BACKGROUND Hepatitis B virus(HBV)is a major cause of hepatocellular carcinoma(HCC).HBV DNA can get integrated into the hepatocyte genome to promote carcinogenesis.However,the precise mechanism by which the integrated ...BACKGROUND Hepatitis B virus(HBV)is a major cause of hepatocellular carcinoma(HCC).HBV DNA can get integrated into the hepatocyte genome to promote carcinogenesis.However,the precise mechanism by which the integrated HBV genome promotes HCC has not been elucidated.AIM To analyze the features of HBV integration in HCC using a new reference database and integration detection method.METHODS Published data,consisting of 426 Liver tumor samples and 426 paired adjacent non-tumor samples,were re-analyzed to identify the integration sites.Genome Reference Consortium Human Build 38(GRCh38)and Telomere-to-Telomere Consortium CHM13(T2T-CHM13(v2.0))were used as the human reference genomes.In contrast,human genome 19(hg19)was used in the original study.In addition,GRIDSS VIRUSBreakend was used to detect HBV integration sites,whereas high-throughput viral integration detection(HIVID)was applied in the original study(HIVID-hg19).RESULTS A total of 5361 integration sites were detected using T2T-CHM13.In the tumor samples,integration hotspots in the cancer driver genes,such as TERT and KMT2B,were consistent with those in the original study.GRIDSS VIRUSBreakend detected integrations in more samples than by HIVID-hg19.Enrichment of integration was observed at chromosome 11q13.3,including the CCND1 pro-moter,in tumor samples.Recurrent integration sites were observed in mitochondrial genes.CONCLUSION GRIDSS VIRUSBreakend using T2T-CHM13 is accurate and sensitive in detecting HBV integration.Re-analysis provides new insights into the regions of HBV integration and their potential roles in HCC development.展开更多
Nonalcoholic fatty liver disease(NAFLD) including nonalcoholic steatohepatitis(NASH) is globally increasing and has become a world-wide health problem. Chronic infection with hepatitis B virus or hepatitis C virus(HCV...Nonalcoholic fatty liver disease(NAFLD) including nonalcoholic steatohepatitis(NASH) is globally increasing and has become a world-wide health problem. Chronic infection with hepatitis B virus or hepatitis C virus(HCV) is associated with hepatic steatosis. Viral hepatitis-associated hepatic steatosis is often caused by metabolic syndrome including obesity,type 2 diabetes mellitus and/or dyslipidemia. It has been reported that HCV genotype 3 exerts direct metabolic effects that lead to hepatic steatosis. In this review,the differences between NAFLD/NASH and viral hepatitis-associated steatosis are discussed.展开更多
Patients who are infected with hepatitis C virus(HCV) and also have advanced fibrosis or cirrhosis have beenrecognized as "difficult-to-treat" patients during an era when peginterferon and ribavirin combinat...Patients who are infected with hepatitis C virus(HCV) and also have advanced fibrosis or cirrhosis have beenrecognized as "difficult-to-treat" patients during an era when peginterferon and ribavirin combination therapy is the standard of care. Recent guidelines have clearly stated that treatment should be prioritized in this population to prevent complications such as decompensation and hepatocellular carcinoma. Recent advances in the treatment of chronic hepatitis C have been achieved through the development of direct-acting antiviral agents(DAAs). Boceprevir and telaprevir are first-generation DAAs that inhibit the HCV NS3/4A protease. Boceprevir or telaprevir, in combination with peginterferon and ribavirin, improved the sustained virological response rates compared with peginterferon and ribavirin alone and were tolerated in patients with HCV genotype 1 infection without cirrhosis or compensated cirrhosis. However, the efficacy is lower especially in prior non-responders with or without cirrhosis. Furthermore, a high incidence of adverse events was observed in patients with advanced liver disease, including cirrhosis, in real-life settings. Current guidelines in the United States and in some European countries no longer recommend these regimens for the treatment of HCV. Next-generation DAAs include second-generation HCV NS3/4A protease inhibitors, HCV NS5 A inhibitors and HCV NS5 B inhibitors, which have a high efficacy and a lower toxicity. These drugs are used in interferon-free or in interferon-based regimens with or without ribavirin in combination with different classes of DAAs. Interferon-based regimens, such as simeprevir in combination with peginterferon and ribavirin, are well tolerated and are highly effective especially in treatmentnave patients and in patients who received treatment but who relapsed. The efficacy is less pronounced in nullresponders and in patients with cirrhosis. Interferonfree regimens in combination with ribavirin and/or two or more DAAs could be used for treatment-nave, treatment-experienced and even for interferon-ineligible or interferon-intolerant patients. Some clinical trials have demonstrated promising results, and have shown that the efficacy and safety were not different between patients with and without cirrhosis. There are also promising regimens for genotypes other than genotype 1. Interferonis contraindicated in patients with decompensated cirrhosis, and further studies are needed to establish the optimal treatment regimen for this population. In the future, interferon-free and ribavirin-free regimens with high efficacy and improved safety are expected for HCVinfected patients with advanced liver diseases.展开更多
Some direct-acting antiviral agents for hepatitis C virus(HCV),such as telaprevir and boceprevir have been available since 2011.It was reported that HCV NS5A is associated with interferon signaling related to HCV repl...Some direct-acting antiviral agents for hepatitis C virus(HCV),such as telaprevir and boceprevir have been available since 2011.It was reported that HCV NS5A is associated with interferon signaling related to HCV replication and hepatocarcinogenesis.HCV NS5A inhibitors efficiently inhibited HCV replication in vitro.Human studies showed that dual,triple and quad regimens with HCV NS5A inhibitors,such as daclatasvir and ledipasvir,in combination with other direct-acting antiviral agents against other regions of HCV with or without peginterferon/ribavirin,could efficiently inhibit HCV replication according to HCV genotypes.These combinations might be a powerful tool for"difficult-to-treat"HCV-infected patients."First generation"HCV NS5A inhibitors such as daclatasvir,ledipasvir and ABT-267,which are now in phaseⅢclinical trials,could result in resistance mutations."Second generation"NS5A inhibitors such as GS-5816,ACH-3102,and MK-8742,have displayed improvements in the genetic barrier while maintaining potency.HCV NS5A inhibitors are safe at low concentrations,which make them attractive for use despite low genetic barriers,although,in fact,HCV NS5A inhibitors should be used with HCV NS3/4A inhibitors,HCV NS5B inhibitors or peginterferon plus ribavirin.This review article describes HCV NS5A inhibitor resistance mutations and recommends that HCV NS5A inhibitors be used in combination regimens potent enough to prevent the emergence of resistant variants.展开更多
Hepatitis B virus(HBV)chronically infects more than350 million people worldwide.HBV causes acute and chronic hepatitis,and is one of the major causes of cirrhosis and hepatocellular carcinoma.There exist complex inter...Hepatitis B virus(HBV)chronically infects more than350 million people worldwide.HBV causes acute and chronic hepatitis,and is one of the major causes of cirrhosis and hepatocellular carcinoma.There exist complex interactions between HBV and the immune system including adaptive and innate immunity.Tolllike receptors(TLRs)and TLR-signaling pathways are important parts of the innate immune response in HBV infections.It is well known that TLR-ligands could suppress HBV replication and that TLRs play important roles in anti-viral defense.Previous immunological studies demonstrated that HBV e antigen(HBeAg)is more efficient at eliciting T-cell tolerance,including production of specific cytokines IL-2 and interferon gamma,than HBV core antigen.HBeAg downregulates cytokine production in hepatocytes by the inhibition of MAPK or NF-κB activation through the interaction with receptor-interacting serine/threonine protein kinase.MicroRNAs(miRNAs)are also able to regulate various biological processes such as the innate immune response.When the expressions of approximately 1000 miRNAs were compared between human hepatoma cells HepG2 and HepG2.2.15,which could produce HBV virion that infects chimpanzees,using real-time RT-PCR,we observed several different expression levels in miRNAs related to TLRs.Although we and others have shown that HBV modulates the host immune response,several of the miRNAs seem to be involved in the TLR signaling pathways.The possibility that alteration of these miRNAs during HBV infection might play a critical role in innate immunity against HBV infection should be considered.This article is intended to comprehensively review the association between HBV and innate immunity,and to discuss the role of miRNAs in the innate immune response to HBV infection.展开更多
Direct-acting antiviral agents(DAAs)for hepatitis C virus(HCV)infection are one of the major advances in its medical treatment.The HCV protease inhibitors boceprevir and telaprevir were the first approved DAAs in the ...Direct-acting antiviral agents(DAAs)for hepatitis C virus(HCV)infection are one of the major advances in its medical treatment.The HCV protease inhibitors boceprevir and telaprevir were the first approved DAAs in the United States,Europe,and Japan.When combined with peginterferon plus ribavirin,these agents increase sustained virologic response rates to70%-80%in treatment-na?ve patients and previoustreatment relapsers with chronic HCV genotype 1 infection.Without peginterferon plus ribavirin,DAA monotherapies increased DAA-resistance mutations.Several new DAAs for HCV are now in clinical development and are likely to be approved in the near future.However,it has been reported that the use of these drugs also led to the emergence of DAA-resistance mutations in certain cases.Furthermore,these mutations exhibit cross-resistance to multiple drugs.The prevalence of DAA-resistance mutations in HCV-infected patients who were not treated with DAAs is unknown,and it is as yet uncertain whether such variants are sensitive to DAAs.We performed a population sequence analysis to assess the frequency of such variants in the sera of HCV genotype 1-infected patients not treated with HCV protease inhibitors.Here,we reviewed the literature on resistance variants of HCV protease inhibitors in treatment na?ve patients with chronic HCV genotype 1,as well as our experience.展开更多
Hepatitis C virus(HCV) infection is a serious problem worldwide.The use of interferon-based therapy has made HCV eradication challenging.The recent appearance of direct-acting antiviral agents(DAAs) has changed HCV th...Hepatitis C virus(HCV) infection is a serious problem worldwide.The use of interferon-based therapy has made HCV eradication challenging.The recent appearance of direct-acting antiviral agents(DAAs) has changed HCV therapy.Combining the use of DAAs with peginterferon and ribavirin has improved treatment efficacy.Furthermore,the combination of different orally administered DAAs has enabled interferon-free therapy with much higher efficacy and safety.In particular,sofosbuvir,a nucleotide-based NS5 B inhibitor,prevents HCV RNA synthesis by acting as a "chain terminator".Treatment with sofosbuvir has attained an extremely high rate of sustained virologic response.The current review summarizes the efficacy and safety of sofosbuvir therapy.展开更多
AIM:To examine the association between the interleukin 28B(IL-28B)genotype and treatment response in hepatitis C virus(HCV)-infected patients with persistently normal alanine aminotransferase(PNALT).METHODS:We compare...AIM:To examine the association between the interleukin 28B(IL-28B)genotype and treatment response in hepatitis C virus(HCV)-infected patients with persistently normal alanine aminotransferase(PNALT).METHODS:We compared the treatment response of HCV-infected patients with PNALT to that of patients with non-PNALT.Between February 2010 and April2013,278 patients infected with HCV were enrolled in this study.All of the patients were treated with peginterferon-alpha 2a or 2b plus ribavirin.In addition,180μg of peginterferon alpha-2a or 1.5μg/kg peginterferon alpha-2b per week plus weight-based ribavirin(600-1000 mg/d)were typically administered for 24 wk to HCV genotype 2-infected patients or for 48-72 wk to HCV genotype 1-infected patients.In all of the patients,the IL-28B rs8099917 genotype was determined using a TaqMan single-nucleotide polymorphism assay.HCV RNA was measured using the COBAS TaqMan HCV test.RESULTS:Female patients were dominant in the PNALT group(P【0.0001).Among 72 HCV genotype 1-infected patients with PNALT,the early virologic response(EVR)rates(P【0.01)and the sustained virologic response(SVR)rates(P【0.01)were higher in patients with the IL-28B TT genotype than in those with the IL-28B TG/GG genotype.In HCV genotype 1-infected patients with PNALT,multivariate logistic-regression analysis showed that SVR was independently predicted by the IL-28B rs8099917 TT type(P【0.05)and having an EVR(P【0.01).The IL-28B rs8099917 TT genotype strongly correlated with treatment response in HCV genotype 1-infected Asian patients with PNALT.CONCLUSION:The IL-28B genotype may be useful for selecting HCV genotype 1-infected patients with PNALT who should receive interferon-based treatment.展开更多
In 2009, several groups reported that interleukin-28B(IL28B) genotypes are associated with the response to peginterferon plus ribavirin therapy for chronic hepatitis C virus(HCV) infection in a genome-wide association...In 2009, several groups reported that interleukin-28B(IL28B) genotypes are associated with the response to peginterferon plus ribavirin therapy for chronic hepatitis C virus(HCV) infection in a genome-wide association study, although the mechanism of this association is not yet well understood. However, in recent years, tremendous progress has been made in the treatment of HCV infection. In Japan, some patients infected with HCV have the IL28 B major genotype, which may indicate a favorable response to interferon-including regimens; however, certain patients within this group are also interferon-intolerant or ineligible. In Japan, interferonfree 24-wk regimens of asunaprevir and daclatasvir are now available for HCV genotype 1b-infected patients who are interferon-intolerant or ineligible or previous treatment null-responders. The treatment response to interferon-free regimens appears better, regardless of IL28 B genotype. Maybe other interferon-free regimens will widely be available soon. In conclusion, although some HCV-infected individuals have IL28 B favorable alleles, importance of IL28 B will be reduced with availability of oral interferon free regimen.展开更多
Myanmar is adjacent to India, Bangladesh, Thailand, Laos and China. In Myanmar, the prevalence of hepatitis C virus(HCV) infection is 2%, and HCV infection accounts for 25% of hepatocellular carcinoma. In this study, ...Myanmar is adjacent to India, Bangladesh, Thailand, Laos and China. In Myanmar, the prevalence of hepatitis C virus(HCV) infection is 2%, and HCV infection accounts for 25% of hepatocellular carcinoma. In this study, we reviewed the prevalence of HCV genotypes in Myanmar. HCV genotypes 1, 3 and 6 were observed in volunteer blood donors in and around the Myanmar city of Yangon. Although there are several reports of HCV genotype 6 and its variants in Myanmar, the distribution of the HCV genotypes has not been well documented in areas other than Yangon. Previous studies showed that treatment with peginterferon and a weight-based dose of ribavirin for 24 or 48 wk could lead to an 80%-100% sustained virological response(SVR) rates in Myanmar. Current interferon-free treatments could lead to higher SVR rates(90%-95%) in patients infected with almost all HCV genotypes other than HCV genotype 3. In an era of heavy reliance on direct-acting antivirals against HCV, there is an increasing need to measure HCV genotypes, and this need will also increase specifically in Myanmar. Current available information of HCV genotypes were mostly from Yangon and other countries than Myanmar. The prevalence of HCV genotypes in Myanmar should be determined.展开更多
AIM:To examine the epidemiological data,hematological safety and treatment responses of peginterferonalpha 2a plus ribavirin therapy for hepatitis C.METHODS:Between March 2008 and February 2011,196 hepatitis C virus(H...AIM:To examine the epidemiological data,hematological safety and treatment responses of peginterferonalpha 2a plus ribavirin therapy for hepatitis C.METHODS:Between March 2008 and February 2011,196 hepatitis C virus(HCV)genotype 1 infected Japanese(127 treatment-naive and 69 treatment-experienced patients)patients treated with peginterferonalpha 2a plus ribavirin were enrolled.We examined the epidemiological data and treatment responses were retrospectively analyzed in terms of hematological safety.HCV RNA was measured by the COBAS TaqMan HCV test.RESULTS:Overall sustained virological response(SVR)rates of treatment-naive and treatment-experienced patients were 56% and 39%,respectively.Multivariate logistic regression analysis showed that SVR was attained independently of early virological response in both treatment-naive and treatment-experienced patients.SVR rates did not differ between the pretreatment hemoglobin < 13 g/dL and ≥ 13 g/dL groups.However,in treatment-naive patients,the SVR rate of the pretreatment platelet count < 130000/μL group was significantly lower than that of the pretreatment platelet count ≥ 130000/μL group.CONCLUSION:Attention should be paid to potential thrombocytopenia in the treatment of chronic hepatitis C patients.展开更多
Chronic hepatitis C virus(HCV) infection can cause liver cirrhosis and hepatocellular carcinoma(HCC). Several studies have demonstrated that the eradication of HCV reduces the occurrence of HCC. In Japan, as many peop...Chronic hepatitis C virus(HCV) infection can cause liver cirrhosis and hepatocellular carcinoma(HCC). Several studies have demonstrated that the eradication of HCV reduces the occurrence of HCC. In Japan, as many people live to an advanced age, HCV-infected patients are also getting older, and the age at HCC diagnosis has also increased. Although older HCV-infected patients have a risk of developing HCC, the treatment response to peginterferon-alpha plus ribavirin therapy is relatively poor in these patients because of drop-out or discontinuation of this treatment due to adverse events. It is established that the mechanism of action between interferon-alpha and interferon-beta is slightly different. Short-term natural interferon-beta monotherapy is effective for patients with acute hepatitis C and patients infected with HCV genotype 2 and low viral loads. Natural interferon-beta plus ribavirin for 48 wk or for 24 wk are also effective for some patients with HCV genotype 1 or HCV genotype 2. Natural interferon-beta plus ribavirin has been used for certain "difficult-totreat" HCV-infected patients. In the era of direct-acting anti-virals, natural interferon-beta plus ribavirin may be one of the therapeutic options for special groups of HCV-infected patients. In the near future, signal transduction pathways of interferon-beta will inform further directions.展开更多
The average age of hepatitis C virus(HCV)-infected individuals is becoming increasingly higher in Japan and steps should be taken to treat older individuals infected with HCV. Until an interferon-free regimen becomes ...The average age of hepatitis C virus(HCV)-infected individuals is becoming increasingly higher in Japan and steps should be taken to treat older individuals infected with HCV. Until an interferon-free regimen becomes available, peginterferon plus ribavirin will play a critical role in the treatment. The perception that older HCVinfected patients may be at higher risk than younger patients for adverse events from peginterferon plus ribavirin treatment but may obtain less clinical benefit from it may be based on the underrepresentation of older patients in clinical trials. A recent genomewide association study revealed that interleukin-28B(IL28B) genotype closely correlates with the treatment response against HCV. The relationship of IL28 B genotype with the treatment response in older HCV-infected patients is also unknown. In this review, we focused on the treatment response in older patients infected with HCV and the effects of IL28 B genotype. IL28 B major genotype is a useful predictor of sustained virological response in the interferon-including treatment of older patients infected with HCV. It also seems useful for avoiding adverse events, although the mechanisms ofthe effects of IL28 B genotype on the treatment outcome are still poorly understood and are currently under investigation. Further studies will be needed.展开更多
Hepatitis C virus (HCV) is a leading cause of cirrhosis and hepatocellular carcinoma (HCC) in the US and Japan.Therefore,eradication of HCV may reduce the occurrence of HCC in HCV-infected individuals.In 2011,the use ...Hepatitis C virus (HCV) is a leading cause of cirrhosis and hepatocellular carcinoma (HCC) in the US and Japan.Therefore,eradication of HCV may reduce the occurrence of HCC in HCV-infected individuals.In 2011,the use of firstgeneration HCV NS3/4A protease inhibitors such as telaprevir and boceprevir was initiated for clinical treatment of HCV.Administration of telaprevir and boceprevir plus peginterferon and ribavirin increased rates of sustained virological response (SVR) in HCV genotype 1-infected patients.However,this treatment regimen also led to severe adverse events.Second-generation direct-acting antiviral agents (DAAs) for HCV,such as simeprevir plus peg-interferon and ribavirin also resulted in higher SVR rates,with similar adverse events to other peg-interferon and ribavirin treatments.Higher SVR rates in HCV genotype 1-and 2-infected patients were achieved with 12-16 weeks of sofosbuvir plus other class DAAs with/without ribavirin and 12 weeks of sofosbuvir plus ribavirin,respectively,For "difficult-to-treat"HCV-infected patients,more therapeutic options are needed.Further studies examining the efficacy and adverse effects of such therapies will be required for the development of additional treatments.展开更多
Hepatitis A virus (HAV) infection is a major cause of acute hepatitis and occasionally leads to acute liver failure in both developing and developed countries.Although effective vaccines for HAV are available,the deve...Hepatitis A virus (HAV) infection is a major cause of acute hepatitis and occasionally leads to acute liver failure in both developing and developed countries.Although effective vaccines for HAV are available,the development of new antivirals against HAV may be important for the control of HAV infection in developed countries where no universal vaccination program against HAV exists,such as Japan.There are two forms of antiviral agents against HAV:direct-acting antivirals (DAAs) and host-targeting agents (HTAs).Studies using small interfering ribonucleic acid (siRNA) have suggested that the HAV internal ribosomal entry site (IRES) is an attractive target for the control of HAV replication and infection.Among the HTAs,amantadine and interferon-lambda 1 (IL-29) inhibit HAV IRES-mediated translation and HAV replication.Janus kinase (JAK) inhibitors inhibit La protein expression,HAV IRES activity,and HAV replication.Based on this review,both DAAs and HTAs may be needed to control effectively HAV infection,and their use should continue to be explored.展开更多
文摘BACKGROUND Hepatitis B virus(HBV)is a major cause of hepatocellular carcinoma(HCC).HBV DNA can get integrated into the hepatocyte genome to promote carcinogenesis.However,the precise mechanism by which the integrated HBV genome promotes HCC has not been elucidated.AIM To analyze the features of HBV integration in HCC using a new reference database and integration detection method.METHODS Published data,consisting of 426 Liver tumor samples and 426 paired adjacent non-tumor samples,were re-analyzed to identify the integration sites.Genome Reference Consortium Human Build 38(GRCh38)and Telomere-to-Telomere Consortium CHM13(T2T-CHM13(v2.0))were used as the human reference genomes.In contrast,human genome 19(hg19)was used in the original study.In addition,GRIDSS VIRUSBreakend was used to detect HBV integration sites,whereas high-throughput viral integration detection(HIVID)was applied in the original study(HIVID-hg19).RESULTS A total of 5361 integration sites were detected using T2T-CHM13.In the tumor samples,integration hotspots in the cancer driver genes,such as TERT and KMT2B,were consistent with those in the original study.GRIDSS VIRUSBreakend detected integrations in more samples than by HIVID-hg19.Enrichment of integration was observed at chromosome 11q13.3,including the CCND1 pro-moter,in tumor samples.Recurrent integration sites were observed in mitochondrial genes.CONCLUSION GRIDSS VIRUSBreakend using T2T-CHM13 is accurate and sensitive in detecting HBV integration.Re-analysis provides new insights into the regions of HBV integration and their potential roles in HCC development.
文摘Nonalcoholic fatty liver disease(NAFLD) including nonalcoholic steatohepatitis(NASH) is globally increasing and has become a world-wide health problem. Chronic infection with hepatitis B virus or hepatitis C virus(HCV) is associated with hepatic steatosis. Viral hepatitis-associated hepatic steatosis is often caused by metabolic syndrome including obesity,type 2 diabetes mellitus and/or dyslipidemia. It has been reported that HCV genotype 3 exerts direct metabolic effects that lead to hepatic steatosis. In this review,the differences between NAFLD/NASH and viral hepatitis-associated steatosis are discussed.
文摘Patients who are infected with hepatitis C virus(HCV) and also have advanced fibrosis or cirrhosis have beenrecognized as "difficult-to-treat" patients during an era when peginterferon and ribavirin combination therapy is the standard of care. Recent guidelines have clearly stated that treatment should be prioritized in this population to prevent complications such as decompensation and hepatocellular carcinoma. Recent advances in the treatment of chronic hepatitis C have been achieved through the development of direct-acting antiviral agents(DAAs). Boceprevir and telaprevir are first-generation DAAs that inhibit the HCV NS3/4A protease. Boceprevir or telaprevir, in combination with peginterferon and ribavirin, improved the sustained virological response rates compared with peginterferon and ribavirin alone and were tolerated in patients with HCV genotype 1 infection without cirrhosis or compensated cirrhosis. However, the efficacy is lower especially in prior non-responders with or without cirrhosis. Furthermore, a high incidence of adverse events was observed in patients with advanced liver disease, including cirrhosis, in real-life settings. Current guidelines in the United States and in some European countries no longer recommend these regimens for the treatment of HCV. Next-generation DAAs include second-generation HCV NS3/4A protease inhibitors, HCV NS5 A inhibitors and HCV NS5 B inhibitors, which have a high efficacy and a lower toxicity. These drugs are used in interferon-free or in interferon-based regimens with or without ribavirin in combination with different classes of DAAs. Interferon-based regimens, such as simeprevir in combination with peginterferon and ribavirin, are well tolerated and are highly effective especially in treatmentnave patients and in patients who received treatment but who relapsed. The efficacy is less pronounced in nullresponders and in patients with cirrhosis. Interferonfree regimens in combination with ribavirin and/or two or more DAAs could be used for treatment-nave, treatment-experienced and even for interferon-ineligible or interferon-intolerant patients. Some clinical trials have demonstrated promising results, and have shown that the efficacy and safety were not different between patients with and without cirrhosis. There are also promising regimens for genotypes other than genotype 1. Interferonis contraindicated in patients with decompensated cirrhosis, and further studies are needed to establish the optimal treatment regimen for this population. In the future, interferon-free and ribavirin-free regimens with high efficacy and improved safety are expected for HCVinfected patients with advanced liver diseases.
基金Supported by Grants for Scientific Research from the Ministry of Education,Culture,Sports,Science,and Technology of Japan(to Nakamoto S,Kanda T)grants from the Ministry of Health,Labour,and Welfare of Japan(to Yokosuka O)
文摘Some direct-acting antiviral agents for hepatitis C virus(HCV),such as telaprevir and boceprevir have been available since 2011.It was reported that HCV NS5A is associated with interferon signaling related to HCV replication and hepatocarcinogenesis.HCV NS5A inhibitors efficiently inhibited HCV replication in vitro.Human studies showed that dual,triple and quad regimens with HCV NS5A inhibitors,such as daclatasvir and ledipasvir,in combination with other direct-acting antiviral agents against other regions of HCV with or without peginterferon/ribavirin,could efficiently inhibit HCV replication according to HCV genotypes.These combinations might be a powerful tool for"difficult-to-treat"HCV-infected patients."First generation"HCV NS5A inhibitors such as daclatasvir,ledipasvir and ABT-267,which are now in phaseⅢclinical trials,could result in resistance mutations."Second generation"NS5A inhibitors such as GS-5816,ACH-3102,and MK-8742,have displayed improvements in the genetic barrier while maintaining potency.HCV NS5A inhibitors are safe at low concentrations,which make them attractive for use despite low genetic barriers,although,in fact,HCV NS5A inhibitors should be used with HCV NS3/4A inhibitors,HCV NS5B inhibitors or peginterferon plus ribavirin.This review article describes HCV NS5A inhibitor resistance mutations and recommends that HCV NS5A inhibitors be used in combination regimens potent enough to prevent the emergence of resistant variants.
基金Supported by Grants for"Asia-Oceania Collaborative Research Grants"from Kanae Foundation for the Promotion of Medical Science(to Kanda T)Grants for Scientific Research from the Ministry of Education,Culture,Sports,Science,and Technology,Japan(to Kanda T)
文摘Hepatitis B virus(HBV)chronically infects more than350 million people worldwide.HBV causes acute and chronic hepatitis,and is one of the major causes of cirrhosis and hepatocellular carcinoma.There exist complex interactions between HBV and the immune system including adaptive and innate immunity.Tolllike receptors(TLRs)and TLR-signaling pathways are important parts of the innate immune response in HBV infections.It is well known that TLR-ligands could suppress HBV replication and that TLRs play important roles in anti-viral defense.Previous immunological studies demonstrated that HBV e antigen(HBeAg)is more efficient at eliciting T-cell tolerance,including production of specific cytokines IL-2 and interferon gamma,than HBV core antigen.HBeAg downregulates cytokine production in hepatocytes by the inhibition of MAPK or NF-κB activation through the interaction with receptor-interacting serine/threonine protein kinase.MicroRNAs(miRNAs)are also able to regulate various biological processes such as the innate immune response.When the expressions of approximately 1000 miRNAs were compared between human hepatoma cells HepG2 and HepG2.2.15,which could produce HBV virion that infects chimpanzees,using real-time RT-PCR,we observed several different expression levels in miRNAs related to TLRs.Although we and others have shown that HBV modulates the host immune response,several of the miRNAs seem to be involved in the TLR signaling pathways.The possibility that alteration of these miRNAs during HBV infection might play a critical role in innate immunity against HBV infection should be considered.This article is intended to comprehensively review the association between HBV and innate immunity,and to discuss the role of miRNAs in the innate immune response to HBV infection.
基金Supported by Grants from the Japan Society for Promotion of Science(JSPS)Scientific Research from the Ministry of Education,Culture,Sports,Science,and Technology of Japanand Grants from the Ministry of Health,Labour,and Welfare of Japan
文摘Direct-acting antiviral agents(DAAs)for hepatitis C virus(HCV)infection are one of the major advances in its medical treatment.The HCV protease inhibitors boceprevir and telaprevir were the first approved DAAs in the United States,Europe,and Japan.When combined with peginterferon plus ribavirin,these agents increase sustained virologic response rates to70%-80%in treatment-na?ve patients and previoustreatment relapsers with chronic HCV genotype 1 infection.Without peginterferon plus ribavirin,DAA monotherapies increased DAA-resistance mutations.Several new DAAs for HCV are now in clinical development and are likely to be approved in the near future.However,it has been reported that the use of these drugs also led to the emergence of DAA-resistance mutations in certain cases.Furthermore,these mutations exhibit cross-resistance to multiple drugs.The prevalence of DAA-resistance mutations in HCV-infected patients who were not treated with DAAs is unknown,and it is as yet uncertain whether such variants are sensitive to DAAs.We performed a population sequence analysis to assess the frequency of such variants in the sera of HCV genotype 1-infected patients not treated with HCV protease inhibitors.Here,we reviewed the literature on resistance variants of HCV protease inhibitors in treatment na?ve patients with chronic HCV genotype 1,as well as our experience.
文摘Hepatitis C virus(HCV) infection is a serious problem worldwide.The use of interferon-based therapy has made HCV eradication challenging.The recent appearance of direct-acting antiviral agents(DAAs) has changed HCV therapy.Combining the use of DAAs with peginterferon and ribavirin has improved treatment efficacy.Furthermore,the combination of different orally administered DAAs has enabled interferon-free therapy with much higher efficacy and safety.In particular,sofosbuvir,a nucleotide-based NS5 B inhibitor,prevents HCV RNA synthesis by acting as a "chain terminator".Treatment with sofosbuvir has attained an extremely high rate of sustained virologic response.The current review summarizes the efficacy and safety of sofosbuvir therapy.
基金Supported by Grants for Scientific Research from the Ministry of Education,Culture,Sports,Science,and Technology,JapanGrants from the Ministry of Health,Labour and Welfare of Japan
文摘AIM:To examine the association between the interleukin 28B(IL-28B)genotype and treatment response in hepatitis C virus(HCV)-infected patients with persistently normal alanine aminotransferase(PNALT).METHODS:We compared the treatment response of HCV-infected patients with PNALT to that of patients with non-PNALT.Between February 2010 and April2013,278 patients infected with HCV were enrolled in this study.All of the patients were treated with peginterferon-alpha 2a or 2b plus ribavirin.In addition,180μg of peginterferon alpha-2a or 1.5μg/kg peginterferon alpha-2b per week plus weight-based ribavirin(600-1000 mg/d)were typically administered for 24 wk to HCV genotype 2-infected patients or for 48-72 wk to HCV genotype 1-infected patients.In all of the patients,the IL-28B rs8099917 genotype was determined using a TaqMan single-nucleotide polymorphism assay.HCV RNA was measured using the COBAS TaqMan HCV test.RESULTS:Female patients were dominant in the PNALT group(P【0.0001).Among 72 HCV genotype 1-infected patients with PNALT,the early virologic response(EVR)rates(P【0.01)and the sustained virologic response(SVR)rates(P【0.01)were higher in patients with the IL-28B TT genotype than in those with the IL-28B TG/GG genotype.In HCV genotype 1-infected patients with PNALT,multivariate logistic-regression analysis showed that SVR was independently predicted by the IL-28B rs8099917 TT type(P【0.05)and having an EVR(P【0.01).The IL-28B rs8099917 TT genotype strongly correlated with treatment response in HCV genotype 1-infected Asian patients with PNALT.CONCLUSION:The IL-28B genotype may be useful for selecting HCV genotype 1-infected patients with PNALT who should receive interferon-based treatment.
文摘In 2009, several groups reported that interleukin-28B(IL28B) genotypes are associated with the response to peginterferon plus ribavirin therapy for chronic hepatitis C virus(HCV) infection in a genome-wide association study, although the mechanism of this association is not yet well understood. However, in recent years, tremendous progress has been made in the treatment of HCV infection. In Japan, some patients infected with HCV have the IL28 B major genotype, which may indicate a favorable response to interferon-including regimens; however, certain patients within this group are also interferon-intolerant or ineligible. In Japan, interferonfree 24-wk regimens of asunaprevir and daclatasvir are now available for HCV genotype 1b-infected patients who are interferon-intolerant or ineligible or previous treatment null-responders. The treatment response to interferon-free regimens appears better, regardless of IL28 B genotype. Maybe other interferon-free regimens will widely be available soon. In conclusion, although some HCV-infected individuals have IL28 B favorable alleles, importance of IL28 B will be reduced with availability of oral interferon free regimen.
文摘Myanmar is adjacent to India, Bangladesh, Thailand, Laos and China. In Myanmar, the prevalence of hepatitis C virus(HCV) infection is 2%, and HCV infection accounts for 25% of hepatocellular carcinoma. In this study, we reviewed the prevalence of HCV genotypes in Myanmar. HCV genotypes 1, 3 and 6 were observed in volunteer blood donors in and around the Myanmar city of Yangon. Although there are several reports of HCV genotype 6 and its variants in Myanmar, the distribution of the HCV genotypes has not been well documented in areas other than Yangon. Previous studies showed that treatment with peginterferon and a weight-based dose of ribavirin for 24 or 48 wk could lead to an 80%-100% sustained virological response(SVR) rates in Myanmar. Current interferon-free treatments could lead to higher SVR rates(90%-95%) in patients infected with almost all HCV genotypes other than HCV genotype 3. In an era of heavy reliance on direct-acting antivirals against HCV, there is an increasing need to measure HCV genotypes, and this need will also increase specifically in Myanmar. Current available information of HCV genotypes were mostly from Yangon and other countries than Myanmar. The prevalence of HCV genotypes in Myanmar should be determined.
基金Supported by A grant from the Chiba University Young Research-Oriented Faculty Member Development Program in Bioscience Areas,to Kanda T
文摘AIM:To examine the epidemiological data,hematological safety and treatment responses of peginterferonalpha 2a plus ribavirin therapy for hepatitis C.METHODS:Between March 2008 and February 2011,196 hepatitis C virus(HCV)genotype 1 infected Japanese(127 treatment-naive and 69 treatment-experienced patients)patients treated with peginterferonalpha 2a plus ribavirin were enrolled.We examined the epidemiological data and treatment responses were retrospectively analyzed in terms of hematological safety.HCV RNA was measured by the COBAS TaqMan HCV test.RESULTS:Overall sustained virological response(SVR)rates of treatment-naive and treatment-experienced patients were 56% and 39%,respectively.Multivariate logistic regression analysis showed that SVR was attained independently of early virological response in both treatment-naive and treatment-experienced patients.SVR rates did not differ between the pretreatment hemoglobin < 13 g/dL and ≥ 13 g/dL groups.However,in treatment-naive patients,the SVR rate of the pretreatment platelet count < 130000/μL group was significantly lower than that of the pretreatment platelet count ≥ 130000/μL group.CONCLUSION:Attention should be paid to potential thrombocytopenia in the treatment of chronic hepatitis C patients.
文摘Chronic hepatitis C virus(HCV) infection can cause liver cirrhosis and hepatocellular carcinoma(HCC). Several studies have demonstrated that the eradication of HCV reduces the occurrence of HCC. In Japan, as many people live to an advanced age, HCV-infected patients are also getting older, and the age at HCC diagnosis has also increased. Although older HCV-infected patients have a risk of developing HCC, the treatment response to peginterferon-alpha plus ribavirin therapy is relatively poor in these patients because of drop-out or discontinuation of this treatment due to adverse events. It is established that the mechanism of action between interferon-alpha and interferon-beta is slightly different. Short-term natural interferon-beta monotherapy is effective for patients with acute hepatitis C and patients infected with HCV genotype 2 and low viral loads. Natural interferon-beta plus ribavirin for 48 wk or for 24 wk are also effective for some patients with HCV genotype 1 or HCV genotype 2. Natural interferon-beta plus ribavirin has been used for certain "difficult-totreat" HCV-infected patients. In the era of direct-acting anti-virals, natural interferon-beta plus ribavirin may be one of the therapeutic options for special groups of HCV-infected patients. In the near future, signal transduction pathways of interferon-beta will inform further directions.
基金Supported by Grant 24590955 for Scientific Research from the Ministry of Education,Culture,Sports,Science,and Technology,Japan to Kanda T
文摘The average age of hepatitis C virus(HCV)-infected individuals is becoming increasingly higher in Japan and steps should be taken to treat older individuals infected with HCV. Until an interferon-free regimen becomes available, peginterferon plus ribavirin will play a critical role in the treatment. The perception that older HCVinfected patients may be at higher risk than younger patients for adverse events from peginterferon plus ribavirin treatment but may obtain less clinical benefit from it may be based on the underrepresentation of older patients in clinical trials. A recent genomewide association study revealed that interleukin-28B(IL28B) genotype closely correlates with the treatment response against HCV. The relationship of IL28 B genotype with the treatment response in older HCV-infected patients is also unknown. In this review, we focused on the treatment response in older patients infected with HCV and the effects of IL28 B genotype. IL28 B major genotype is a useful predictor of sustained virological response in the interferon-including treatment of older patients infected with HCV. It also seems useful for avoiding adverse events, although the mechanisms ofthe effects of IL28 B genotype on the treatment outcome are still poorly understood and are currently under investigation. Further studies will be needed.
文摘Hepatitis C virus (HCV) is a leading cause of cirrhosis and hepatocellular carcinoma (HCC) in the US and Japan.Therefore,eradication of HCV may reduce the occurrence of HCC in HCV-infected individuals.In 2011,the use of firstgeneration HCV NS3/4A protease inhibitors such as telaprevir and boceprevir was initiated for clinical treatment of HCV.Administration of telaprevir and boceprevir plus peginterferon and ribavirin increased rates of sustained virological response (SVR) in HCV genotype 1-infected patients.However,this treatment regimen also led to severe adverse events.Second-generation direct-acting antiviral agents (DAAs) for HCV,such as simeprevir plus peg-interferon and ribavirin also resulted in higher SVR rates,with similar adverse events to other peg-interferon and ribavirin treatments.Higher SVR rates in HCV genotype 1-and 2-infected patients were achieved with 12-16 weeks of sofosbuvir plus other class DAAs with/without ribavirin and 12 weeks of sofosbuvir plus ribavirin,respectively,For "difficult-to-treat"HCV-infected patients,more therapeutic options are needed.Further studies examining the efficacy and adverse effects of such therapies will be required for the development of additional treatments.
文摘Hepatitis A virus (HAV) infection is a major cause of acute hepatitis and occasionally leads to acute liver failure in both developing and developed countries.Although effective vaccines for HAV are available,the development of new antivirals against HAV may be important for the control of HAV infection in developed countries where no universal vaccination program against HAV exists,such as Japan.There are two forms of antiviral agents against HAV:direct-acting antivirals (DAAs) and host-targeting agents (HTAs).Studies using small interfering ribonucleic acid (siRNA) have suggested that the HAV internal ribosomal entry site (IRES) is an attractive target for the control of HAV replication and infection.Among the HTAs,amantadine and interferon-lambda 1 (IL-29) inhibit HAV IRES-mediated translation and HAV replication.Janus kinase (JAK) inhibitors inhibit La protein expression,HAV IRES activity,and HAV replication.Based on this review,both DAAs and HTAs may be needed to control effectively HAV infection,and their use should continue to be explored.
