ALF Research Strategy

American Liver Foundation Research Strategy for Hepatitis C
Adapted from the American Liver Foundation's Research Agenda for 25 Million Americans:
Research Goals and Strategies to Treat, Prevent, and Conquer Liver Disease

In the arena of HCV, research strategies employed to help meet these goals should be devoted to:

  • Elucidating basic mechanisms of recovery from viral infection, development of persistent infection, and progression of disease.

    We need to determine what variables at the host and/or viral levels influence recovery versus persistence. The issue of how the virus evades the host immune system is critical to our understanding of the above questions. Close linkage to clinical investigators should be fostered so that rapid progress can be made in verifying findings and exploring treatment strategies.
  • Understanding the basic mechanisms of hepatocellular injury and variable expression and progression of disease associated with HCV infection.

    The degree of disease associated with HCV infection varies with the individuals, with time, and likely with the virus itself. There is a complex network of interactions between the virus and the host. Crucial information is needed on how the virus alters physiology, biology and functioning of both the hepatocytes at the cellular level and liver at the organ level at all stages of disease. The mechanisms of disease progression are largely unknown. It will be important to understand the role of viral variants in severity and progression of liver disease. Studies in model systems should progress to more complex systems and be applied rapidly to human disease.
  • Developing more effective antivirals to inhibit viral entry, replication and assembly, as well as new immunomodulatory compounds and related strategies to correct deficiencies m the host immune response.

    Each year basic research investigators identify potential new targets. Translating these into antiviral strategies and moving them through preclinical drug development are key to bringing new candidates to the clinic.

  • Improving outcomes for those chronic viral carriers who progress to liver failure and cancer.

Liver transplantation represents a last-stage attempt to prolong the lives of the severely affected chronic carriers. We need to explore the involvement of extrahepatic sites in re-infection of the liver by HCV and methods of preventing re-infection. Many questions still remain regarding the natural history of re-infection and the mechanisms of liver injury and rejection in the transplantation setting.

With respect to research strategies in HCV, we need to learn from the experiences with other human viruses, such as HIV and HBV, and we need to support all levels of basic and clinical investigation of the virus. In

addition to individual research efforts, we need to establish multidisciplinary approaches to understand the disease. In addition to those research strategies outlined above, we need to garner more information about:

  • The epidemiology and natural history of HCV infection.
  • Develop effective vaccines and other preventive measures to limit the spread of infection.
  • Elucidate the replicative pathway of viral infection.
  • Unravel in detail the structure and function of each viral protein.
  • Understand the mechanisms and consequences of viral mutations as in viral quasispecies.
  • Develop useful tissue culture systems and animal models to grow and study the virus, as well as to test vaccines and antivirals.
  • Intensify our search for more effective antiviral treatments.

Finally, we also support research efforts directed at the identification and characterization of other forms of hepatitis viruses.

Funding Requirements

Research funding in viral hepatitis has come mostly from federal government, through the extramural division of the National Institutes of Health (NIH). NIAID sponsors the lion's share of this funding resource, followed by NCI and NIDDK. Other divisions of NIH have supported a variety of small research programs on viral hepatitis. The current annual NIH funding for HCV is estimated at $11.9 million. In comparison, the funding for AIDS was $1.4 billion in 1994. Given the comparable impact of hepatitis C and AIDS on American's public health and socioeconomic system, this disparity is rather remarkable. A variety of private funding sources, including industry, private foundations and academic societies, are available to support research in viral hepatitis. Research sponsored by pharmaceutical companies tends to focus on lengthy therapeutic protocols which, although important, provide little impetus to the overall scientific progress of research in this disease. The private sector sources are often inadequate to support full research programs.

Based on the magnitude of problems discussed above, we call for a renewed commitment of federal and private finding agencies to support targeted areas of research in HCV (as outlined above). Given the inadequacy of current funding in HCV research, we advocate an increase in funding support to 10 times that of the present level. A minimum l-year commitment is necessary to attain the goals of our research strategy.

Original Hepatitis Research Agenda drafted (l995)by: T. Jake Liang, MD, Chair

Contributing Authors: Teresa L. Wright, MD, and Raymond S. Koff; MD