Management of chronic hepatitis B in severe liver disease

In the past few decades,chronic hepatitis B(CHB)has evolved from a disease that was untreatable and progressive,to one that can be easily controlled with antiviral therapy.However,patients with severe liver disease still remain difficult to treat despite the availability of highly potent nucleos(t)ide analogs.These include those with underlying cirrhosis,severe flares of CHB,hepatocellular carcinoma(HCC),and for those undergoing liver transplantation.For those with established cirrhosis,antiviral therapy should be considered for all,as unpredictable flares can still occur,which can be fatal for those with advanced chronic liver disease.However,even with effective viral suppression,the development of HCC can still occur.For patients with severe flares of CHB,although the use of antiviral can improve long term outcomes,a significant proportion may still die without liver transplantation.The short term prognosis of these patients is dependent on both the severity of flare and underlying pre-existing liver disease.In patients with decompensated cirrhosis,liver failure secondary to severe flares,or those with HCC,liver transplantation may be curative.After liver transplantation,long term antiviral therapy is required to prevent graft loss from recurrent hepatitis B infection.The use of hepatitis B immune globulin(HBIG)in combination with an oral antiviral agent has been the mainstay of post-transplant antiviral regimen for over adecade.With newer and more potent antiviral agents such as tenofovir and entecavir,use of these agents along with HBIG have demonstrated to be effective in preventing significant recurrence in the long term.     

Alpha-Fetoprotein (AFP) and AFP-L3 Is Most Useful in Detection of Recurrence of Hepatocellular Carcinoma in Patients after Tumor Ablation and with Low AFP Level

Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and is a leading cause of mortality worldwide. While there are many risk factors for HCC including alcohol, obesity, and diabetes, hepatitis B virus (HBV) and hepatitis C virus (HCV) infection still account for the majority of HCC worldwide. Globally, HBV is the leading risk factor for HCC. Patients with chronic hepatitis B (CHB) and advanced liver disease are at high risk for HCC. Screening for HCC is done routinely with ultrasound with or without alpha-fetoprotein (AFP) at six-month intervals. The combination of ultrasound and AFP has been shown to provide some additional detection of 6–8% of cases compared to ultrasound alone; however, this also increases false-positive results. This is because AFP can be elevated not only in the setting of HCC, but also in chronic hepatitis, liver cirrhosis, or ALT flare in CHB, which limits the specificity of AFP. AFP-L3 is a subfraction of AFP that is produced by malignant hepatocytes. The ratio of AFP-L3 to total AFP is reported as a percentage, and over 10% AFP-L3 is consistent with a diagnosis of HCC. Here, we review five cases of patients with CHB, cirrhosis, and HCC, and their levels of AFP and the AFP-L3% at various stages of disease including ALT flare, cirrhosis, initial diagnosis of HCC, and recurrence of HCC. These cases emphasize the utility of AFP-L3% in identifying early, new or recurrent HCC prior to the presence of imaging findings.     

Early Treatment Consideration in Patients with Hepatitis B ‘e’ Antigen-Positive Chronic Infection: Is It Time for a Paradigm Shift?

Chronic hepatitis B (CHB) is associated with significant morbidity and mortality, due to the adverse sequelae of cirrhosis and hepatocellular carcinoma (HCC). To date, antiviral therapy has been reserved for patients with ostensibly active liver disease, fibrosis or cirrhosis, and/or increased risk of HCC. Historically, patients with hepatitis B ‘e’ antigen (HBeAg)-positive chronic infection, were not offered antiviral therapy. Nevertheless, there has been compelling evidence emerging in recent years, demonstrating that this disease phase is in fact not characterized by immunological tolerance. HBV integration into the human genome is a frequent event found in these patients. Additionally, it may well be associated with active inflammation and fibrosis, even in the presence of persistently normal liver enzymes. Likewise, it appears that the mechanisms of hepatocarcinogenesis are already present during this early stage of the disease. This was reflected in the European Association for the Study of the Liver (EASL) guidelines, where treating patients above the age of 30 years with HBeAg-positive chronic infection was proposed. Lowering the treatment threshold to broaden treatment eligibility is likely to slow disease progression and reduce the risk of developing HCC. The current review discusses the reasons to consider early antiviral therapy in HBeAg-positive chronic infection.     

Risk for hepatocellular carcinoma in the course of chronic hepatitis B virus infection and the protective effect of therapy with nucleos(t)ide analogues

Hepatocellular carcinoma(HCC) is a major health problem worldwide, representing one of the leading causes of death. Chronic hepatitis B virus(HBV) infection(CHB) is the most important etiologic factor of this tumor, accounting for the development of more than50% of the cases in the world. Primary prevention ofHCC is possible by hepatitis B vaccination conferring protection from HBV infection. However, according to the World Health Organization Hepatitis B Fact sheet N° 204(update of July 2014) globally there exists a large pool of 240 million people chronically infected with HBV who are at risk for development of HCC. These individuals represent a target population for secondary prevention both of cirrhosis and of HCC. Since ongoing HBV replication in CHB is linked with the progression of the underlying liver disease to cirrhosis as well as with the development of HCC, effective antiviral treatment in CHB has also been evaluated in terms of secondary prevention of HCC. Currently, most patients with active CHB are subjected to long term treatment with the first line nucleos(t)ide analogues entecavir and tenofovir. These compounds are of high antiviral potency and have a high barrier to HBV resistance compared to lamivudine, adefovir dipivoxil and even telbivudine. Many studies have shown that patients under antiviral treatment, especially those in virological remission, develop less frequently HCC compared to the untreated ones. However, the risk for development of HCC cannot be eliminated. Therefore, surveillance for the development of HCC of patients with chronic hepatitis B must be lifelong or until a time in the future when new treatments will be able to completely eradicate HBV from the liver particularly in the early stages of CHB infection. In this context, the aim of this review is to outline the magnitude of the risk for development of HCC among patients with CHB, in the various phases of the infection and in relation to virus, host and environmental factors as evaluated in the world literature. Moreover, the benefits of antiviral treatment of CHB with nucleos/tide analogs, which have changed the natural history of the disease and have reduced but not eliminated the risk of HCC are also reviewed.     

Role of antiviral therapy in the natural history of hepatitis B virus-related chronic liver disease

Hepatitis B virus(HBV) infection is a dynamic state ofinteractions among HBV, hepatocytes, and the host immune system. Natural history studies of chronic hepatitis B(CHB) infection have shown an association between active viral replication and adverse clinical outcomes such as cirrhosis and hepatocellular carcinoma. The goal of therapy for CHB is to improve quality of life and survival by preventing progression of the disease to cirrhosis, decompensation, end-stage liver disease, hepatocellular carcinoma(HCC) and death. This goal can be achieved if HBV replication is suppressed in a sustained manner. The accompanying reduction in histological activity of CHB lessens the risk of cirrhosis and of HCC, particularly in non-cirrhotic patients. However, CHB infection cannot be completely eradicated, due to the persistence of covalently closed circular DNA in the nucleus of infected hepatocytes, which may explain HBV reactivation. Moreover, the integration of the HBV genome into the host genome may favour oncogenesis, development of HCC and may also contribute to HBV reactivation.     

HBV genotypes in India: do they influence disease severity?

Aims:  Association of HBV genotypes (especially A and D) with severity of liver disease is controversial. We studied the influence of HBV genotypes on liver disease severity among Indian patients.
Methods:  We selected 247 HBV infected patients (42 acute hepatitis, 87 carriers, 44 chronic hepatitis B [CHB], 35 liver cirrhosis [LC] and 40 hepatocellular carcinoma [HCC]). Genotyping of stored sera was performed using genotype-specific enzyme-linked immunosorbent assay (ELISA) and restriction fragment length polymorphism (RFLP). The distribution of genotypes in disease states of differing clinical, histological and biochemical severity were compared.
Results:  The most common genotype was D (162/237, 68.3%), followed by A (61, 25.7%) and C (14, 5.9%). The distribution of HBV genotypes between patients with acute hepatitis and CHB (carriers + CHB + LC + HCC), or between carriers and disease states (CHB + LC + HCC), or between mild chronic infection (carriers + CHB) and complications of chronic HBV infection (LC + HCC) was similar. Eighty-seven patients had liver biopsy; the median histological activity index (HAI) and fibrosis stage at baseline were similar between genotype groups (four [1–9] genotype A [ n  = 28]), three (2–4) genotype C ( n  = 4) and four (1–10) genotype D ( n  = 55); P  = 0.33 for HAI score; (0.5 [0–6] genotype A, 0.5 [0–4] genotype C and 1 [0–6] genotype D; P  = 0.92 for fibrosis stage). The response to therapy was similar between the genotypes.
Conclusion:  Clinical, histological severity and therapeutic responses are similar among patients with HBV genotypes A and D.     

Long term nucleotide and nucleoside analogs treatment in chronic hepatitis B HBeAg negative genotype D patients and risk for hepatocellular carcinoma

Background and rationale of the study. Effect of Long-term nucleoside/nucleotide (NUC) on hepatocellular carcinoma (HCC) incidence in a population of HBeAg-negative genotype D patients has not been adequately studied in real-life cohorts. Our aim was to evaluate the impact of liver fibrosis and other variables on HCC incidence in this population of patients. Of 745 patients with chronic hepatitis B (CHB), 306 HBeAg-negative genotype D were selected and included in this study. All patients received treatment with NUC for at least 18 months. Patients with CHB or compensated cirrhosis were included. Patients with HCC diagnosed before or during the first 18 months of NUC therapy were excluded.Results. HCC was diagnosed in 2 CHB patients (1.0%) and 23 cirrhosis patients (20%) (OR = 24.41, 95% CI 5.40 < OR < 153.2; p < 0.0001). Multivariate analysis revealed that HCC risk was independently associated with age ≥ 60 years (OR = 6.45, 95% CI 1.22 to 34.0; p = 0.02) and liver cirrhosis (OR = 12.1, 95% CI 1.39 to 106.2; p = 0.02), but not with virological response (VR), and previous resistance to NUC, or rescue therapy. Multivariate analysis in cirrhosis patients revealed that only age ≥ 60 years was an independent risk factor associated with HCC (p = 0.003). Conclusions. Liver cirrhosis and age > 60 years are the stronger risk factors for HCC in genotype D HBeAnegative patients. Previous resistance to NUC in patients that achieved a VR after rescue therapy was not a predictive factor regarding HCC. VR does not appear to significantly reduce the overall incidence of HCC when a patient has already progressed to liver cirrhosis.     

Surveillance for hepatocellular carcinoma in chronic viral hepatitis: Is it time to personalize it?

Surveillance with abdominal ultrasound with or without alpha-fetoprotein is recommended by clinical practice guidelines for patients who are considered to be at risk of developing hepatocellular carcinoma (HCC), including those with cirrhosis, advanced fibrosis and special subgroups of chronic hepatitis B (CHB). Application of the standard surveillance strategy to all patients with chronic liver disease (CLD) with or without cirrhosis imposes major sustainability and economic burdens on healthcare systems. Thus, a number of HCC risk scores were constructed, mainly from Asian cohorts, to stratify the HCC prediction in patients with CHB. Similarly, even if less than for CHB, a few scoring systems were developed for chronic hepatitis C patients or cirrhotic patients with CLD of different etiologies. Recently, a few newsworthy HCC-risk algorithms were developed for patients with cirrhosis using the combination of serologic HCC markers and clinical parameters. Overall, the HCC risk stratification appears at hand by several validated multiple score systems, but their optimal performance is obtained only in populations who show highly homogenous clinic-pathologic, epidemiologic, etiologic and therapeutic characteristics and this limitation poses a major drawback to their sustainable use in clinical practice. A better understanding of the dynamic process driving the progression from CLD to HCC derived from studies based on molecular approaches and genetics, epigenetics and liquid biopsy will enable the identification of new biomarkers to define the individual risk of HCC in the near future, with the possibility to achieve a real and cost/effective personalization of surveillance.     

Long-term follow-up of cumulative incidence of hepatocellular carcinoma in hepatitis B virus patients without antiviral therapy

BACKGROUNDChina has a high prevalence of hepatitis B virus (HBV), but most chronic hepatitis B (CHB) patients do not receive standardized antiviral therapy. There are few relevant reports addressing the outcomes of the large number of CHB patients who do not receive antiviral therapy.AIMTo observe the outcomes of long-term follow-up of patients with CHB without antiviral treatment.METHODSThis study included 362 patients with CHB and 96 with hepatitis B cirrhosis without antiviral treatment and with only liver protection and anti-inflammatory treatment from 1993 to 1998. The median follow-up times were 10 and 7 years, respectively. A total of 203 CHB and 129 hepatitis B cirrhosis patients receiving antiviral therapy were selected as the control groups. The median follow-up times were 8 and 7 years, respectively. Kaplan-Meier curves were used to analyze the cumulative incidence of hepatocellular carcinoma (HCC), and the Cox regression model was used to analyze the risk factors for HCC.RESULTSAmong the patients in the non-antiviral group, 16.9% had spontaneous decreases in HBV DNA to undetectable levels, and 32.8% showed hepatitis B e antigen (HBeAg) seroconversion. In the antiviral group, 87.2% of patients had undetectable HBV DNA, and 52% showed HBeAg seroconversion. Among CHB and hepatitis B cirrhosis patients, the cumulative incidence rates of HCC were 14.9% and 53.1%, respectively, in the non-antiviral group and were 10.7% and 31.9%, respectively, in the antiviral group. There was no difference between the two groups regarding the CHB patients (P = 0.842), but there was a difference between the groups regarding the hepatitis B cirrhosis patients (P = 0.026). The cumulative incidence rates of HCC were 1.6% and 22.3% (P = 0.022) in the groups with and without spontaneous HBeAg seroconversion, respectively. The incidence rates of HCC among patients with and without spontaneous declines in HBV DNA to undetectable levels were 1.6% and 19.1%, respectively (P = 0.051). There was no difference in the cumulative incidence of HCC between the two groups regarding the patients with drug-resistant CHB (P = 0.119), but there was a significant difference between the two groups regarding the patients with cirrhosis (P = 0.004). The Cox regression model was used for regression of the corrected REACH-B score, which showed that alanine aminotransferase > 400 U/L, history of diabetes, and family history of liver cancer were risk factors for HCC among men aged > 40 years (P < 0.05). Multifactorial analysis showed that a family history of HCC among men was a risk factor for HCC.CONCLUSIONAntiviral therapy and non-antiviral therapy with liver protection and anti-inflammatory therapy can reduce the risk of HCC. Antiviral therapy may mask the spontaneous serological response of some patients during CHB. Therefore, the effect of early antiviral therapy on reducing the incidence of HCC cannot be overestimated.     

Treatment of chronic hepatitis C virus infection in patients with cirrhosis

Chronic hepatitis C virus (HCV) infection eventually leads to cirrhosis in 20–30% of patients and to hepatocellular carcinoma (HCC) in 1–5% of patients. Rates of sustained virological response with standard interferon-α (IFN-α) are low in patients without cirrhosis (generally < 20%) and are even lower in those with cirrhosis. Combination therapy with IFN and ribavirin improves response rates in patients with chronic hepatitis C without cirrhosis, and the results from subgroups of HCV-infected patients with advanced fibrosis or cirrhosis are encouraging. Importantly, treatment with IFN slows progression of liver fibrosis, regardless of HCV genotype or early response to therapy, and reduces the risk of HCC by two- to fivefold. The risk of development of HCC is also lower in patients who show at least a partial response to IFN therapy compared with those who show no response. There is a clear need for more definitive studies of treatment in patients with chronic hepatitis C and cirrhosis, ideally using therapies with greater efficacy. Nonetheless, based on the potential to slow the progression of liver fibrosis (regardless of treatment response) and to reduce the risk of HCC, a greater number of HCV-infected patients with cirrhosis should be considered as candidates for IFN treatment. Preliminary data indicate that pegylated IFNs have improved virological response rates and may have additional clinical benefits in the prevention or reduction of fibrosis and retardation of progression of cirrhosis and HCC in these patients.     

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).     

乙型肝炎病毒感染者肝组织IL-12表达及其意义

目的探讨乙型肝炎病毒感染者肝组织白细胞介素12（IL-12）表达与临床表现和肝脏病理学变化的关系。方法应用免疫组化法检测9例正常肝脏组织、183例慢性乙型肝炎（CHB）、41例乙型肝炎肝硬化、37例HBV相关肝癌患者肝组织IL-12表达情况,并与临床特点和病理分级等进行相关性分析。结果 CHB患者肝组织IL-12以弱阳性表达为主,阳性和强阳性表达的比例仅为26.8%,而肝硬化和肝癌患者阳性和强阳性表达的比例分别为36.6%和48.6%,均显著高于CHB患者（P＜0.05）;HBeAg阴转且HBV DNA阴转的CHB患者肝内IL-12阳性表达比例为64.3%,显著高于HBeAg阳性伴肝功能异常者（30.0%）和肝功能正常者（20.4%）（P＜0.05）;未发现IL-12表达与肝脏炎症分级或纤维化分期具有相关性。结论 IL-12可能参与HBV感染后的疾病进展与转归。     

慢性乙型肝炎和肝硬化患者血清HBV基因型分析

目的 分析慢性乙型肝炎和肝硬化患者血清乙型肝炎病毒(HBV)分型分布情况。方法 2015年6月～2018年5月南京中医药大学附属南京市第二医院就诊的慢性乙型肝炎患者261例,乙型肝炎肝硬化患者30例,肝细胞癌4例,采用测序法检测血清HBV基因型。结果 在295例HBV感染者中,有132例(44.7%)为B型感染,161例(54.6%)为C型感染,2例(0.7%)为D型感染;慢性乙型肝炎患者与肝硬化患者血清TBIL、ALT和AST水平比较差异均无统计学意义(P>0.05);肝硬化患者血清肝纤维化指标(P<0.05)、血清HBV DNA载量(P<0.05)和血清HBeAg阳性率(x²=5.798,P<0.05)均显著高于慢性乙型肝炎患者;乙型肝炎肝硬化患者和肝细胞癌患者C型感染比例均显著高于慢性乙型肝炎患者,差异具有统计学意义(P<0.05)结论 慢性乙型肝炎和肝硬化患者HBV感染以B基因型和C基因型为主,而肝硬化患者以C型感染居多,提示C型感染患者可能比B型患者更容易出现严重的肝损伤,并产生严重的临床结局。     

National Survey of Hepatocellular Carcinoma in Heavy Drinkers in Japan

Background: The major cause of hepatocellular carcinoma (HCC) in the general Japanese population is an infection related to hepatotropic viruses, especially hepatitis virus C (HCV). Even in heavy drinkers, the major cause of HCC is HCV infection. However, HCC without viral infection has been reported in heavy drinkers. Alcohol has been also reported to be associated with an increased risk of cancer. In this study, we investigated aspects of HCC pathogenesis in heavy drinkers in Japan.
Methods: Questionnaires were sent to 1350 hospitals authorized by the Japanese Society of Gastroenterology. The questionnaires asked about the number of inpatients with the different types of alcoholic liver diseases, admitted to each hospital between 1998 and 2001.
Results: The percentage of heavy drinkers among all admitted patients with liver diseases or liver cirrhosis was approximately 15%. Of the patients with alcoholic liver cirrhosis, the cirrhosis was derived from alcohol alone in 61% and from alcohol plus a virus in 39% of patients. Furthermore, the percentage of patients with alcoholic liver cirrhosis caused by alcohol alone and who did not have HCC was 80%. However, the percentage of HCC patients who tested negative for viral hepatitis serum markers was 27% of the total number of heavy drinkers admitted for HCC. A study mainly on liver cirrhosis performed in the early 1990s demonstrated that the alcohol-alone group accounted for 44% of admitted patients with alcoholic liver cirrhosis and 18% of heavy drinkers admitted for HCC.
Conclusions: Because the consumption of alcohol is increasing in Japan, the frequency and number of cases of alcoholic liver cirrhosis are increasing. Viral hepatitis infection, however, still plays an important role in hepatocarcinogenesis in heavy drinkers. Radiographical examination is recommended even in patients with alcoholic liver cirrhosis who test negative for serum markers of viral hepatitis.     

National Survey of Hepatocellular Carcinoma in Heavy Drinkers in Japan

Background: The major cause of hepatocellular carcinoma (HCC) in the general Japanese population is an infection related to hepatotropic viruses, especially hepatitis virus C (HCV). Even in heavy drinkers, the major cause of HCC is HCV infection. However, HCC without viral infection has been reported in heavy drinkers. Alcohol has been also reported to be associated with an increased risk of cancer. In this study, we investigated aspects of HCC pathogenesis in heavy drinkers in Japan. Methods: Questionnaires were sent to 1350 hospitals authorized by the Japanese Society of Gastroenterology. The questionnaires asked about the number of inpatients with the different types of alcoholic liver diseases, admitted to each hospital between 1998 and 2001. Results: The percentage of heavy drinkers among all admitted patients with liver diseases or liver cirrhosis was approximately 15%. Of the patients with alcoholic liver cirrhosis, the cirrhosis was derived from alcohol alone in 61% and from alcohol plus a virus in 39% of patients. Furthermore, the percentage of patients with alcoholic liver cirrhosis caused by alcohol alone and who did not have HCC was 80%. However, the percentage of HCC patients who tested negative for viral hepatitis serum markers was 27% of the total number of heavy drinkers admitted for HCC. A study mainly on liver cirrhosis performed in the early 1990s demonstrated that the alcohol‐alone group accounted for 44% of admitted patients with alcoholic liver cirrhosis and 18% of heavy drinkers admitted for HCC. Conclusions: Because the consumption of alcohol is increasing in Japan, the frequency and number of cases of alcoholic liver cirrhosis are increasing. Viral hepatitis infection, however, still plays an important role in hepatocarcinogenesis in heavy drinkers. Radiographical examination is recommended even in patients with alcoholic liver cirrhosis who test negative for serum markers of viral hepatitis.     

The Management of Chronic Hepatitis B in Asian Americans

Hepatitis B virus (HBV) infection is common with major clinical consequences worldwide. In Asian Americans, the HBsAg carrier rate ranges from 7 to 16%; HBV is the most important cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). Patients are first diagnosed at different stages of clinical disease, which is categorized by biochemical and virologic tests. Patients at risk for liver complications should be identified and offered antiviral therapy. The two antiviral agents recommended for first-line treatment of chronic hepatitis B (CHB) are entecavir and tenofovir. The primary goal of therapy is sustained suppression of viral replication to achieve clinical remission, reverse fibrosis, and prevent and reduce progression to end-stage liver disease and HCC. Asian patients with chronic hepatitis, either HBeAg-positive or -negative, with HBV DNA levels >10⁴ copies/mL (>2,000 IU/mL) and alanine aminotransferase (ALT) values above normal are candidates for antiviral therapy. HBeAg-negative patients with HBV DNA >10⁴ copies/mL (>2,000 IU/mL) and normal ALT levels but who have either serum albumin ≤3.5 g/dL or platelet count ≤130,000 mm³, basal core promoter mutations, or who have first-degree relatives with HCC should be offered treatment. Patients with cirrhosis and detectable HBV DNA must receive antiviral therapy. Considerations for treatment include pregnant women with high viremia, coinfected patients, and those requiring immunosuppressive therapy. In HBsAg-positive patients with risk factors, lifelong surveillance for HCC with alpha-fetoprotein testing and abdominal ultrasound examination at 6-month intervals is required. These recommendations are based on a review of relevant literature and the opinion of a panel of Asian American physicians with expertise in hepatitis B treatment.     

Update on the management and treatment of hepatitis C virus infection: recommendations from the Department of Veterans Affairs Hepatitis C Resource Center Program and the National Hepatitis C Program Office

Chronic hepatitis C virus (HCV) infection affects approximately 1.3 % of the United States population and 4 % of veterans who use Department of Veterans Affairs medical services. Chronic HCV is the primary cause of cirrhosis, hepatocellular carcinoma (HCC), and end-stage liver disease requiring liver transplantation in the United States. Management of chronic HCV is aimed at halting disease progression, preventing cirrhosis decompensation, reducing the risk of HCC, and treating extrahepatic complications of the infection. As part of a comprehensive HCV management strategy, peginterferon alfa and ribavirin, along with the addition of a hepatitis C protease inhibitor therapy for many genotype 1-infected patients, are the current standard of care. Antiviral therapy should be provided to those individuals who are clinically stable, have moderate liver disease or compensated cirrhosis, and are motivated to pursue therapy. Many patients have comorbid medical and psychiatric conditions, which may affect their adherence to antiviral therapy or worsen while on antiviral therapy. To optimally manage hepatitis C and associated comorbidities, patients benefit from multidisciplinary teams that can provide HCV-specific care and treatment. Sustained virologic response is associated with "cure" of chronic HCV, and results in improved liver disease outcomes and prolonged survival.     

Hepatocellular carcinoma in the post-hepatitis C virus era: Should we change the paradigm?

Hepatocellular carcinoma (HCC) is a common and deadly malignancy. The disease usually develops on a background of chronic liver disease. Until recently, the most common etiology was infection with the hepatitis C virus (HCV). The advent of direct-acting antiviral (DAA) therapies has been a major breakthrough in HCV treatment. Sustained virologic response can now be achieved in almost all treated patients, even in patients with a high risk for the development of HCC, such as the elderly or those with significant fibrosis. Early reports raised concerns of a high risk for HCC occurrence after DAA therapy both in patients with previous resection of tumors and those without previous tumors. As the World Health Organization’s goals for eradication of HCV are being endorsed worldwide, the elimination of HCV seems feasible. Simultaneous to the decrease in the burden of cirrhosis from HCV, non-alcoholic fatty liver disease (NAFLD) incidence has been increasing dramatically including significant increased incidence of cirrhosis and HCC in these patients. Surprisingly, a substantial proportion of patients with NAFLD were shown to develop HCC even in the absence of cirrhosis. Furthermore, HCC treatment and potential complications are known to be influenced by liver steatosis. These changes in etiology and epidemiology of HCC suggest the beginning of a new era: The post–HCV era. Changes may eventually undermine current practices of early detection, surveillance and management of HCC. We focused on the risk of HCC occurrence and recurrence in the post–HCV era, the surveillance needed after DAA therapy and current studies in HCC patients with NAFLD.     

Active antiviral therapy for chronic hepatitis B and hepatocellular carcinoma

The ultimate goal of treatment for chronic hepatitis B (CHB) is to prevent hepatocellular carcinoma (HCC). During the last decade, great strides have been made in the treatment of hepatitis B virus (HBV) infections. Six highly effective anti-HBV agents are currently available and more agents are on the horizon. Prospective and retrospective studies of large numbers of CHB patients with advanced liver disease, including cirrhosis, have demonstrated that the treatment with lamivudine not only delays the disease progression but also reduces the incidence of HCC. In a large prospective study of 3,653 HBV carriers in Taiwan, 164 persons developed HCC in a 12-year follow-up period; an extensive analysis of their condition led to the conclusion that the most important risk factor for HCC is an increased serum level of HBV DNA >10,000 copies/mL regardless of the HBeAg status, alanine aminotransferase levels or presence of cirrhosis. The incidence of HCC correlated with serum HBV DNA level at entry in a dose-response relationship. These pivotal studies re-emphasize the need for an active anti-HBV therapy for CHB patients with viral replication as the ultimate prevention and/or delay for the development of HCC.     

Etiology of non-B non-C hepatocellular carcinoma in the eastern district of Tokyo

Background  This study was carried out to clarify the carcinogenic factors associated with nonviral hepatocellular carcinoma (HCC). Methods  A total of 320 HCC patients diagnosed and treated from January 2000 to December 2006 were enrolled. The clinical characteristics of non-B non-C HCC patients were examined to determine possible carcinogenic factors. Results  Of 320 HCC patients, 64 were classified as having non-B non-C HCC. The proportion of non-B non-C HCC increased from 17.8% in 2000 to 28.6% in 2006. Non-B non-C HCC patients had a significantly higher rate of early stage cirrhosis (Child-Pugh classification) than viral HCC patients. Significantly fewer non-B non-C HCC patients had periodic intensive medical assessments than viral HCC patients. Forty-five non-B non-C HCC patients were habitual alcohol drinkers, ten had nonalcoholic fatty liver disease (NAFLD), and seven had no apparent etiology. In habitual drinkers, the stage of underlying liver disease varied widely, while most NAFLD patients had early stage cirrhosis. On the other hand, more than half of the patients with HCC of undetermined etiology had noncirrhotic liver disease. Among habitual drinkers, the underlying liver disease was more progressive, and the T stage was more advanced in those with high daily alcohol intake than in those with low daily alcohol intake. Periodic intensive medical assessments were crucial for detecting early stage HCC. Conclusions  Alcohol consumption and NAFLD may be important etiological factors in non-B non-C HCC. Periodic medical assessments for all patients with non-B non-C cirrhosis are crucial for early diagnosis and curative therapy.