Symposium: Current and future issues in hepatitis C treatment : New emerging therapy for hepatitis C -The rational use of specifically targeted agents against hepatitis C infection

Raymond T. Chung 대한간학회 2009 Clinical and Molecular Hepatology(대한간학회지) Vol.15 No.4(S)

The development of specifically targeted antiviral agents against hepatitis C (STAT-C) is a major therapeutic advance that promises to dramatically improve treatment response rates in patients with chronic infection. However, rapid emergence of drug resistance has already been described, the consequences of which are not yet understood. While there are important differences between HCV and HIV infection, the judicious use of candidate agents against HCV should be guided by principles that have been established in the HIV therapeutic arena. In this review, we attempt to draw useful parallels between the development of antiretroviral therapy for HIV and preliminary data on antiviral agents for hepatitis C virus infection. Applying concepts learned in HIV therapeutics will hopefully lead to a prudent and cautious path in HCV treatment paradigms, particularly with respect to drug resistance.

Treatment Options in HCV Relapsers and Nonresponders

( Raymond T. Chung ) 대한간학회 2007 Clinical and Molecular Hepatology(대한간학회지) Vol.13 No.5(S)

Review : New treatments for chronic hepatitis C

( Jae Young Jang ),( Raymond T. Chung ) 대한간학회 2010 Clinical and Molecular Hepatology(대한간학회지) Vol.16 No.3

Treatments for chronic hepatitis C has evolved significantly in the past 15 years. The standard of care (SOC) is peginterferon alfa-2a/-2b with ribavirin for 48 weeks or 24 weeks in patients infected with HCV genotype 1 or 2/3, respectively. The treatment duration can be individualized based on the baseline viral load and the speed of the virologic response during treatment. However, current therapies are associated with side effects, complications, and poor patient tolerability. Therefore, there is an urgent need to identify better strategies for treating this disease. An improved sustained virologic response (SVR) can be achieved with new HCV-specific inhibitors against NS3/4A and NS5B polymerases. Recent trials have found SVR rates in patients with HCV genotype 1 infection of 61~68% and 67~75% for combining the SOC with the protease inhibitors telaprevir and boceprevir, respectively. Several new HCV-specific inhibitors such as protease inhibitors and nucleoside and non-nucleoside polymerase inhibitors as well as non-HCV-specific compounds with anti-HCV activity are currently in clinical evaluation. In this review we discuss these new treatments for chronic hepatitis C. (Korean J Hepatol 2010;16:263-277)

Review Article : New Antiviral Therapies for Hepatitis C

( Jacqueline O Leary ),( Raymond T. Chung ) 대한간학회 2003 Clinical and Molecular Hepatology(대한간학회지) Vol.9 No.4

Hepatitis C virus (HCV), originally known as non-A non-B hepatitis, was identified and sequenced in 1989.1 Since its molecular cloning, seroepidemiologic studies have revealed that 170 million people worldwide, and 1.8% of the US population, are chronically infected.2-4 End stage liver disease attributable to chronic HCV infection is the leading indication for liver transplantation worldwide, and is a major risk factor for the development of hepatocellular carcinoma.5 ?Antiviral therapy for HCV has not changed dramatically since the introduction of interferon alfa (IFN) in 1986.6 IFN has protean antiviral effects, both direct and indirect, against a large number of DNA and RNA viruses: (1) It prevents viral entry and uncoating. (2) Through the action of the Jak-Stat kinase signal transduction pathway, it induces a large number of host genes that participate in direct inhibition of viral protein and RNA synthesis. For instance, the protein PKR, potently induced by IFN, inhibits both host and viral protein synthesis by phosphorylating and inactivating the eukaryotic translation initiation factor (eIF-2). (3) It upregulates viral antigen expression at the cell surface, increasing recognition of virally infected cells by cytolytic T lymphocytes. (4) It has immunomodulatory effects on T cell and natural killer cell function. The precise mechanism by which IFN acts against HCV is unknown, but recent evidence from RNA replicon and other cell culture systems demonstrate that IFN can act directly to suppress HCV replication.7,8 ?Unfortunately, clinical trials of IFN monotherapy were met with disappointing rates (5-10%) of sustained virologic response (SVR), defined as clearance of HCV RNA using a sensitive qualitative nucleic acid amplification assay 24 weeks after completion of therapy. Only with addition of ribavirin (RBV), a guanosine nucleoside analogue active against other RNA and DNA viruses, to IFN did SVR rates increase appreciably, to approximately 40%.9-12 Its mechanism of action against HCV remains unclear, but data suggest that RBV acts both as an immunomodulator13 and an RNA mutagen.14 ?Because of pharmacokinetic concerns regarding the loss of antiviral efficacy with conventional IFN dosing (thrice weekly), the most important recent advance in the management of chronic hepatitis C has been a manipulation of the IFN alfa molecule to extend its bioavailability. The covalent addition of a polyethylene glycol (PEG) to either the IFN-alfa 2a [PEG-IFN-alfa-2a (40 kD)] or IFN-alfa 2b [PEG-IFN-alfa-2b (12 kD)] in combination with ribavirin was associated with an increase in overall SVR rates to 54-56%.15,16 Unfortunately, to achieve these SVR rates, patients receiving these regimens must often endure significant side effects for up to 48 weeks. Furthermore, persons harboring genotype 1 HCV infection, the most common genotype in the U.S. (75%), experience less than optimal SVR rates of 42- 45%. In addition, the very populations of patients who are most in need of effective antiviral therapy, including persons with decompensated cirrhosis, recipients of liver transplants, and persons coinfected with HIV, experience yet lower SVR rates and are even less able to tolerate curative doses of these medications. ?In view of these limitations, new therapies with greater efficacy, improved side effect profiles, and broader applicability are desirable. This review will consider new agents for hepatitis C in two groups: (1) modifications of currently available therapies, and (2) agents designed to interrupt specific steps in the life cycle of the virus.

Review : Chronic Hepatitis C

( Jae Young Jang ),( Raymond T. Chung ) 대한소화기기능성질환·운동학회(구 대한소화관운동학회) 2011 Gut and Liver Vol.5 No.2

The goal of antiviral therapy for patients with chronic hepatitis C virus (HCV) infection is to attain a sustained virologic response (SVR), which is defined as undetectable serum HCV-RNA levels at 6 months after the cessation of treatment. Major improvements in antiviral therapy for chronic hepatitis C have occurred in the past decade. The addition of ribavirin to interferon-alfa therapy and the introduction of pegylated interferon (PEG-IFN) have substantially improved SVR rates in patients with chronic hepatitis C. The optimization of HCV therapy with PEG-IFN and ribavirin continues to evolve. Studies are ongoing that use viral kinetics to tailor therapy to an individual`s antiviral response and determine the ideal length of treatment to maximize the chance of SVR. Improved SVR can be achieved with new specifi c inhibitors that target the HCV NS3/4A protease and the NS5B polymerase. Several long-term follow-up studies have shown that SVR, when achieved, is associated with a very low risk of virologic relapse. Furthermore, antiviral therapy can reduce the morbidity and mortality rates associated with chronic hepatitis C by reducing fi brosis progression, the incidence of cirrhosis, and hepatocellular carcinoma. (Gut Liver 2011;5:117-132)

구연 : 아이리스; C형 간염 바이러스가 감염된 간세포에의 인슐린 신호전달 억제에 따른 감소된 인터페론 신호전달 (초)

정우진,김은수,장병국,박경식,조광범,황재석,장재영,( Raymond T. Chung ) 대한간학회 2010 Clinical and Molecular Hepatology(대한간학회지) Vol.16 No.3(S)

Review : Hepatitis C virus and hepatocarcinogenesis

( Soung Won Jeong ),( Jae Young Jang ),( Raymond T. Chung ) 대한간학회 2012 Clinical and Molecular Hepatology(대한간학회지) Vol.18 No.4

Hepatitis C virus (HCV) is an RNA virus that is unable to integrate into the host genome. However, its proteins interact with various host proteins and induce host responses. The oncogenic process of HCV infection is slow and insidious and probably requires multiple steps of genetic and epigenetic alterations, the activation of cellular oncogenes, the inactivation of tumor suppressor genes, and dysregulation of multiple signal transduction pathways. Stellate cells may transdifferentiate into progenitor cells and possibly be linked to the development of hepatocellular carcinoma (HCC). Viral proteins also have been implicated in several cellular signal transduction pathways that affect cell survival, proliferation, migration and transformation. Current advances in gene expression profile and selective messenger RNA analysis have improved approach to the pathogenesis of HCC. The heterogeneity of genetic events observed in HCV-related HCCs has suggested that complex mechanisms underlie malignant transformation induced by HCV infection. Considering the complexity and heterogeneity of HCCs of both etiological and genetic aspects, further molecular classification is required and an understanding of these molecular complexities may provide the opportunity for effective chemoprevention and personalized therapy for HCV-related HCC patients in the future. In this review, we summarize the current knowledge of the mechanisms of hepatocarcinogenesis induced by HCV infection. (Clin Mol Hepatol 2012;18:347-356)

Secreted Tenascin C from Activated Hepatic Stellate Cells Promotes Epithelial-mesenchymal Transition in Hepatic Cancer Cell

( Sae Hwan Lee ),( Hong Jian ),( Xiao Liu ),( Wenyu Lin ),( Raymond T Chung ) 대한간학회 2016 춘·추계 학술대회 (KASL) Vol.2016 No.1

Aims: Hepatic stellate cell (HSC) plays a pivotal role in hepatocarcinogenesis through direct effects on hepatocytes and modulation of the peri-tumoral stroma and immune response. A change in HSC secretory phenotype upon activation is closely correlated with increased proliferation, migration, and invasion of hepatocellular carcinoma (HCC) cells in vitro studies. Tenascin C (TNC) is a large hexameric extracellular matrix glycoprotein and highly expressed in several solid cancer including HCC. The aim of this study was to investigate the TNC expression by activated human HSC lines and the role of TNC in metastasis of HCC cells. Methods: Two HSC lines, LX2 and TWNT4, were stimulated with transforming growth factor-β for 48 hours and protein expression of TNC in media was evaluated with Western blot and ELISA. LX2 was transfected with TNC siRNA for 48 hours and was continued culture for 48 hours after media change. Huh7, hepatic cancer cell line, were incubated for 24 hours with conditioned media from TNC knockdown LX2. Epithelial-mesenchymal transition (EMT)-related genes expression of Huh7 were estimated by quantitative real-time reverse transcription. Results: TNC mRNA expressions were significantly increased in stimulated LX2 and TWNT4 and TNC protein in the media were also highly expressed in both activated HSC lines. TNC knockdown was successfully observed and TNC protein level was also significantly deceased in the media from TNC siRNA transfected LX2. E-cadherin expression was significantly increased and vimentin expression was decreased in Huh7 treated with conditioned media from TNC knockdown LX2. Conclusions: TNC expression was significantly increased in activated human HSC lines and secreted TNC from LX2 promote upregulation EMT in Huh7.