Perspective on the management of hepatitis C in the DAA era

( T Jake Liang ),( Liver Diseases Branch ) 대한간학회 2012 춘·추계 학술대회 (KASL) Vol.2012 No.-

The therapy of hepatitis C has experienced a tremendous growth and improvement over the last two decades. The initial monotherapy with interferon α had a dismal result of less than 10% sustained virologic response rate. The combination of interferon α with an old antiviral drug, ribavirin, led to a remarkable increase in the response rate. Next the improved formulation of pegylated interferon resulted in an even higher rate of treatment response. But for many years, the scientific community struggled with the development of new therapeutic regimens to improve on the response rate and to minimize the side effects from interferon based therapy. Basic scientific advances came to the rescue. Based on the knowledge of the viral life cycle and gene functions, a new era of hepatitis C therapy is dawning. With years of discovery work, preclinical testing and finally clinical trials, two direct acting antivirals (DAAs) targeting the protease function of the virus, telaprevir and boceprevir, were approved by the FDA last year. Many other DAAs, closely following behind, would likely be approved in the next few years. The DAAs, in combination with peginterferon and ribavirin, can generate a sustained virologic response rate of more than 60% in HCV genotype 1 patients. The DAAs will likely change the landscape of treatment for hepatitis C. They are associated with more side effects than the standard peginterferon and ribavirin combination, and therefore need careful management. The DAAs also cannot be used alone and should only be used in genotype 1 patients. The DAAs are not approved for liver transplant, HIV/HCV co-infected, hemodialysis or pediatric patients. Deviation from recommended regimens may result in poorer response and potential unanticipated morbidity. Many questions regarding the DAAs remain and need to be adequately addressed, As the armamentarium of DAAs grows for therapy of hepatitis C in the next few years, it will be imperative to develop a rigorous evidence based algorithm and set of recommendations for the use of these drugs.

Perspective on the management of hepatitis C in the DAA era

( T Jake Liang ),( Liver Diseases Branch ),( Niddk ) 대한간학회 2012 춘·추계 학술대회 (KASL) Vol.2012 No.1

The therapy of hepatitis C has experienced a tremendous growth and improvement over the last two decades. The initial monotherapy with interferon?α had a dismal result of less than 10% sustained virologic response rate. The combination of interferon?α with an old antiviral drug, ribavirin, led to a remarkable increase in the response rate. Next the improved formulation of pegylated interferon resulted in an even higher rate of treatment response. But for many years, the scientific community struggled with the development of new therapeutic regimens to improve on the response rate and to minimize the side effects from interferon based therapy. Basic scientific advances came to the rescue. Based on the knowledge of the viral life cycle and gene functions, a new era of hepatitis C therapy is dawning. With years of discovery work, preclinical testing and finally clinical trials, two direct acting antivirals (DAAs) targeting the protease function of the virus, telaprevir and boceprevir, were approved by the FDA last year. Many other DAAs, closely following behind, would likely be approved in the next few years. The DAAs, in combination with peginterferon and ribavirin, can generate a sustained virologic response rate of more than 60% in HCV genotype 1 patients. The DAAs will likely change the landscape of treatment for hepatitis C. They are associated with more side effects than the standard peginterferon and ribavirin combination, and therefore need careful management. The DAAs also cannot be used alone and should only be used in genotype 1 patients. The DAAs are not approved for liver transplant, HIV/HCV co-infected, hemodialysis or pediatric patients. Deviation from recommended regimens may result in poorer response and potential unanticipated morbidity. Many questions regarding the DAAs remain and need to be adequately addressed. As the armamentarium of DAAs grows for therapy of hepatitis C in the next few years, it will be imperative to develop a rigorous evidence?based algorithm and set of recommendations for the use of these drugs.

Host genetic factors and hepatitis C: Susceptibility, disease progression and treatment response

( T Jake Liang ) 대한간학회 2012 춘·추계 학술대회 (KASL) Vol.2012 No.1

Hepatitis C follows a variable course with some patients developing progressive liver fibrosis, cirrhosis and hepatocellular carcinoma, while others have minimal or no significant liver disease after decades of infection. Success of therapy for hepatitis C is also variable and difficult to predict. Studies have identified both host and viral factors associated with disease progression and treatment response. The importance of general factors such as age, gender, immune status, metabolic parameters, and environmental factors such as alcohol consumption has long been recognized to be associated with progressive fibrosis. Other factors, such as ALT level, liver histology, viral genotype, baseline viral level have also been associated with treatment response. Recently, polymorphisms in a wide array of genes have been linked to disease progression and treatment response. How specific viral proteins may contribute to disease progression has also been studied. This lecture will highlight what is currently known about the genetic factors associated with progressive liver injury and treatment response in patients with hepatitis C. A greater understanding of the determinants of disease progression will hopefully lead to improved utilization of existing treatments and ultimately may aid in identification of new therapeutic targets.

Host genetic factors and hepatitis C: Susceptibility, disease progression and treatment response

( T Jake Liang ) 대한간학회 2012 춘·추계 학술대회 (KASL) Vol.2012 No.-

Hepatitis C follows a variable course with some patients developing progressive liver fibrosis, cirrhosis and hepatocellular carcinoma, while others have minimal or no significant liver disease after decades of infection. Success of therapy for hepatitis C is also variable and difficult to predict. Studies have identified both host and viral factors associated with disease progression and treatment response. The importance of general factors such as age, gender, immune status, metabolic parameters, and environmental factors such as alcohol consumption has long been recognized to be associated with progressive fibrosis. Other factors, such as ALT level, liver histology, viral genotype, baseline viral level have also been associated with treatment response. Recently, polymorphisms in a wide array of genes have been linked to disease progression and treatment response. How specific viral proteins may contribute to disease progression has also been studied. This lecture will highlight what is currently known about the genetic factors associated with progressive liver injury and treatment response in patients with hepatitis C. A greater understanding of the determinants of disease progression will hopefully lead to improved utilization of existing treatments and ultimately may aid in identification of new therapeutic targets.

Establishment of Full Genomic Length Resistance-Associated Variant Genotype 2 Hepatitis C Viruses and Applications for Future Therapeutic Strategies

( Hyung Joon Yim ),( Billy Lin ),( Shanshan He ),( Zongyi Hu ),( T. Jake Liang ) 대한간학회 2016 춘·추계 학술대회 (KASL) Vol.2016 No.1

Aims: Several directly acting antiviral agents (DAA) were currently approvedfor the treatment of chronic hepatitis C (CHC). AlthoughDAA therapies are associated with better tolerability and improvedresponse rates, occurrence of drug resistance has been the drawback.The aim of the present study is to develop full-length resistance associatedvariants (RAV) HCV culture systems to evaluate the efficacyand the cross resistance of current antiviral drugs for future therapeuticstrategies.Methods: Resistance associated substitutions on NS3 (A156T, D168V),NS5A (L31V, Y93H, L31V+Y93H), and NS5B (S282T) domains weregenerated by site directed mutagenesis and cloned into genotype2a J6/JFH1 HCV plasmid with or without luciferase gene. After In vitro RNA transcription, RNAs of RAV were transfected into Huh 7.5.1cells. HCVcc in the supernatants were collected and used for thereinfection and treatment experiment to confirm drug susceptibility.We performed HCV core staining and Renilla luciferease assays toassess treatment response to multiple DAAs and other antiviral drugswith different mechanism of action after transfection or infectionof RAVs.Results: DAAs in the same classes shared cross resistance to correspondingRAVs: boceprevir, telaprevir, simeprevir, and asunaprevirto NS3 RAVs; daclatasvir and ledipasvir to NS5A RAVs; sofosbuvirto NS5B RAV. However, DAAs of the other classes effectively suppressedRAVs as well as wild type. All the RAVs were sensitive todrugs with different action of mechanism including interferon alfa,ribavirin, cyclosporine (cyclophilin inhibitor) or chlorcyclizine (entry inhibitors).Conclusions: We developed full-length RAV HCV culture systemsbased on genotype 2a strain. This system will be useful to assessantiviral response of drugs with different action of mechanisms.Combination of different classes of DAA or new drugs with differentaction mechanisms (e.g. cyclophilin inhibitor or entry inhibitors) shouldbe a future therapeutic strategy for overcoming drug resistance inthe treatment of CHC.