Hepatitis B virus replication and liver disease progression: the impact of antiviral therapy

Chronic hepatitis B virus (HBV) infection is a serious health issue worldwide. The presence of HBV replication markers--hepatitis B e antigen (HBeAg) or HBV DNA--is associated with continuing hepatitis activity or intermittent hepatitis flares and subsequent disease progression, including hepatic decompensation and development of liver cirrhosis or hepatocellular carcinoma (HCC). Long-term (>10 years) prospective studies in patients >30 years of age have shown that HBeAg seropositivity is associated with increased risk of disease progression, and the risk of cirrhosis and HCC begins to increase at an HBV DNA level of 10(4) copies/ml. Therefore, elimination of HBV, or at least sustained or maintained suppression of HBV, is the key to reducing hepatitis and thereby halting or preventing disease progression. Therapy with interferon-alpha or a direct antiviral agent has been shown to reduce the risk of cirrhosis and prevent further disease worsening. In both the woodchuck hepatitis model and in HBV patients, maintained suppression of HBV replication by a direct antiviral agent may reduce the progression to HCC. However, the efficacy of current antiviral therapy is still far from satisfactory. The ability to achieve a high rate of sustained or maintained HBV suppression with a low risk of drug resistance would be the ultimate goal in the treatment of chronic HBV infection.     

Does antiviral therapy prevent hepatocellular carcinoma?

Chronic infection with HBV or HCV can lead to the development of hepatocellular carcinoma (HCC). The major risk factors for HBV-related HCC are persistent presence of hepatitis B e antigen (HBeAg) and/or high serum HBV DNA levels, and cirrhosis. The major risk factor for HCV-related HCC is cirrhosis. One randomized double blind controlled trial of lamivudine in patients with HBeAg and/or high serum HBV DNA levels showed that antiviral therapy prevented disease progression and reduced the incidence of HCC. A beneficial effect of antiviral therapy on the risk of HCC has also been shown in cohort studies and meta-analyses, particularly among responders. Several randomized controlled trials of interferon in patients with HCV-related cirrhosis showed that treated patients had a lower incidence of HCC. A greater effect was observed in patients who achieved sustained virological response, while the benefit in non-responders is unclear. Antiviral therapies for hepatitis B and hepatitis C can prevent but not completely eliminate HCC. Improvement in identification of infected persons, accessibility of care and affordability of treatment is needed for antiviral therapy to have a major impact on the global incidence of HCC.     

Entecavir for the long-term treatment of chronic hepatitis B

Hepatitis B virus is a major cause of chronic liver disease worldwide and is associated with an increased risk of hepatocellular carcinoma, progressive hepatic fibrosis and end-stage liver disease. Suppression of HBV replication is recognized as the primary on-treatment goal of antiviral therapy, as reduction of serum HBV DNA to low or undetectable levels is highly likely to have a positive impact on long-term clinical outcomes in HBV-associated chronic liver disease. Entecavir is an oral nucleoside analogue that effectively inhibits HBV polymerase, resulting in rapid viral suppression. Long-term data on patients receiving entecavir for chronic hepatitis B have demonstrated high potency, a low incidence of antiviral drug resistance and good tolerability, making entecavir an ideal first-line agent for the treatment of chronic hepatitis B.     

Treatment of hepatitis B: the next five years

The natural history of individuals chronically infected with hepatitis B typically fluctuates, with periods of active viral replication with or without an associated hepatitis and sometimes prolonged periods of spontaneous viral suppression and inactive liver disease. In the majority, this chronic infection is clinically silent unless either liver failure and/or hepatocellular carcinoma (HCC) supervenes. Thus proactive steps are needed to first identify those with hepatitis B infection and to then serially monitor those found to be chronically infected for both level of alanine aminotransferase (ALT) and hepatitis B virus DNA (HBV-DNA) (using sensitive polymerase chain reaction techniques. Antiviral therapy significantly reduces the risk of liver disease progression and HCC in those with ongoing viral replication > 10(5) c/mL and advanced hepatic fibrosis. The decision of when to initiate (possibly lifelong) treatment has to be made judiciously. Before introducing therapy both patient and physician must recognise the need for compliance with both treatment and viral surveillance so as to minimise the development of drug resistance. Drug resistance needs to be identified prior to recurrence of hepatitis (rise in ALT) to prevent hepatic decompensation, this necessitates serial HBV-DNA testing.     

Medical therapies to extend survival in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a serious malignancy with 21,000 new cases estimated for 2008. Several common diseases are associated with an increased risk of the development of HCC, including viral hepatitis, cirrhosis, and other chronic liver diseases. Most patients present with advanced disease, and therefore have only limited therapeutic options. However, advancements in screening and surveillance have allowed more patients to be identified and diagnosed with earlier-stage disease, increasing their therapeutic options. Several treatment modalities exist for early- and intermediate-stage disease, including ablative techniques and embolization methods. Additionally, advances in targeted therapy have resulted in the approval of the oral multitargeted tyrosine kinase inhibitor sorafenib, resulting in improved length of survival. In this roundtable discussion, the current epidemic of HCC is addressed, including factors contributing to an increased rate of occurrence. Additionally, the optimal screening and diagnosis of HCC patients is discussed, and the appropriate treatment modalities for each stage of HCC are presented.     

脂联素与慢性乙型肝炎病毒感染肝纤维化的关系研究

目的研究脂联素在慢性乙型肝炎病毒感染患者中的表达,并对部分患者抗病毒治疗前后的结果进行对比,探讨脂联素与慢性乙型肝炎肝纤维化的相关性。方法采用酶联免疫法（ELISA）定量检测血清脂联素水平,免疫组织化学法检测肝活检组织脂联素的表达,同时检测患者肝功能以及HBV DNA变化,并对患者进行抗病毒治疗前后的纤维化程度进行比较。结果血清脂联素在肝纤维化的各个阶段均有表达且与肝纤维化的分级呈正相关（r=0.976,P〈0.01）,与转氨酶水平及HBV DNA浓度无相关性（P〉0.05）;血清脂联素与肝硬化呈独立相关（P=0.02,相对危险度为1.07,95%可信区间为1.00～1.14）。在抗病毒治疗后,肝纤维化程度改善以及获得持续病毒学应答的患者血清脂联素水平降低。结论血清脂联素在慢性乙型肝炎肝纤维化的进展过程中发挥了作用,血清脂联素水平在抗病毒治疗后显著下降,并与肝纤维化改善有关。     

Long-term lamivudine therapy reduces the risk of long-term complications of chronic hepatitis B infection even in patients without advanced disease

BACKGROUND: Long-term effects of lamivudine treatment on chronic hepatitis B patients without advanced disease remain unknown. Our aim was to investigate the effects of long-term lamivudine treatment and lamivudine-resistant virus (YMDD) on the development of cirrhosis and hepatocellular carcinoma (HCC) in asymptomatic patients without advanced disease. METHODS: One hundred and forty-two hepatitis B e antigen (HBeAg)-positive patients (median age: 33.9 years) on long-term lamivudine (median treatment duration: 89.9 months) and 124 HBeAg-positive controls (median age: 33.4 years) were prospectively followed up. Patients were monitored for the development of cirrhosis and HCC, liver biochemistry, hepatitis B virus (HBV) DNA levels, HBeAg seroconversion and hepatitis flares. YMDD mutations (YMDD-MT) were determined annually. RESULTS: Lamivudine-treated patients had a significantly lower cumulative rate of development of cirrhosis and/or HCC compared with controls (P = 0.005). YMDD-MT occurred in 76.3% of patients after 8 years of lamivudine treatment. When compared with controls and patients with YMDD-MT, patients without YMDD-MT had the greatest reduction of HBV DNA and bilirubin levels, slowest decline of albumin level, highest rate of HBeAg seroconversion and lowest risk of hepatitis flare. Patients with YMDD-MT still had a lower risk for developing cirrhosis and/or HCC (P = 0.024) and a greater HBV DNA reduction (P = 0.001) in comparison with controls. Patients with YMDD-MT and controls had a similar chance of hepatitis flares and hepatic decompensation. CONCLUSIONS: Long-term lamivudine treatment was associated with a reduced chance of developing cirrhosis and HCC in patients without advanced disease. Although YMDD-MT reduced the benefits from lamivudine therapy, the outcome of these patients was still better than untreated patients.     

Interferon

More than 50 years have passed since interferon (IFN) was discovered. Until now, the signaling pathway and function of IFN were basically elucidated. IFN has been clinically used for patients with hepatitis B virus (HBV) or hepatitis C virus (HCV). In Japan, pegylated IFN (PEG-IFN) is just approved for patients with HBV related chronic hepatitis. Also, the adding of direct-acting antiviral agents to the combination therapy with PEG-IFN plus ribavirin will improve anti-HCV effect. Another important effect of IFN is a suppression of hepatocarcinogenesis in patients with viral related chronic liver diseases. Maintenance therapy with low dose of PEG-IFN or IFN can improve the prognosis of patients with advanced hepatic fibrosis.     

Antiviral treatment of hepatitis C: present status and future prospects

Hepatitis C virus (HCV) infection is a major cause of chronic hepatitis. A substantial proportion of patients with chronic hepatitis C eventually develop hepatocellular carcinoma (HCC), which is one of the leading causes of death worldwide. Therefore, efficient antiviral treatments for HCV have long been needed. A recently developed combination therapy of pegylated interferon and ribavirin has dramatically improved the outcome of antiviral therapy for HCV infection. In genotype 1b HCV infection, 48 weeks of the combination therapy achieved eradication of the virus in 50% of patients, and in genotype 2 HCV infection, 24 weeks of the therapy resulted in viral eradication in 80%–90% of patients. By this eradication, an improvement in the hepatic fibrosis, an inhibition of HCC development, and an improvement in life expectancy were attained. Patients who did not respond to the combination therapy may be treated with long-term interferon monotherapy, which is not intended to eradicate HCV, but will lower the serum alanine aminotransferase (ALT) level. Thus, the treatment for HCV infection has progressed significantly, but therapies with new modalities, such as inhibitors of viral protease or RNA polymerase, are still being awaited.     

Hepatocellular nodules in liver cirrhosis: MR evaluation

Liver cirrhosis is a major public health problem worldwide. Common causes of cirrhosis include hepatitis C virus, hepatitis B virus, alcohol consumption, and nonalcoholic steatohepatitis. Cirrhotic livers are characterized by advanced hepatic fibrosis and the development of hepatocellular nodules such as regenerative nodules, dysplastic or neoplastic nodules. Cirrhosis is the strongest predisposing factor for hepatocellular carcinoma (HCC). For example, viral hepatitis is the main risk factor for cirrhosis and is associated with the increased incidence (1%–4% per year) of HCC after development of cirrhosis. Currently, a variety of imaging modalities, including ultrasound (US), computed tomography (CT), magnetic resonance imaging (MRI), and positron-emission tomography (PET) are used in noninvasive evaluation of patients with chronic liver disease and suspected HCC. With technological development of MR scanners, MR imaging has emerged as an important imaging modality for assessing cirrhosis and its complications such as HCC. The recent advance in MR is the introduction of faster sequences which have allowed high-quality imaging of the entire liver with high intrinsic soft-tissue contrast, and also multiphasic dynamic MRI that is essential for the detection and characterization of HCC. In addition, functional MRI including diffusion-weighted MRI, MR elastography, and new MR contrast agent with dual function have been investigated for the clinical utility of detection and characterization of HCCs. In this article, we provide an overview of the state-of-the-art MR imaging techniques being used for noninvasive assessment of hepatocellular nodules including conventional dynamic imaging, liver-specific contrast-enhanced MR imaging, diffusion-weighted imaging, MR spectroscopy, and MR elastography.     

Clevudine therapy with vaccine inhibits progression of chronic hepatitis and delays onset of hepatocellular carcinoma in chronic woodchuck hepatitis virus infection

We examined a rational approach to therapy of chronic hepatitis B virus (HBV) infection that utilized the reduction of viral load combined with appropriately timed immune modulation/stimulation. In a placebo-controlled study, chronic woodchuck hepatitis virus (WHV) carrier woodchucks received clevudine (L-FMAU), previously shown to have especially potent and sustained antiviral activity in woodchucks, for 32 weeks followed by WHV surface antigen (WHsAg) alum-adjuvanted vaccine at 32, 36, 40 and 48 weeks. Clevudine induced significant reductions in viraemia, surface antigenaemia, hepatic WHV nucleic acids, and hepatic core and surface antigens. Viral replication markers remained markedly suppressed in 75% of the clevudine-treated woodchucks following drug withdrawal, but remained at high levels in the vaccine monotherapy and placebo groups. Combination drug and vaccine therapy had benefits based on sustained reduction of viraemia, antigenaemia, and hepatic WHV DNA and RNA; inhibition of progression of chronic hepatitis; reduced frequency of chronic liver injury; and delayed onset of hepatocellular carcinoma (HCC). Combination therapy contributed to prevention of HCC in up to 38% of treated carriers, although the growth rate of established HCC was not affected. This study demonstrates enhanced benefits of combination chemo-immunotherapy against viral load and disease progression in chronic hepadnaviral infection, and provides a platform for further development of such treatment regimens.     

Current status of hepatitis C virus infection in Korea

Chronic liver disease, including liver cirrhosis and hepatocellular carcinoma (HCC), has been a major cause of mortality in Korea. The prevalence rates of hepatitis C virus (HCV) and hepatitis B virus (HBV) infections in the general population of Korea are approximately 1 and 5%, respectively. The most common genotypes of HCV in Korea are 1b and 2a. The sustained virological response rates after antiviral therapies, including combined interferon-alpha and ribavirin, have been reported to be 38-59%. The annual incidence of HCC among HCV-related liver cirrhosis has been estimated at 5%, and approximately 12% of HCC is attributable to HCV and 68% to HBV in Korea. The mean age of patients with HCV-related HCC at the time of diagnosis was consistently 10 years older than that of patients with HBV-related HCC. Moreover, HCV-related HCC was accompanied by more advanced liver cirrhosis than HBV-related HCC. Coinfection with HBV seemed to increase the risk of developing HCC in chronic HCV infection. After the successful program of hepatitis B vaccination, HCV infection is now emerging as an important etiology of chronic liver disease in Korea, which warrants more detailed and large-scale studies.     

Update on Chronic Hepatitis B

Chronic hepatitis B virus (HBV) infection affects over 350 million people worldwide and over 1 million die annually of HBV-related chronic liver disease. The prolonged immunologic response to HBV infection leads to the development of cirrhosis, liver failure, or hepatocellular carcinoma (HCC) in up to 40% of patients. The implementation of mass immunization programs has dramatically decreased the incidence of HBV infection among infants, children, and adolescents in many countries, but there remains a large number who were infected with HBV before such programs. A variety of host, viral, and external factors influence HBV disease progression and the risk of chronic infection. Six drugs are currently FDA-approved for the treatment of chronic HBV infection. While novel antiviral drugs have improved the management of cirrhosis, strategies to prevent and treat HCC remain inadequate.     

Failure of interferon to prevent recurrent hepatitis B infection in hepatic allograft

Chronic liver disease associated with hepatitis B virus infection is both common and serious; no satisfactory treatment currently exists. Orthotopic liver transplantation is an option for patients with end-stage liver disease associated with hepatitis B virus infection despite the risk of allograft reinfection. Passive immunoprophylaxis has been attempted perioperatively to prevent graft infection but has not been beneficial. Some patients with chronic type B hepatitis have benefited clinically from antiviral therapy and, in particular, interferon, but its use has not previously been reported as an approach to prevent allograft infection. We administered recombinant leukocyte A interferon perioperatively to a patient who underwent liver transplantation for type B chronic active hepatitis and cirrhosis. Circulating hepatitis B virus DNA was found postoperatively while the patient was receiving interferon, and stainable viral antigen subsequently reappeared in the transplanted liver. Thus, the drug failed to prevent viral replication and allograft infection. Thus far, no evidence of progression of the chronic hepatitis has been noted.     

血清高尔基体蛋白73在肝硬化诊断及分级中的价值

目的:探讨血清高尔基体蛋白73(GP73)在慢性乙型肝炎(乙肝)、肝硬化中的表达及其与肝硬化分期间的关系。方法:采用酶联免疫吸附试验,定量检测198名正常对照组、171例慢性乙肝组患者、144例肝硬化患者和164例原发性肝细胞肝癌(HCC)患者血清中GP73水平,计算GP73检测受试者工作特征(ROC)曲线下面积及GP73检测对肝硬化诊断的灵敏度与特异度。检测慢性乙肝组和肝硬化组的乙肝病毒(HBV)-DNA载量和HBeAg水平,并对肝硬化组进行血清肝纤维化指标检测及Child-Pugh分级,分析以上指标与GP73水平间的相关性。结果:正常对照组、慢性乙肝组、肝硬化组和肝癌组的中位GP73水平分别为40.80 ng/mL、42.49 ng/mL、83.46 ng/mL和45.19 ng/mL,肝硬化组GP73水平明显高于正常对照组及慢性乙肝组(P<0.05)。结论:血清GP73水平在肝硬化患者代偿期即升高,而随着肝硬化的进展,其呈显著上升趋势,且与HBV活动相关。因此,GP73可作为肝硬化诊断及慢性肝病进展期病情监测的新指标。     

中西医结合治疗慢性乙型肝炎肝纤维化及早期肝硬化的临床分析

目的分析研究中西医结合治疗慢性乙型肝炎肝纤维化及早期肝硬化的疗效。方法临床上诊断明确的慢性乙型肝炎肝纤维化及早期肝硬化患者100倒,将患者分为对照组50例,治疗组50例。对照组采用仅一干扰素治疗;治疗组在采用西医治疗的基础上,根据中医辨证论治,选用有特别疗效的中药方剂。经过治疗一个疗程后,观察两种疗效。结果治疗组总有效率90．0％高于对照组的54．0％,组间疗效差异具有明显统计学意义（P〈0．05）。治疗后症状和体征,各项肝功能、纤维化指标变化和腹部超声下影像改善情况治疗组均优于对照组,差异均具有显著性（P〈0．05）。结论中西医结合是治疗慢性乙型肝炎肝纤维化及早期肝硬化的有效办法,经济实用,副作用少,值得在临床上推广。     

Natural history of hepatitis B virus infection: an update for clinicians

Hepatitis B virus (HBV) is a common viral pathogen that causes a substantial health burden worldwide. Significant progress has been made in the past few decades in understanding the natural history of HBV infection. A dynamic balance between viral replication and host immune response is pivotal to the pathogenesis of liver disease. In immunocompetent adults, most HBV infections spontaneously resolve, whereas in most neonates and infants they become chronic. Those with chronic HBV may present in 1 of 4 phases of infection: (1) in a state of immune tolerance, (2) with hepatitis B e antigen (HBeAg)positive chronic hepatitis, (3) as an inactive hepatitis B surface antigen carrier, or (4) with HBeAg-negative chronic hepatitis. Of these, HBeAg-positive and HBeAg-negative chronic hepatitis may progress to cirrhosis and its long-term sequelae including hepatic decompensation and hepatocellular carcinoma. Several prognostic factors, such as serum HBV DNA concentrations, HBeAg status, serum aminotransferases, and certain HBV genotypes, have been identified to predict long-term outcome. These data emphasize the importance of monitoring all patients with chronic HBV infection to identify candidates for and select optimal timing of antiviral treatment, to recognize those at risk of complications, and to implement surveillance for early detection of hepatocellular carcinoma.     

Hepatitis C: role of the advanced practice nurse

Hepatitis C virus (HCV) is a common but insidious and indolent viral infection that can lead to chronic hepatitis, cirrhosis, and hepatocellular carcinoma. This article provides the advanced practice nurse with current information on prevalence, incidence, spread, and clinical course of hepatitis C. It presents a discussion of the methods of diagnosis, treatment, and management of affected patients. To date, the diagnosis of hepatitis C in the United States has been serendipitous because no surveillance and screening programs have been established. It has been estimated that approximately 4 million persons in the United States are infected with HCV, with only 30% presently diagnosed. Patients with hepatitis C must make informed choices regarding their care and treatment. As more people are diagnosed with hepatitis C, the advanced practice nurse is at the forefront of providing information about spread and diagnosis, treatment options available, and potential side effects of antiviral therapy. The decision to treat chronic HCV must be made in collaboration with other medical experts in hepatology and antiviral therapy, and it must be made with knowledge and understanding of all facets of the disease process and adverse effects of therapy.     

恩替卡韦治疗乙型肝炎肝硬化与慢性乙型肝炎96周的疗效

目的观察比较恩替卡韦治疗乙型肝炎肝硬化与慢性乙型肝炎患者96周的疗效。方法收集初治的乙型肝炎肝硬化患者71例(肝硬化组),慢性乙型肝炎患者89例(乙型肝炎组),均给予恩替卡韦0.5mg,每日1次,口服治疗,持续抗病毒治疗96周,观察两组患者在治疗前、治疗第12、24、48、96周时病毒学、血清学、生物化学指标、出凝血时间、Child-Pugh积分及肾功能等变化情况。结果①恩替卡韦治疗后,两组患者乙型肝炎病毒核糖核酸(HBV DNA)、丙氨酸转氨酶(ALT)水平均较治疗前明显下降,发生乙型肝炎e抗原(HBeAg)阴转及血清学转换的例数逐渐增加,但两组各时间点比较,差异均无统计学意义。②肝储备功能方面,恩替卡韦治疗后,两组患者白蛋白、总胆红素、凝血酶原时间均有不同程度改善,随着治疗的延长,白蛋白不断升高,总胆红素持续下降,凝血酶原时间减小,两组患者治疗48及96周白蛋白、总胆红素、凝血酶原时间及Child-Pugh积分与基线值比较,差异均有统计学意义(P0.05或0.01)。组间比较显示,白蛋白升高水平、总胆红素及凝血酶原时间下降水平在肝硬化失代偿组最高,肝硬化代偿组次之,慢性乙型肝炎组最低,差异均具有统计学意义。③两组患者治疗过程中,均未出现血清肌酐增高超过正常参考值范围情况。结论应用恩替卡韦抗病毒治疗,乙型肝炎肝硬化患者的病毒学、血清学及生化学应答均与慢性乙型肝炎患者相似,同时抗病毒治疗能明显改善各阶段乙型肝炎患者肝储备功能,其中乙型肝炎肝硬化失代偿期患者最为显著。     

The protein C system in chronic hepatic diseases, and anti-viral therapy

The purpose of the investigation was to study the condition of the protein C system in chronic virial hepatitis (CVH) and viral hepatic cirrhosis (HC) during the course of antiviral therapy. The total protein C system activity (in a form of normalized ratio - NR) was studied before and 6 month after antiviral therapy in 27 patients with CVH B, in 79 patients with CVH C, and in 5 patients CVH D, as well in 29 patients with viral HC and 29 patients with alcoholic HC/. The total protein C system activity was decreased in chronic viral hepatic disease, and was minimal in patients with HC; the most severe disturbances were observed in patients with poor prognosis of HC and decompensated portal hypertension. The study found a correlation between NR values and histological manifestation of the pathology, which demonstrates an important role of the protein C system in the progress of chronic hepatic diseases. Anti-virial drugs had a positive effect of the functioning of the protein C system, which may be one of the ways of the realization of their antifibrotic effect.