Over the past 15 years, the treatment options for chronic hepatitis C virus (HCV) have improved, thanks to the development of combination therapies. While the current standard of care, peginterferon alfa and ribavirin, produces a 54 to 56 percent rate of sustained viral clearance, it is poorly tolerated due to complications, including flu-like symptoms, neuropsychiatric side effects, bone marrow suppression, and the exacerbation of autoimmune diseases like lupus and rheumatoid arthritis.
Given the strong need to develop better strategies for the 180 million people infected with HCV worldwide, liver specialists at the Massachusetts General Hospital Digestive Healthcare Center have been studying the tenacious nature of HCV and exploring new approaches for treating this chronic infection.
Better Understanding of HCV’s Interaction with
its Target Cell
Unlike other hepatitis viruses, hepatitis C is exceptional in that 75 to 80 percent of acute infections lead to chronic infection. To help uncover why this occurs, the Hepatitis C Center for Human Immunology (HCV CHI) at Mass General is one of eight institutions participating as a Cooperative Center for Translational Research on Human Immunology and Biodefense (CCHI). The HCV CHI was awarded a $15 million grant from the National Institute of Allergy and Infectious Diseases to better understand the human immune response to hepatitis C. Raymond T. Chung, MD, director of hepatology and vice chief of gastroenterology at Mass General Hospital, is the principal investigator of the HCV CHI and leader of a project aimed at understanding the mechanisms by which the immune system fails to contain HCV.
Dr. Chung’s team aims to identify the host factors involved in promoting resistance of the virus to customary antiviral defense mechanisms as well as to study how immune cells become dysfunctional. In particular, researchers have focused their attention on characterizing the host response to viral replication at the mRNA and protein level, uncovering several of the mechanisms by which viral proteins subvert innate antiviral immunity. The research team has concentrated on the actions of one of the viral proteins, the HCV core protein, which induces selective degradation and inhibition of STAT1 phosphorylation. Researchers are using chemical and genetic libraries to screen compounds and genes that, by regulating HCV replication, can identify cellular proteins that control the HCV life cycle. Georg Lauer, MD, PhD, of the HCV CHI is also exploring similar screening approaches to identify host genes and chemicals that restore function to disabled immune cells that would ordinarily clear virally infected liver cells.
By helping to define some of the steps in the HCV lifestyle at which the virus subverts innate immunity, Dr. Chung and his team hope to develop therapies that block replication, restore host immunity, and lead to sustained clearance of HCV. These strategies would be used in conjunction with direct antiviral agents already under development.
Protease and Polymerase Inhibitors Against
The best treatment for HCV may likely be a “cocktail” of therapies that both suppress the virus and minimize resistance selection, which might then obviate the need for interferon. The ideal cocktail might include several protease and polymerase inhibitors with sufficiently distinct resistance profiles.
Studies suggest that adding protease and polymerase inhibitors to peginterferon and ribavirin therapy can improve the sustained virologic response, particularly in patients with the stubborn HCV genotype 1, which represents three-quarters of HCV infections.
Physician-researchers at the Digestive Healthcare Center helped develop the first generation of these drugs and are currently studying the second-generation agents in clinical trials. The second-generation protease inhibitors under investigation at Mass General have improved pharmacokinetic profiles and can be given once a day rather than three times a day. They also have enhanced side effect profiles and can be given across more strains—not just genotype 1. In addition, researchers are studying protease inhibitors combined with polymerase inhibitors, with reduced or even obviated use of interferon. The ability to develop much better tolerated all-oral cocktails of direct antiviral agents will allow many more patients with HCV to be treated. Another trial focuses on HCV/HIV co-infected patients.
Statins for HCV
Mass General researchers were among the first to use statin drugs and other novel compounds that reduce circulating cholesterol levels as a potential substitute for or adjunct to antiviral drugs. In persons who do not respond to conventional therapy, statins may offer promise when combined with other drugs to improve response rates.
A Flavonoid for Fighting HCV?
Dr. Chung’s team is leading a translational trial to determine the preliminary efficacy of naringenin, a naturally occurring flavonoid derived from grapefruit that inhibits very low-density lipoprotein (VLDL) secretion from liver cells. Researchers have learned that HCV exits the cell tethered to VLDL. However, when naringenin is applied to the cells, secretion of HCV is blocked. Scientists think that oral naringenin could be used in combination with other agents with different mechanisms against the virus.
A New Strategy Against Re-infection
One of the many challenges of treating HCV in the liver transplant population is re-infection with HCV, which takes an accelerated course after transplant and leads to premature graft failure and mortality. Indeed, recurrent HCV is the most challenging problem in liver transplant medicine today. Unfortunately, because of its side effect profile, peginterferon is usually not an option before or after transplant.
As an alternative, physicians at the Digestive Healthcare Center are studying monoclonal antibodies given at the time of transplant to try to prevent re-infection of the graft altogether, eliminating the threat of HCV to graft function. Dr. Chung, who is also medical director of the Liver Transplant Program at Mass General, theorizes that the successful prevention of graft re-infection using this strategy, possibly in conjunction with direct-acting antiviral agents, could have a dramatic impact on survival after transplant.
Genomic, Proteomic Approaches Being Applied
to Liver Diseases
Scientists have learned that genomics can be applied well to hepatitis C therapy. For example, a polymorphism in the IL28B gene has been found that accurately predicts response to interferon therapy. Patients with the variable gene type have an 80 percent response to interferon therapy, while those without the gene type can expect a less favorable response—only about 35 percent. Dr. Chung’s team is investigating how a polymorphism in the IL28B gene produces such differences in response to interferon.
Genomic approaches are also helping to point researchers toward new ways to manage some of the serious complications of HCV. For example, Dr. Chung and his colleagues have identified that the analysis of gene polymorphisms in the epidermal growth factor (EGF) gene can improve early detection for hepatocellular carcinoma (HCC) in patients with high-risk conditions, such as cirrhosis. HCC is a largely incurable complication of chronic HCV.
A History of Progress
Physicians at the Mass General Digestive Healthcare Center were among the first to use antiviral therapies for HCV, as well as hepatitis B (HBV). Jules Dienstag, MD, from the Mass General Gastrointestinal Unit, and his colleagues were part of the original study group that introduced interferon for chronic HCV and pioneered the first use of lamivudine, an oral nucleoside antiviral treatment, against HBV.
Dr. Chung and his colleagues identified HCV as the causative agent of cryogloblinemia, an immune complex disease that causes kidney failure and neuropathy. His group also was among the first to demonstrate, using a mouse model, that HCV can directly lead to liver cancer (HCC) and that it can also cause insulin resistance and diabetes.
Today, physicians at the Digestive Healthcare Center are providing expert management of patients with hepatitis, whose treatment regimens will become increasingly complex as the next wave of therapies gains approval beginning in 2011. While past HCV treatment largely centered on helping patients manage their side effects, physicians may become increasingly challenged by managing patients’ complicated combination therapies. Physicians at the Digestive Healthcare Center understand the nuances of the different approaches and can provide guidance to physicians and treatment services to patients, as well as access to the latest agents under investigation.
- Kim S, Peng L, Lin W, Choe W, Sakamoto N, Schreiber S, Chung R. (2007). A cell-based, high-throughput screen for small molecule regulators of hepatitis C virus replication. Gastroenterology, 132(1): 311-20.
- Lin W, Choe WH, Hiasa Y, Kamegaya Y, Blackard J, Schmidt E, Chung R. (2005). Hepatitis C virus expression suppresses interferon signaling by degrading STAT1. Gastroenterology, 128(4): 1034-41.
- Lin W, Kim S, Yeung E, Kamegaya Y, Blackard J, Kim K, Holtzman M, Chung R. (2006). Hepatitis C virus core protein blocks interferon signaling by interaction with the STAT1 SH2 domain. J Virol, 80: 9226-35.
- Nahmias Y, Goldwasser J, Casali M, van Poll D, Wakita T, Chung R, Yarmush M. (2008). Apolipoprotein B-dependent hepatitis C virus secretion is inhibited by the grapefruit flavonoid naringenin. Hepatology, 47(5): 1437-45.
- Peng L, Kim S, Matchacheep S, Lei X, Su S, Lin W, Punguphan W, Choe W, Sakamoto N, Ikeda M, Kato N, Beeler A, Porco J Jr, Schreiber S, Chung R. (2007). Identification of novel epoxide inhibitors of HCV replication using a high-throughput screen. Antimicrob Agents Ch, 10: 3756-59.
- Tai A, Benita Y, Peng L, Kim S, Sakamoto N, Xavier R, Chung R. (2009). A functional genomic screen identifies cellular cofactors of hepatitis C virus replication. Cell Host Microbe, 5: 298-307.
|Raymond T. Chung, MD
The Massachusetts General Hospital Digestive Healthcare Center is a collaborative practice of gastroenterologists, endoscopists, surgeons, radiologists, pathologists, hepatologists, oncologists, and radiation oncologists dedicated to the prevention, diagnosis, treatment, and management of digestive diseases. The Digestive Healthcare Center offers a full range of medical and surgical treatments for digestive diseases, including conditions of the esophagus, stomach, small and large intestines, liver, gallbladder, pancreas, and colon.
The Liver Center and Transplant Program is located at: 55 Fruit Street, Blake 4, Boston, MA 02114. Access line: 617-724-6006
The Digestive Healthcare Center is organized into six disease areas dedicated to the diagnosis and management of digestive health issues. For more information about these services, visit the Digestive Healthcare Center website
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