Hepatocellular carcinoma in patients with chronic hepatitis C virus infection in the Asia–Pacific region

Hepatocellular carcinoma (HCC) is the third-leading cause of cancer-related mortality worldwide. Although hepatitis B still remains the most common risk factor worldwide, chronic hepatitis C virus (HCV) infection is the driving force for the increased incidence of HCC especially in Western countries and Japan. In hepatitis B virus (HBV)-endemic areas, after successful vaccination programs against HBV, chronic HCV infection is now emerging as an important cause of chronic liver diseases. Unlike patients with chronic hepatitis B, those with chronic hepatitis C (CHC) develop HCC in the presence of established cirrhosis in most cases. However, a significant minority of CHC develops HCC in the absence of cirrhosis. Although HCV is a RNA virus with little potential for integrating its genetic material into host genome, various HCV proteins, including core, envelope, and nonstructural proteins, have oncogenic properties by inducing oxidative stress, disturbing cellular regulatory pathways associated with proliferation and apoptosis, and suppressing host immune responses. Overall, a combination of virus-specific, host genetic, environmental, and immune-related factors are likely to determine progression to HCC. Strategies aimed at eliminating the virus may provide opportunities for effective prevention of the development of HCC. Pegylated interferon plus ribavirin therapy appears to be effective at reducing the risk of HCC in patients who achieve sustained virologic responses. In summary, with the emerging importance of CHC, mechanisms of HCV-associated hepatocellular carcinogenesis should be clarified to provide insight into advanced therapeutic and preventive approaches, which eventually decrease the incidence and mortality of HCC.     

Effects of antiviral therapy on preventing liver tumorigenesis and hepatocellular carcinoma recurrence

Chronic hepatitis B virus(HBV)infection is the key driving force of liver disease progression,resulting in the development of hepatic dysfunction,cirrhosis and hepatocellular carcinoma(HCC).The primary aim of therapy is to suppress or eliminate HBV replication to reduce the activity of hepatitis,thus reducing the risk of,or slowing the progression of,liver disease.Nucleos(t)ide analogues(Nucs)may result in rapid suppression of HBV replication with normalization of serum transaminases and restore liver function,thus increasing survival in patients with hepatic decompensation.Long-term Nuc therapy may result in histological improvement or reversal of advanced fibrosis and reduction in disease progression,including the development of HCC.The long-term benefits of a finite course of interferon(IFN)-αtherapy also include a sustained and cumulative response,as well as hepatitis B surface antigen seroclearance and reduction in the development of cirrhosis and/or HCC.Pegylated IFN and newer Nucs may achieve better long-term outcomes because of improved efficacy and a low risk of drug resistance.However,treatment outcomes are still far from satisfactory.Understanding the effects of anti-HBV treatment against HCC incidence and recurrence after hepatectomy or liver transplantation is required for further improvement of outcome.     

Effect of antiviral treatment on the risk of hepatocellular carcinoma in patients with chronic hepatitis B

Chronic hepatitis B (CHB) is a major risk factor for hepatocellular carcinoma (HCC). The prevention of HCC is of paramount importance in patients with CHB, particularly in those with cirrhosis. Antiviral treatment can potentially reduce the risk for HCC since it suppresses viral replication, induces HBeAg seroconversion and improves liver histology. However, most evidence supporting a protective effect of antiviral treatment originates from non-randomized or retrospective studies and is limited to conventional interferon and lamivudine. There is a paucity of data on the effects of pegylated interferon and "newer" oral agents (telbivudine, tenofovir, entecavir) on HCC risk. However, it should be emphasized that the existing randomized control studies in patients with CHB were relatively short-term and not designed to assess the effects of antiviral treatment on HCC risk. Since viral load directly correlates with HCC risk, it is reasonable to hypothesize that the reduction in viral load with antiviral treatment will also lower the risk of HCC. This benefit might become more readily apparent with the newer agents used in the management of CHB which are more effective and have a more favorable resistance profile.     

Role of antiviral treatment for HCC prevention

Chemoprevention of hepatocellular carcinoma (HCC) is listed as a yet highly debated long-term benefit of a successful treatment of patients with chronic viral hepatitis. In the hepatitis B virus (HBV) arena, the retrospective scrutiny of both interferon and nucleos(t)ide analogues (NUC) studies failed to provide robust evidence for HCC chemoprevention, due to a number of confoundings in the studies that were originally designed to assess the antiviral activity of interferon therapy. However, the reanalysis of outcomes following patients stratification for risk factors of HCC, provided a clue to find an association between NUC therapy and a reduced risk of liver cancer in non cirrhotic patients, only. In the hepatitis C scenario, a meta analysis of 30 observational studies of patients treated with interferon demonstrated a more than 70% reduction of HCC risk occurring independently of severity of underlying liver fibrosis which was less pronounced in aged patients and those with more advanced liver fibrosis. While the reasons for the residual risk of HCC in virological responders remain largely unexplained, international societies recommend surveillance for HCC of both HBV and HCV responders to antiviral therapy.     

Prevention of hepatocellular carcinoma in hepatitis B virus infection

Chronic hepatitis B is the main risk factor for hepatocellular carcinoma (HCC) in Asia. The most important preventive strategy's adoption of the universal hepatitis B vaccination program is now in its third decade. There is a clear reduction in both chronic hepatitis B virus (HBV) infection (hepatitis B surface antigen "carriage") but also in childhood HCC in Taiwan. An outstanding concern is variability in vaccine coverage between countries. For patients with chronic hepatitis B, serum HBV DNA levels have emerged as the key risk factor for development of HCC. The initial treatment for chronic hepatitis B was interferon. One randomized control trial, and several case–control or cohort studies have shown benefits for preventing HCC, particularly in cirrhotic patients who responded to therapy. With nucleos(t)ide analogs, the most important study has been the Asian Cirrhosis Lamivudine multicenter randomized controlled trial. This showed that lamivudine can reduce disease progression in HBV-related cirrhosis, including an approximately 50% decrease in HCC incidence. Such efficacy was achieved despite emergence of drug resistance in approximately 50% of cases. Case–control studies have suggested that hepatitis B cases without cirrhosis may also benefit. In conclusion, it is now possible to prevent HBV-related HCC. The most effective method is hepatitis B vaccination, which prevents chronic HBV infection and chronic liver disease resulting therefrom. Interferon therapy appears to confer benefit but the evidence is weaker. First-generation oral antiviral (lamivudine) reduces HCC risk, particularly in cirrhotics. Long-term outcome data with newer, more potent HBV antivirals that have a higher genetic barrier to drug resistance are eagerly awaited.     

Hepatitis C virus and hepatocellular carcinoma

The sequential development of cirrhosis and hepatocellular carcinoma (HCC) in patients with transfusion-associated hepatitis was a clue leading to the identification of hepatitis C virus (HCV) as a risk factor for HCC. The incidence of HCV-related liver cancer is increasing in many developed countries: tumours arise in older patients, are almost invariably associated with cirrhosis and often have a less aggressive course than is seen in HCC related to other aetiological factors. Most HCCs grow as a single hepatic nodule for several years before generating satellite or distant tumour nodules. Tumour progression and hepatic failure are the leading causes of death. HCV might promote cancer through cirrhosis, which is per se an important risk factor for this tumour. HCV might also have oncogenic properties by interacting with cellular genes that regulate cell growth and differentiation. The primary prevention of HCC through vaccination against HCV is not yet available. The treatment of patients with chronic hepatitis C with interferon might attenuate the risk of HCC.     

Hepatic Fas protein expression might be a predictive factor for hepatocellular carcinoma development in patients with chronic hepatitis C undergoing interferon therapy

BACKGROUND: Several studies have revealed that interferon treatment may reduce the incidence of hepatocellular carcinoma (HCC) in patients with chronic hepatitis C virus (HCV). However, even after eradication of HCV, patients remain at risk for developing HCC. STUDY: Of 153 consecutive HCV patients who were treated with interferon and followed up for 5 years, 17 (11.1%) developed HCC. To elucidate predictive factors of HCC development, multivariate analysis was done for the 153 patients, and Fas protein expression in the biopsied specimens of liver before interferon treatment was examined in 17 patients who developed HCC and 17 patients who did not. RESULTS: Among the independent factors (sex, age, HCV genotype, HCV-RNA level, effect of interferon therapy, serum alanine aminotransferase before interferon therapy, and histologic stage and grade) tested by Cox proportional-hazards analysis, histologic stage (hepatic fibrosis) before interferon was significantly associated with HCC development (p = 0.01). In addition, the intensity of Fas protein expression was significantly greater in the liver specimens of the patients who developed HCC than in those who did not (p = 0.015). CONCLUSION: Histologic stage (hepatic fibrosis) and Fas protein expression before interferon treatment might be indicative of the need for intensive follow-up in patients with chronic hepatitis C undergoing interferon therapy.     

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.     

Pleiotropic effects of statins in the diseases of the liver

Statins are a class of molecules that inhibit HMG Co A reductase. They are usually prescribed as a lipid lowering medication. However, there is accumulating evidence that statins have multiple secondary effects both related and unrelated to their lipid-lowering effect. This narrative review of the literature aims to provide the reader with information from clinical studies related to the effect of statin and statins' potential use in patients with liver diseases. In patients with advanced liver disease due to any etiology, statins exhibit an antifibrotic effect possibly through the prevention of hepatic sinusoidal microthrombosis. Two randomized controlled trials confirmed that statins decrease hepatic vein pressure gradient in patients with portal hypertension and improve the survival of patients after variceal bleeding. Lower rates of infections were observed in patients with cirrhosis who received statin treatment. Statins decrease the risk of hepatocellular carcinoma(HCC) in patients with advanced liver disease in general but particularly in patients with chronic hepatitis B and C. Statins in patients with chronic hepatitis C likely increase the virological response to the treatment with pegylated interferon and ribavirin and have the potential to decrease the rate of fibrosis. Finally, data from randomized controlled trials also confirmed that the addition of statin prolongs the survival of patients with advanced HCC even more than sorafenib. Statins are a very promising group of drugs especially in patients with liver disease, where therapeutic options can often be limited. Some indications, such as the prevention of re-bleeding from esophageal varices and the palliative treatment of HCC have been proven through randomized controlled trials, while additional indications still need to be confirmed through prospective studies.     

Managing hepatitis B to prevent liver cancer: recent advances

Chronic hepatitis B (CHB) infection is a major cause of human mortality worldwide. The majority of people with CHB are infected early in life, and 20–40% of men and 15% of women with chronic infection will develop hepatocellular carcinoma (HCC). Antiviral therapy is recommended for patients with CHB who have cirrhosis or active disease with the aims of reducing disease progression to cirrhosis, liver failure and liver cancer, thereby preventing death. Evidence that treatment with interferon or with early nucleos(t)ide analogue therapy reduces HCC has been somewhat conflicting, however evidence is emerging to support a significant role in HCC prevention of the more effective antivirals, entecavir and tenofovir. Older patients, those with cirrhosis, and those undergoing curative treatments for HCC derive the greatest medium-term benefit in terms of HCC reduction, but HCC can still occur and long-term surveillance is recommended.     

Does interferon therapy prevent hepatocellular carcinoma in patients with chronic viral hepatitis?

Chronic hepatitis C and B are well-recognized and potentially preventable risk factors for hepatocellular carcinoma (HCC) development. Clinical and epidemiological studies suggest that therapy with interferon-α may reduce the overall risk of HCC development in patients with chronic hepatitis C, who achieve sustained virological response, but even in those who fail to eradicate the infection. In chronic hepatitis B, interferon therapy reduces the risk of HCC development in HBeAg-positive and cirrhotic patients who achieve persistent suppression of viral replication, while in HBeAg-negative patients the beneficial effect of interferon-α is not definitively confirmed. The preventive role of interferon-α after potentially curative treatment for HCC in both chronic hepatitis B and C is uncertain due to methodological flaws of the existing studies and prospective randomized controlled trials with pegylated interferon-α are needed to clarify this issue.     

Optimizing Management Strategies in Special Patient Populations

Chronic hepatitis B infection presents a number of challenges to clinicians. There are additional considerations when defining management strategies for individuals with advanced liver disease, or coinfection, or those at high risk of developing hepatocellular carcinoma (HCC). Treatment of decompensated cirrhosis is particularly important. Evidence suggests that suppression of viral replication through nucleos(t)ide analog therapy leads to longer time to transplantation, improved liver function, and improved survival times. The use of interferon in patients with decompensated hepatitis B is associated with serious complications and is currently contraindicated for these patients by the AASLD Practice Guidelines. Hepatitis B coinfection is often associated with more extensive disease. In patients with HBV/HCV coinfection, one disease is usually dominant and consequently should be the focus of therapy. HIV/HBV coinfection increases the risk of progressive liver disease. Therapeutic agents active against both viruses should be utilized at the correct dose to limit the development of resistance. Agents specific for HBV, e.g. , entecavir, enable hepatitis to be treated while avoiding the risk of HIV resistance developing. Dual infection with HBV and HDV is particularly challenging. Nucleos(t)ide analogs are ineffective in treating HDV infection, and there is limited data concerning the efficacy of interferon in this setting. The association between chronic hepatitis B infection and hepatocellular carcinoma (HCC) is well established. In patients at high risk of HCC, screening regimes may be effective. Furthermore, there is an increasing body of evidence indicating that effective suppression of viral replication may be associated with a reduced risk of HCC.     

Management before hepatectomy for hepatocellular carcinoma with cirrhosis

The global distribution of hepatocellular carcinoma (HCC) varies markedly among regions, and patients in East Asia and Central Africa account for about 80% of all cases. The risk factors are hepatitis B, hepatitis C, alcohol, and etc. The risk of carcinogenesis further increases with progression to hepatic cirrhosis in all liver disorders. Radical treatment of HCC by liver resection without causing liver failure has been established as a safe approach through selection of an appropriate range of resection of the damaged liver. This background indicates that both evaluation of hepatic functional reserve and measures against concomitant diseases such as thrombocytopenia accompanying portal hypertension, prevention of rupture of esophageal varices, reliable control of ascites, and improvement of hypoalbuminemia are important issues in liver resection in patients with hepatic cirrhosis. We review the latest information on perioperative management of liver resection in HCC patients with hepatic cirrhosis.     

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.     

Hepatitis B virus-related cirrhosis: natural history and treatment

In patients with compensated hepatitis B virus (HBV) cirrhosis, active viral replication correlates significantly with the risk of hepatic flare, decompensation, and the development of hepatocellular carcinoma (HCC). The 5-year survival of patients with compensated cirrhosis was reported to be 80 to 85%, and is significantly lower in patients with replicative HBV. Both interferon and maintenance lamivudine therapy have been shown to reduce the risk of decompensation or HCC and prolong survival in responders. A finite course of interferon is recommended as the first-line agent. For patients who had a contraindication for or who have failed interferon therapy, direct antiviral(s) can be considered for long-term treatment. Once decompensation occurs, mortality increases remarkably. Early treatment with nucleoside analogues should be instituted. Lamivudine therapy is associated with rapid viral suppression, improvement in Child-Pugh scores, and improved survival, but drug resistance is a major problem and is associated directly with a poor clinical outcome. Adefovir or entecavir is preferred in patients with decompensated cirrhosis who require long duration of treatment, due to the lower rate of development of resistance.     

Systematic review of risk factors of hepatocellular carcinoma after hepatitis B surface antigen seroclearance

There is no consensus about factors that increase risk of hepatocellular carcinoma (HCC) among patients with chronic hepatitis B who have achieved seroclearance of hepatitis B surface antigen (HBsAg). To assess the available evidence about risk factors for HCC after HBsAg seroclearance, Scopus, EMBASE, PubMed and Cochrane Library databases were systematically searched for relevant studies published through 15 September 2017. A total of 28 studies involving more than 105 411 patients with chronic hepatitis B were included. HBsAg seroclearance occurred spontaneously in 7656, while it occurred after interferon or nucleos(t)ide analogue therapy in 1248. The rate of HBsAg seroclearance was 6.77%. Incidence of HCC was significantly lower among patients who experienced HBsAg seroclearance than among those who remained HBsAg‐positive (1.86% vs 6.56%, P < .001). Risk factors of HCC occurrence included cirrhosis (incidence with vs without: 9.51% vs 1.66%), male gender (2.34% vs 0.64%) and age ≥ 50 year at HBsAg seroclearance (2.34% vs 0.63%) (all P < .001). The available evidence suggests that HCC can develop at a low rate after HBsAg seroclearance, so periodic surveillance is recommended, especially for male patients, patients with cirrhosis and patients who experience HBsAg seroclearance when at least 50 years old.     

Then and now: The progress in hepatitis B treatment over the past 20 years

The ultimate goals of treating chronic hepatitis B(CHB)is prevention of hepatocellular carcinoma(HCC)and hepatic decompensation.Since the advent of effective antiviral drugs that appeared during the past two decades,considerable advances have been made not only in controlling hepatitis B virus(HBV)infection,but also in preventing and reducing the incidence of liver cirrhosis and HCC.Furthermore,several recent studies have suggested the possibility of reducing the incidence of recurrent or new HCC in patients even after they have developed HCC.Currently,six medications are available for HBV treatment including,interferon and five nucleoside/nucleotide analogues.In this review,we will examine the antiviral drugs and the progresses that have been made with antiviral treatments in the field of CHB.     

肝硬化患者肝细胞癌的预防和治疗

肝硬化患者肝细胞癌的预防主要在于如何降低相关危险因素,尤其是对HBV、HCV相关性肝硬化的预防。HBV、HCV疫苗的应用是预防的关键,抗病毒药物预防有助于减少HBV、HCV的复制,降低HCC的发生率。HCC的根治治疗主要包括手术切除和肝移植,对于不能行根治的患者选用适当的非手术切除的多种介入疗法;其他治疗如辅以免疫治疗、分子靶向治疗也有助于改善肝细胞癌患者的预后。     

Does HCV antiviral therapy decrease the risk of hepatocellular carcinoma?

Whether antiviral therapy for hepatitis C virus (HCV) infection can prevent hepatocellular carcinoma (HCC) independent of a sustained virologic response (SVR) has been debated since a randomized trial from Japan in 1995. Incidence of HCC in patients with chronic hepatitis C with SVR is reduced through cirrhosis prevention, but HCC is also prevented in cirrhosis by reduction of necroinflammatory activity and possibly cell turnover. However, HCV patients with cirrhosis who achieve an SVR still have a risk, although a lower one, of HCC, so surveillance must continue. The potential antiproliferative effect of interferon (IFN) with respect to HCC has been discounted by a prospective randomized clinical trial in nonresponders to IFN (Hepatitis C Antiviral Long-term Treatment Against Cirrhosis [HALT-C]), in which IFN did not modify any outcomes. Thus, the best strategy to reduce HCC is to treat HCV-infected patients before they develop cirrhosis and to increase the SVR rate.     

Hepatocellular carcinoma in non-alcoholic fatty liver disease: an emerging menace

Hepatocellular carcinoma (HCC) is a common cancer worldwide that primarily develops in cirrhosis resulting from chronic infection by hepatitis B virus and hepatitis C virus, alcoholic injury, and to a lesser extent from genetically determined disorders such as hemochromatosis. HCC has recently been linked to non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of obesity and related metabolic disorders such as diabetes. This association is alarming due to the globally high prevalence of these conditions and may contribute to the rising incidence of HCC witnessed in many industrialized countries. There is also evidence that NAFLD acts synergistically with other risk factors of HCC such as chronic hepatitis C and alcoholic liver injury. Moreover, HCC may complicate non-cirrhotic NAFLD with mild or absent fibrosis, greatly expanding the population potentially at higher risk. Major systemic and liver-specific molecular mechanisms involved include insulin resistance and hyperinsulinemia, increased TNF signaling pathways, and alterations in cellular lipid metabolism. These provide new targets for prevention, early recognition, and effective treatment of HCC associated with NAFLD. Indeed, both metformin and PPAR gamma agonists have been associated with lower risk and improved prognosis of HCC. This review summarizes current evidence as it pertains to the epidemiology, pathogenesis, and prevention of NAFLD-associated HCC.