Viral hepatitis and hepatocellular carcinoma: From molecular pathways to the role of clinical surveillance and antiviral treatment

Hepatocellular carcinoma (HCC) is a global health challenge. Due to the high prevalence in low-income countries, hepatitis B virus (HBV) and hepatitis C virus infections remain the main risk factors for HCC occurrence, despite the increasing frequencies of non-viral etiologies. In addition, hepatitis D virus coinfection increases the oncogenic risk in patients with HBV infection. The molecular processes underlying HCC development are complex and various, either independent from liver disease etiology or etiology-related. The reciprocal interlinkage among non-viral and viral risk factors, the damaged cellular microenvironment, the dysregulation of the immune system and the alteration of gut-liver-axis are known to participate in liver cancer induction and progression. Oncogenic mechanisms and pathways change throughout the natural history of viral hepatitis with the worsening of liver fibrosis. The high risk of cancer incidence in chronic viral hepatitis infected patients compared to other liver disease etiologies makes it necessary to implement a proper surveillance, both through clinical-biochemical scores and periodic ultrasound assessment. This review aims to outline viral and microenvironmental factors contributing to HCC occurrence in patients with chronic viral hepatitis and to point out the importance of surveillance programs recommended by international guidelines to promote early diagnosis of HCC.     

Hepatocellular carcinoma: From diagnosis to treatment

Hepatocellular carcinoma(HCC) is the sixth most prevalent malignancy worldwide and is a rising cause of cancer related mortality. Risk factors for HCC are well documented and effective surveillance and early diagnosis allow for curative therapies. The majority of HCC appears to be caused by cirrhosis from chronic hepatitis B and hepatitis C virus. Preventive strategies include vaccination programs and anti-viral treatments.Surveillance with ultrasonography detects early stage disease and improves survival rates. Many treatment options exist for individuals with HCC and are determined by stage of presentation. Liver transplantation is offered to patients who are within the Milan criteria and are not candidates for hepatic resection. In patients with advanced stage disease, sorafenib shows some survival benefit.     

Clinical factors associated with hepatitis B screening andvaccination in high-risk adults

BACKGROUND Hepatitis B virus is a viral infection that can lead to acute and/or chronic liver disease, and hepatocellular carcinoma(HCC). Hepatitis B vaccination is 95% effective in preventing infection and the development of chronic liver disease and HCC due to hepatitis B. In 2011, the Centers for Disease Control updated their guidelines recommending that adults at high-risk for hepatitis B infection be vaccinated against hepatitis B including those with diabetes mellitus(DM). We hypothesize that adults at high-risk for hepatitis B infection are not being adequately screened and/or vaccinated for hepatitis B in a large urban healthcare system.AIM To investigate clinical factors associated with Hepatitis B screening and vaccination in patients at high-risk for Hepatitis B infection.METHODS We conducted a retrospective review of 999 patients presenting at a large urban healthcare system from 2012-2017 at high-risk for hepatitis B infection. Patients were considered high-risk for hepatitis B infection based on hepatitis B practice recommendations from the Center for Disease Control. Medical history including hepatitis B serology, concomitant medical diagnoses, demographics, insurance status and social history were extracted from electronic health records.Multivariate logistic regression was used to identify clinical risk factors independently associated with hepatitis B screening and vaccination.RESULTS Among the 999 patients, 556(55.7%) patients were screened for hepatitis B. Of those who were screened, only 242(43.5%) patients were vaccinated against hepatitis B. Multivariate regression analysis revealed end-stage renal disease[odds ratio(OR): 5.122; 2.766-9.483], alcoholic hepatitis(OR: 3.064; 1.020-9.206),and cirrhosis or end-stage liver disease(OR: 1.909; 1.095-3.329); all P 0.05 were associated with hepatitis B screening, while age(OR: 0.785; 0.680-0.906),insurance status(0.690; 0.558-0.854), history of DM(OR: 0.518; 0.364-0.737), and human immunodeficiency virus(OR: 0.443; 0.273-0.718); all P 0.05 were instead not associated with hepatitis B screening. Of the adults vaccinated for hepatitis B,multivariate regression analysis revealed age(OR: 0.755; 0.650-0.878) and DM were not associated with hepatitis B vaccination(OR: 0.620; 0.409-0.941) both P 0.05.CONCLUSION Patients at high-risk for hepatitis B are not being adequately screened and/or vaccinated. Improvements in hepatitis B vaccination should be strongly encouraged by all healthcare systems.     

Hepatitis B virus/hepatitis D virus epidemiology: Changes over time and possible future influence of the SARS-CoV-2 pandemic

Hepatitis D virus (HDV) is a defective liver-tropic virus that needs the helper function of hepatitis B virus (HBV) to infect humans and replicate. HDV is transmitted sexually or by a parenteral route, in co-infection with HBV or by super-infection in HBV chronic carriers. HDV infection causes acute hepatitis that may progress to a fulminant form (7%-14% by super-infection and 2%-3% by HBV/HDV co-infection) or to chronic hepatitis (90% by HDV super-infection and 2%-5% by HBV/HDV co-infection), frequently and rapidly progressing to cirrhosis or hepatocellular carcinoma (HCC). Peg-interferon alfa the only recommended therapy, clears HDV in only 10%-20% of cases and, consequently, new treatment strategies are being explored. HDV endemicity progressively decreased over the 50 years from the identification of the virus, due to improved population lifestyles and economic levels, to the use of HBV nuclei(t)side analogues to suppress HBV replication and to the application of universal HBV vaccination programs. Further changes are expected during the severe acute respiratory syndrome coronavirus-2 pandemic, unfortunately towards increased endemicity due to the focus of healthcare towards coronavirus disease 2019 and the consequently lower possibility of screening and access to treatments, lower care for patients with severe liver diseases and a reduced impulse to the HBV vaccination policy.     

Prevention of hepatocellular carcinoma in the Asia–Pacific region: Consensus statements

Among approximately 650 000 people who die from hepatocellular carcinoma (HCC) each year, at least two‐thirds live in Asia. Efforts to improve early diagnosis and treatment have not yet impacted mortality. An Asia–Pacific Working Party convened in Hong Kong in June 2008 to consider ways to prevent HCC in this region. Separate reviews have summarized epidemiology of HCC, preventive approaches related to hepatitis B virus (HBV), hepatitis C virus (HCV) and non‐viral liver diseases, and the role of surveillance to detect HCC at a curative stage. We now present Consensus Statements from these deliberations and reviews. As chronic hepatitis B is the most common cause of HCC in Asia, effective hepatitis B vaccination programs are the most important strategy to reduce HCC incidence. Prevention of HCV by screening blood donors, universal precautions against blood contamination in health‐care settings and reducing HCV transmission from injection drug use are also vital. There is strong evidence that effective antiviral therapy to control HBV infection or eradicate HCV substantially reduces (but does not abolish) HCC risk. With hemochromatosis, family screening, early diagnosis and correcting iron overload to prevent liver fibrosis prevents HCC. There is currently insufficient evidence to give firm recommendations on alcohol, obesity/metabolic risk factors and other liver diseases. HCC surveillance for high‐risk groups is recommended in individual cases but cost‐effectiveness is not as high as infant hepatitis B vaccination and screening blood for HCV. Widespread application of HCC surveillance in Asia–Pacific countries depends on economic factors and health‐care priorities.     

Induced immunity against hepatitis B virus

Prevention of hepatitis B virus (HBV) infection with its consequent development of HBV chronic liver disease and hepatocellular carcinoma is a global mandatory goal. Fortunately, safe and effective HBV vaccines are currently available. Universal hepatitis B surface antigen HBV vaccination coverage is almost done. Growing knowledge based upon monitoring and surveillance of HBV vaccination programs has accumulated and the policy of booster vaccination has been evaluated. This review article provides an overview of the natural history of HBV infection, immune responses and the future of HBV infection. It also summarizes the updated sources, types and uses of HBV vaccines, whether in the preclinical phase or in the post-field vaccination.     

Liver disease in Viet Nam: screening, surveillance, management and education: a 5-year plan and call to action

Despite a high prevalence of liver disease in Viet Nam, there has been no nationwide approach to the disease and no systematic screening of at-risk individuals. Risk factors include chronic hepatitis B (estimated prevalence of 12%), chronic hepatitis C (at least 2% prevalence), and heavy consumption of alcohol among men. This combination of factors has resulted in liver cancer being the most common cause of cancer death in Viet Nam. There is a general lack of understanding by both the general public and health-care providers about the major risk to health that liver disease represents. We report here the initial steps taken as part of a comprehensive approach to liver disease that will ultimately include nationwide education for health-care providers, health educators, and the public; expansion of nationwide screening for hepatitis B and C followed by hepatitis B virus vaccination or treatment of chronic hepatitis B and/or hepatitis C; education about alcoholic liver disease; long-term surveillance for liver cancer; reduction of infection transmission related to medical, commercial, and personal re-use of contaminated needles, syringes, sharp instruments, razors, and inadequately sterilized medical equipment; and ongoing collection and analysis of data about the prevalence of all forms of liver disease and the results of the expanded screening, vaccination, and treatment programs. We report the beginning results of our pilot hepatitis B screening program. We believe that this comprehensive nationwide approach could substantially reduce the morbidity and mortality from liver disease and greatly lessen the burden in terms of both lives lost and health-care costs.     

Current impact of viral hepatitis on liver cancer development: The challenge remains

Chronic infections due to hepatitis B and hepatitis C viruses are responsible for most cases of hepatocellular carcinoma (HCC) worldwide, and this association is likely to remain during the next decade. Moreover, viral hepatitis-related HCC imposes an important burden on public health in terms of disability-adjusted life years. In order to reduce such a burden, some major challenges must be faced. Universal vaccination against hepatitis B virus, especially in the neonatal period, is probably the most relevant primary preventive measure against the development of HCC. Moreover, considering the large adult population already infected with hepatitis B and C viruses, it is also imperative to identify these individuals to ensure their access to treatment. Both hepatitis B and C currently have highly effective therapies, which are able to diminish the risk of development of liver cancer. Finally, it is essential for individuals at high-risk of HCC to be included in surveillance programs, so that tumors are detected at an early stage. Patients with hepatitis B or C and advanced liver fibrosis or cirrhosis benefit from being followed in a surveillance program. As hepatitis B virus is oncogenic and capable of leading to liver cancer even in individuals with early stages of liver fibrosis, other high-risk groups of patients with hepatitis B are also candidates for surveillance. Considerable effort is required concerning these strategies in order to decrease the incidence and the mortality of viral hepatitis-related HCC.     

Low Prevalence of Vaccination or Documented Immunity to Hepatitis A and Hepatitis B Viruses Among Individuals with Chronic Liver Disease

BackgroundDespite national guidelines emphasizing the importance of vaccination or documenting immunity to hepatitis A virus and hepatitis B virus for patients with chronic liver disease, the success of adhering to these recommendations is suboptimal. We aim to evaluate the prevalence of vaccination or documented reactivity to hepatitis A antibody and hepatitis B surface antibody among US adults with chronic liver disease.MethodsUsing 2011-2018 National Health and Nutritional Examination Survey data, adults with nonalcoholic fatty liver disease, alcoholic liver disease, hepatitis B, and hepatitis C were evaluated to determine prevalence of vaccination (self-reported completion) and hepatitis A antibody reactivity or hepatitis B surface antibody reactivity.ResultsOverall prevalence of vaccination or hepatitis A antibody reactivity was lowest among individuals with nonalcoholic fatty liver disease (60.8%; 95% confidence interval [CI], 57.9-63.6) and alcoholic liver disease (61.8%; 95% CI, 59.0-64.6), and highest among individuals with hepatitis B (82.9%; 95% CI, 76.8-89.0). Prevalence of vaccination or hepatitis B surface antibody reactivity was much lower: 38.6% (95% CI, 35.7-41.4) in nonalcoholic fatty liver disease, 40.7% (95% CI, 34.4-47.0) in chronic hepatitis C virus, and 47.1% (95% CI, 44.3-49.9) in alcoholic liver disease.ConclusionAmong US adults with chronic liver disease, prevalence of vaccination or documented reactivity to hepatitis A antibody and hepatitis B surface antibody was alarmingly low. These observations are particularly concerning given that underlying chronic liver disease increases risks of severe liver injury and decompensation from acute hepatitis A or hepatitis B infections.     

Hepatocellular carcinoma: an Asian perspective

Hepatocellular carcinoma (HCC) is one of the most frequently occurring malignancies in Asia. The incidence exceeds 30 cases/100,000/year in the east Asian region. Worldwide, it accounts for almost 1 million deaths/year. The high incidence in Asia is due to the high prevalence of chronic viral hepatitis, mainly chronic hepatitis B. With the introduction of universal vaccination for hepatitis B in some Asian countries in the mid 1980s, some of these countries are experiencing a decline in the incidence of HCC. This probably underscores the point that HCC caused by hepatitis B is a malignancy preventable by vaccine. Due to the relative paucity of symptoms in the early stages and the rapid doubling time of the tumor, most HCCs are discovered late in advanced stages at presentation. Most Asian countries have adopted a screening program for patients at risk. Earlier and smaller HCCs are detected through such programs but these programs have yet to demonstrate improved patient survival. Physicians managing patients with HCC are faced with two main challenges, the malignancy itself and the underlying liver disease. The extent of the tumor and the existing liver function limits the therapeutic choices available. Hepatic resection remains the treatment of choice. However, the majority of patients present with nonresectable tumors. Transarterial chemoembolization, percutaneous ethanol injection and radiofrequency ablation are the other treatment modalities. In patients with small tumors (<5 cm) and poor liver function, liver transplant offers a viable treatment alternative. In summary, the risk factor for HCC in Asia is predominantly chronic hepatitis B. Universal vaccination against hepatitis B is likely to reduce the incidence. The prognosis and outcome of treatment remains poor with a 5-year survival of 35% for patients treated surgically and less than 10% for nonresectable tumors. Current management is aimed at earlier detection and more effective treatment of early HCC. In future, the challenge will be managing HCC in the premalignant stage.     

Significance of viral status on occurrence of hepatitis B-related hepatocellular carcinoma

Hepatitis B virus (HBV) infection remains a challenging global health problem, with more than 350 million people chronically infected and at risk of developing hepatocellular carcinoma (HCC). Interactions that occur among host, environmental, and viral factors determine the natural course and predict the prognosis of patients with chronic HBV infection. In the past decades, several important viral factors of predictive of HCC have been identified, such as high hepatitis B surface antigen level, seropositivity of hepatitis B e antigen, high viral load, viral genotype, and specific viral sequence mutations. Identification of certain viral risk factors for HCC development and stratification of patient risk are very important to perform future surveillance programs. In this article, we thus reviewed the risk of viral factors involved in hepatocarcinogenesis.     

Occult hepatitis B virus infection is not associated with disease progression of chronic hepatitis C virus infection

AIM To clarify the prevalence of occult hepatitis B virus(HBV) infection(OBI) and the association between OBI and liver disease progression, defined as development of liver cirrhosis or hepatocellular carcinoma(HCC), worsening of Child-Pugh class, or mortality in cases of chronic hepatitis C virus(HCV) infection. METHODS This prospective cohort study enrolled 174 patients with chronic HCV infection(chronic hepatitis, n = 83; cirrhosis, n = 47; HCC, n = 44), and evaluated disease progression during a mean follow-up of 38.7 mo. OBI was defined as HBV DNA positivity in 2 or moredifferent viral genomic regions by nested polymerase chain reaction using 4 sets of primers in the S, C, P and X open reading frame of the HBV genome. RESULTS The overall OBI prevalence in chronic HCV patients at enrollment was 18.4%, with 16.9%, 25.5% and 13.6% in the chronic hepatitis C, liver cirrhosis and HCC groups, respectively(P = 0.845). During follow-up, 52 patients showed disease progression, which was independently associated with aspartate aminotransferase 40 IU/L, Child-Pugh score and sustained virologic response(SVR), but not with OBI positivity. In 136 patients who were not in the SVR state during the study period, OBI positivity was associated with neither disease progression, nor HCC development. CONCLUSION The prevalence of OBI in chronic HCV patients was 18.4%, and OBI was not associated with disease progression in South Koreans.     

Does antiviral therapy for hepatitis B and C prevent hepatocellular carcinoma?

Approximately 75% to 80% of hepatocellular carcinomas (HCC) worldwide are attributed to chronic hepatitis B virus (HBV) and chronic hepatitis C virus (HCV) infection. Thus, effective prevention of HBV and HCV infection and progression from acute HBV and HCV infection to chronic hepatitis, cirrhosis and HCC might prevent as many as 450,000 deaths from HCC each year. The most effective approach to preventing HCC is to prevent HBV and HCV infection through vaccination. Indeed HBV vaccine is the first vaccine demonstrated to prevent cancers. However, a vaccine for HCV is not available and for persons who are chronically infected with HBV or HCV, antiviral therapy is the only option for preventing HCC. Direct evidence supporting a benefit of antiviral therapy on the prevention of HCC has been shown in a few randomized controlled trials. There is abundant evidence that antiviral therapy, in patients with long-term virological response, can improve liver histology, providing indirect support that antiviral therapy may prevent HCC by slowing progression of liver disease and possibly even reversing liver damage. Nevertheless, the risk of HCC remains in patients with chronic HBV or chronic HCV infection if treatment is initiated after cirrhosis is established. These data indicate that treatment might be of greater benefit if instituted earlier in the course of chronic hepatitis B or C. Safer, more effective, and more affordable antiviral therapies are needed for both hepatitis B and hepatitis C so more patients can benefit from treatment and more HCCs can be prevented.     

Association between metabolic factors and chronic hepatitis B virus infection

There are limited data regarding the relationship between chronic hepatitis B virus (HBV) infection and metabolic factors. This article aims to highlight the link of metabolic factors with hepatitis B surface antigen (HBsAg) serostatus, HBV load, and HBV-related hepatocellular carcinoma (HCC). Although HBsAg-positive serostatus was positively correlated with a high risk of metabolic syndrome in students, chronic HBV-infected individuals have high serum adiponectin levels. The androgen pathway in HBV carriers with a low body mass index is more triggered which leads to enhanced HBV replication. High HBV load was inversely associated with obesity in hepatitis B e antigen (HBeAg)-seropositive HBV carriers; while in HBeAg-seronegative HBV carriers, high HBV load was inversely related to hypertriglyceridemia rather than obesity. For overweight and obese HBV-infected patients, high HBV load was positively associated with serum adiponectin levels. Several large cohort studies have revealed a positive link of diabetes with incidence of HBV-related HCC. However, the association between incidence of HCC and metabolic factors other than diabetes is still inconclusive. More long-term prospective studies should elucidate the association of chronic HBV infection and its outcomes with metabolic factors in clinical practice.     

我国乙型肝炎疫苗研究及接种的新进展

乙型肝炎病毒(Hepatitis B virus,HBV)引起的相关疾病仍然是困扰医疗界的一大难题,全球每年有(100～150)万人死于与HBV相关的疾病,尤其以慢性乙型肝炎者尚无有效的治疗方法,这使得接种乙型肝炎疫苗成为了目前防治乙型肝炎的最经济和有效的手段,乙型肝炎疫苗研究也因此有了长足发展。本文对乙型肝炎疫苗的现状及研究进展进行了整理,以提高临床医师对乙型肝炎疫苗的认识。     

Hepatitis B among Asian Americans:Prevalence,progress, and prospects for control

After tobacco use, chronic hepatitis B(CHB) viral infections are the most important cause of cancer globally in that 1 out of 3 individuals have been infected with the hepatitis B virus(HBV). Though infection rates are low( 1%) in the United States, Asian Americans who comprise about 6% of the population experience about 60% of the CHB burden. This paper reviews the magnitude of hepatitis B(HBV) burden among Asian Americans and the progress being made to mitigate this burden, primarily through localized, communitybased efforts to increase screening and vaccination among Asian American children, adolescents, and adults. This review brings to light that despite the numerous community-based screening efforts, a vast majority of Asian Americans have not been screened and that vaccination efforts, particularly for adults, are sub-optimal. Greater efforts to integrate screenings by providers within existing healthcare systems are urged. Evidence-based strategies are offered to implement CDC's three major recommendations to control and prevent hepatitis B through targeted screening and enhanced vaccination efforts.     

The changing pattern of hepatitis B virus infection over the past three decades in Italy

By the end of 1970s, Italy was a country at medium endemic level of hepatitis B virus infection, with wide geographical differences; intrafamily transmission was the major mode by which infection spread; hepatitis B e antigen positivity and hepatitis Delta positivity were frequently detected in hepatitis B surface antigen chronic carriers; a high proportion of subjects with chronic liver disease resulted as hepatitis B surface antigen positive. Three decades apart, the picture was completely changed, as documented by several surveys. Nowadays, Italy is a country at very low endemic level of hepatitis B, without geographical differences; the infection is mostly sexually transmitted; hepatitis B e antigen positivity and hepatitis Delta positivity are rarely detected in hepatitis B surfaces antigen chronic carriers; a low proportion of subjects with chronic liver disease result hepatitis B surface antigen positive. These important changes may be due to both non-specific (i.e. improvement in socio-demographic features) and specific (i.e. a comprehensive vaccination program against hepatitis B) preventive measures.     

The effectiveness of the national hepatitis B vaccination program 25 years after its introduction in Iran: a historical cohort study

IntroductionHepatitis B virus (HBV) is responsible for one of the most common human viral infections. An estimated 257 million people are living with chronic HBV infection worldwide, and mortality has reached 900,000 deaths in recent years. In 2001, the World Health Organization reported a prevalence of chronic hepatitis B infection in Iran between 2–7%.ObjectiveTo assess the effect of the national HBV mass vaccination program after 25 years.MethodsA retrospective cohort study was conducted in vaccinated and unvaccinated people according to the year of birth. Blood samples were obtained from each enrolled person and data about demographic variables, and medical and vaccination history were collected using a standardized questionnaire. Persons were considered uninfected if they were negative for both HBsAg and anti-HBc. Also, Vaccine effectiveness was measured by calculating the risk of disease among vaccinated and unvaccinated persons and defining the percentage risk reduction of infection in the vaccinated group.ResultsA total of 2720 persons were interviewed. The rate of HBV breakthrough infection among the vaccinated group was significantly lower than in unvaccinated group. One hundred ninety-four cases with positive HBV markers of infection were identified. The risk ratio of HBV infection was 0.71, 95% CI: 0.54–0.94 (vaccinated/unvaccinated). The estimated vaccination effectiveness against Hepatitis B infection was 29% (95% CI: 6%–46%).ConclusionsIran has successfully combined hepatitis B vaccination into regular immunization programs. The WHO goal of reducing HBsAg prevalence to an equivalent of 1% by 2020 has been reached. With respect to vaccination effectiveness and low prevalence of the disease in the country, catch-up hepatitis B vaccination programs for adolescents can guarantee the immunity of the population.     

Natural history of hepatitis-related hepatocellular carcinoma

Hepatocellular carcinoma （HCC） is an important cause of cancer death in the world. It has great regional differences in the pathology and epidemiology. The variation is greatly influenced by the aetiologies of the disease. Hepatitis B and C infection are the most important risk factors. HCC incidence rates are higher but in decreasing trend in developing countries. However, the figures in the developed countries are contrary. Successful hepatitis B virus （HBV） vacdnation programs, better food hygiene, increased global hepatitis C virus {HCV） prevalence and population migration are the possible explanations. A number of clinical and pathogenic differences exist between HBV- and HCV- related HCC. HBV infection leads to the development of HCC through direct and indirect pathways as it has the ability to integrate into the host genome affecting cellular signaling and growth control. HCV causes HCC mainly through indirect pathways： chronic inflammation, cell deaths and proliferation. As a result, HCC is almost exclusively found in cirrhotic HCV patients while HCC is sometimes found in HBV patients without significant liver cirrhosis. Due to the different severities of liver cirrhosis and HCC extent, therapeutic strategies from resection, liver transplantation to symptoms palliation are available. Poorly differentiated histology, lack of fibrous capsule, large tumour size, early vascular invasion and elevated serum levels of alpha fetoprotein （AFP） are the features for more aggressive disease. Combined with markers of liver reserve and performance status, accurate scoring systems and models have been developed to predict patients＇ survival and match best treatment option.