggest that HBV capsid protein confers sensitivity to the SBAs. In summary, SBAs represent a novel chemical entity with superior activity and a unique antiviral mechanism and are thus warranted for further development as novel antiviral therapeutics for the treatment of chronic hepatitis B.     

New therapeutic vaccination strategies for the treatment of chronic hepatitis B

Chronic hepatitis B virus (CHB) is currently treated with either interferon-based or nucleot(s)ide-based antiviral therapies. However, treatment with pegylated interferon alpha results in a durable antiviral response in only about 30% patients and is associated with side effects. Most patients receiving nucleot(s)ide analogue treatment do not establish long-term, durable control of infection and have rebounding viremia after cessation of therapy. Thus, novel therapy strategies are necessary to achieve the induction of potent and durable antiviral immune responses of the patients which can maintain long-term control of viral replication. Therapeutic vaccination of HBV carriers is a promising strategy for the control of hepatitis B. Here the authors review new therapeutic vaccination strategies to treat chronic hepatitis B which may be introduced for patient treatment in the future.     

Animal models for the study of hepatitis B virus infection

Even with an effective vaccine, an estimated 240 million people are chronically infected with hepatitis B virus(HBV) worldwide. Current antiviral therapies,including interferon and nucleot(s)ide analogues,rarely cure chronic hepatitis B. Animal models are very crucial for understanding the pathogenesis of chronic hepatitis B and developing new therapeutic drugs or strategies. HBV can only infect humans and chimpanzees, with the use of chimpanzees in HBV research strongly restricted. Thus, most advances in HBV research have been gained using mouse models with HBV replication or infection or models with HBV-related hepadnaviral infection. This review summarizes the animal models currently available for the study of HBV infection.     

Hepatitis B Surface Antigen Concentrations in Patients with HIV/HBV Co-Infection

HBsAg clearance is associated with clinical cure of chronic hepatitis B virus (HBV) infection. Quantification of HBsAg may help to predict HBsAg clearance during the natural course of HBV infection and during antiviral therapy. Most studies investigating quantitative HBsAg were performed in HBV mono-infected patients. However, the immune status is considered to be important for HBsAg decline and subsequent HBsAg loss. HIV co-infection unfavorably influences the course of chronic hepatitis B. In this cross-sectional study we investigated quantitative HBsAg in 173 HBV/HIV co-infected patients from 6 centers and evaluated the importance of immunodeficiency and antiretroviral therapy. We also compared 46 untreated HIV/HBV infected patients with 46 well-matched HBV mono-infected patients. HBsAg levels correlated with CD4 T-cell count and were higher in patients with more advanced HIV CDC stage. Patients on combination antiretroviral therapy (cART) including nucleos(t)ide analogues active against HBV demonstrated significant lower HBsAg levels compared to untreated patients. Importantly, HBsAg levels were significantly lower in patients who had a stronger increase between nadir CD4 and current CD4 T-cell count during cART. Untreated HIV/HBV patients demonstrated higher HBsAg levels than HBV mono-infected patients despite similar HBV DNA levels. In conclusion, HBsAg decline is dependent on an effective immune status. Restoration of CD4 T-cells during treatment with cART including nucleos(t)ide analogues seems to be important for HBsAg decrease and subsequent HBsAg loss.     

siRNA抑制乙肝病毒的研究进展

乙型肝炎作为一种发病率高、死亡率高的传染性疾病,已严重威胁人类健康,乙肝病毒（hepatitis B virus,HBV）是诱发乙型肝炎的重要病因。目前,最主要的治疗方法是运用抗病毒药物控制病情,但这些药物都不能完全治愈乙型肝炎且复发率高。近年来,RNA干扰技术（RNA interference, RNAi）逐渐成为有效、快速治疗乙型肝炎的新疗法。利用RNA干扰技术体外合成针对HBV基因的siRNA,选择适当的载体将其运送至靶细胞,使HBV基因沉默,从而抑制病毒复制,可有效达到治疗乙肝的效果。本文围绕siRNA沉默HBV基因的设计原理、递送载体、靶向策略、以及治疗效果与应用前景等方面进行了系统综述,为今后siRNA治疗乙肝的临床应用提供参考。     

Hepatitis B in China: from Guideline to Practice

Chronic hepatitis B infection is a very important health problem in China, which is carrying an enormous economic and social burdens. The major routs of chronic hepatitis B infection in China are mother-infant vertical transmission and early childhood horizontal transmission. After more than 10 years implementation of universal vaccination against hepatitis B in newborns and safety injection in health care settings, the prevalence of HBsAg in general population has decreased from 9.75% to around 7%. In China, patients with hepatitis are cared by either hepatologists or physicians of infectious diseases. The Chinese Society of Hepatology, and Chinese Society of Infectious Diseases jointly issued an evidence-based guideline on the prevention and treatment of chronic hepatitis B in 2005. This guideline concisely describes the virology, epidemiology, natural history and prevention, as well as diagnosis and management of chronic hepatitis B. It also highlights the importance of active viral replication in disease progression in chronic HBV infection and explicitly states the necessity of antiviral therapy in patient care. The cornerstone of anti-hepatitis B therapy is optimal use of interferons or nucleos(t)ide analogs in those patients with active viral replication and elevated serum transaminase levels. Through an independent continue medical educational agency, a panel of selected speakers were trained to give well-formatted talks on the key points of the guideline in over 60 major cities across China. This educational campaign among health care providers has greatly improved the awareness and the stand of care for antiviral therapy.     

Hepatitis B in China： from Guideline to Practice

Chronic hepatitis B infection is a very important health problem in China, which is carrying an enormous economic and social burdens. The major routs of chronic hepatitis B infection in China are mother-infant vertical transmission and early childhood horizontal transmission. After more than 10 years implementation of universal vaccination against hepatitis B in newborns and safety injection in health care settings, the prevalence of HBsAg in general population has decreased from 9.75% to around 7%. In China, patients with hepatitis are cared by either hepatologists or physicians of infectious diseases. The Chinese Society of Hepatology, and Chinese Society of Infectious Diseases jointly issued an evidence-based guideline on the prevention and treatment of chronic hepatitis B in 2005. This guideline concisely describes the virology, epidemiology, natural history and prevention, as well as diagnosis and management of chronic hepatitis B. It also highlights the importance of active viral replication in disease progression in chronic HBV infection and explicitly states the necessity of antiviral therapy in patient care. The cornerstone of anti-hepatitis B therapy is optimal use of interferons or nucleos(t)ide analogs in those patients with active viral replication and elevated serum transaminase levels. Through an independent continue medical educational agency, a panel of selected speakers were trained to give well-formatted talks on the key points of the guideline in over 60 major cities across China. This educational campaign among health care providers has greatly improved the awareness and the stand of care for antiviral therapy.     

Hepatitis B Virus: From Diagnosis to Treatment

Hepatitis B infection is still a global concern progressing as acute-chronic hepatitis, severe liver failure, and death. The infection is most widely transmitted from the infected mother to a child, with infected blood and body fluids. Pregnant women, adolescents, and all adults at high risk of chronic infection are recommended to be screened for hepatitis B infection. The initial analysis includes serological tests that allow differentiation of acute and chronic hepatitis. Molecular assays performed provide detection and quantification of viral DNA, genotyping, drug resistance, and precore/core mutation analysis to confirm infection and monitor disease progression in chronic hepatitis B patients. All patients with chronic hepatitis B should be treated with antiviral medications and regularly monitored for efficient treatment. The current treatment is based on nucleos(t)ide analogs and pegylated interferons that save lives by decreasing liver cancer death, liver transplant, slow or reverse the progression of liver disease as well as the virus infectivity.Key words: hepatitis B virus (HBV), serology, nucleic acid testing, antiviral treatment     

CK1α upregulates the IFNAR1 expression to prompt the anti-HBV effect of type I IFN in hepatoma carcinoma cells

Casein kinase 1α (CK1α) mediates the phosphorylation and degradation of interferon-α/β receptor 1 (IFNAR1) in response to viral infection. However, how CK1α regulates hepatitis B virus (HBV) replication and the anti-HBV effects of IFN-α are less reported. Here we show that CK1α can interact with IFNAR1 in hepatoma carcinoma cells and increased the abundance of IFNAR1 by reducing the ubiquitination levels in the presence of HBV. Furthermore, CK1α promotes the IFN-α triggered JAK-STAT signaling pathway and consequently enhances the antiviral effects of IFN-α against HBV replication. Our results collectively provide evidence that CK1α positively regulates the anti-HBV activity of IFN-α in hepatoma carcinoma cells, which would be a promising therapeutic target to improve the effectiveness of IFN-α therapy to cure CHB.     

Anti-hepatitis B virus drugs in clinical and preclinical development

Up to date, there are two types of drugs approved to treat hepatitis B: interferons and nucleos (t) ide analogues. However, the therapies are limited in the clinical context because of the negative side effects of interferon-α and the development of substantial viral resistance to nucleos (t) idic inhibitors. Therefore, new drugs with novel structures and mechanisms are needed. In this article, the drugs approved by FDA or the European Commission for treating chronic hepatitis B virus infection, as well as those under clinical trials, and several compounds in preclinical studies are reviewed. Additionally, some potential targets and strategies to combat chronic hepatitis B virus infection are discussed.     

Long-Term Nucleos(t)ide Analogues Therapy for Adults With Chronic Hepatitis B reduces the Risk of Long-Term Complications: a meta-analysis

Background

The effect of antiviral therapy in chronic hepatitis B (CHB) on reducing the risk of long-term complications (LTCs) remains unclear so far. To study whether long-term nucleos(t)ide analogues therapy can reduce the risk of long-term complications.

Methods

We searched MEDLINE, EMBASE, OVID, the Cochrane Central Register of Controlled Trials. Relative risks (RRs) of long-term complications with or without treatment were studied. Also subgroup analyses including the status of drug-resistance, HBeAg and pre-existing compensated cirrhosis were done using relative risks of long-term complications either with or without treatment or among nucleos(t)ide analogues treatment groups.

Results

Six eligible studies (3644 patients in all) were included. Data showed the incidence of long-term complications in treatment groups was induced by 74%(RR:0.26, 95% CI: 0.15-0.47) compared with no treatment. Whether drug-resistant happened or not during the long-term therapy, the incidence of long-term complications was still significantly induced respectively by 45%(RR: 0.55,95%CI:0.40-0.76) and 78% (RR:0.22, 95%CI: 0.13-0.36). For both different status of HBeAg and pre-existing compensated cirrhosis, there was significant lower incidence of long-term complications in treatment groups compared with no treatment, too. Moreover, among the NA treatment groups, patients with drug-resistance had 2.64 times (RR:2.64, 95%CI: 1.58-4.41) higher chance of developing to long-term complications, and patients with pre-existing compensated cirrhosis also had 3.07 times (RR:3.07, 95%CI: 1.04-9.11) higher chance of developing to long-term complications.

Conclusions

Long-term nucleos(t)ide analogue therapy for adults with CHB prevents or delays the development of long-term complications including decompensated cirrhosis, CHB-related death or CHB-related HCC in patients with CHB. The patients who need take antiviral drugs should receive the antiviral therapy as soon as possible.

     

Antiviral therapy against chronic hepatitis B in Brazil: high rates of lamivudine resistance mutations and correlation with HBV genotypes

The effectiveness of antiviral treatments of chronic hepatitis B has been poorly studied in Brazil. Here, hepatitis B virus (HBV) DNA positivity, drug resistance mutations and their association with HBV genotypes were evaluated in chronically HBV-infected patients under different drug regimens in Brazil. The study involved 129 patients under interferon or nucleos(t)ide analogue therapy for a median treatment time of 12 months. One hundred and five (81%) of these patients were treated with lamivudine (LAM), either in monotherapy or in combination with newer drugs, such as entecavir (ETV) or tenofovir (TDF). High (37.5-100%) rates of HBV DNA positivity were observed with all but one drug regimen (LAM + ETV). However, patients that were treated with ETV alone, TDF alone or with LAM combination therapies had a mean viral load that was 3-4 log lower than patients treated with LAM monotherapy. Of the patients treated with LAM, 47% developed resistance mutations. HBV genotypes A (59.1%), D (30.3%) and F (9.1%) were found. There was no association between the presence of LAM resistance mutations and genotypes, HBeAg status or treatment duration. Nevertheless, the rtM204V mutation was observed more frequently (12/13, 92%) in genotype A than in the others (p = 0.023). Six out of nine isolates that contained the rtM204I mutation belonged to genotype D and half of them displayed a single mutation. Genotype D isolates with the rtM204V variant preferentially displayed a triple mutation, while genotype A preferentially displayed a double mutation (p = 0.04).     

抗原抗体复合物型治疗性疫苗(乙克)临床研究中患者血清乙型肝炎病毒表面抗原下降的分析与启示

近年来全球慢性乙型肝炎(chronic hepatitis B,CHB)防治指南提出了“功能性治愈”(functional cure)的概念,即患者经过治疗达到血清乙型肝炎病毒表面抗原(hepatitis B virus surface antigen,HBsAg)消失,但现有抗病毒治疗很难实现这一目标。本研究对既往临床试验中经抗原抗体复合物型治疗性疫苗(乙克)治疗后的CHB患者HBsAg下降情况进行了归纳分析,结果显示,经乙克治疗随访后达到乙型肝炎e抗原(hepatitis B e antigen,HBeAg)血清学转换者的HBsAg下降高达0.95log₁₀IU/mL,显著高于未达到HBeAg血清学转换者的0.32log₁₀IU/mL(P<0.01),而经氢氧化铝佐剂治疗随访后发生HBeAg血清学转换(0.49log₁₀IU/mL)者与未发生HBeAg血清学转换者(0.36log₁₀IU/mL)之间HBsAg下降无统计学差异。乙克组治疗过程中,丙氨酸氨基转移酶(alanine aminotransferase,ALT)骤升(ALT flare)在HBsAg下降>1.0log₁₀IU/mL者中较多见,氢氧化铝组未观察到此现象。回归分析显示,乙克治疗后HBsAg下降的影响因素有患者出现HBeAg血清学转换、感染的HBV为B基因型、治疗过程中ALT出现10倍增高,以及基线血清HBsAg为高水平。结果提示,乙克诱导的特异性免疫对降低CHB患者血清HBsAg水平有一定效果,采用“抗病毒药物治疗＋针对HBsAg的中和性抗体被动免疫＋乙克主动免疫”的“三明治”治疗策略可能会提高“功能性治愈”率。     

慢性乙型肝炎抗病毒治疗研究进展

乙肝病毒的慢性感染是肝纤维化、肝细胞癌的重要病因,积极有效地抗病毒治疗,可显著改善HBV感染者的生活质量。干扰素、核苷（酸）类药物的抗乙肝病毒疗效已得到全球公认,本文就上述两类药物的研究进展进行综述。