This is an exciting time for basic research and drug development in hepatitis C. Since 2003, a number of important papers and presentations have substantially added to our body of knowledge about the hepatitis C virus (HCV) and offered hope for the advent of new therapies. Key findings include:
- Proof-of-concept from human studies of an HCV NS3 protease inhibitor (BILN 2061), with other candidates moving into clinical trials;
- Initial clinical data on a new HCV polymerase inhibitor (NM283);
- A range of other HCV drugs entering phase II and III studies;
- Encouraging research on the prospects for developing a vaccine to prevent HCV, based on increased understanding of the correlates of protective immunity in chimpanzees and humans;
- New insights into the role of HCV proteins and the dynamics of viral replication;
- New data on the role of the HCV NS3 protease in regulating the interferon response within cells, offering clues to viral persistence;
- Advances in HCV replicon models used to study viral replication in vitro and test the activity of new drugs;
- A promising new in vitro model for studying HCV entry into target cells;
- Establishment of an HCV genetic database at the Los Alamos National Laboratory, with a database of T cell epitopes to follow.
These developments represent the culmination of 15 years of research since the discovery of HCV. But despite remarkable progress, much work remains. Critical aspects of HCV pathogenesis and the viral replication cycle are not fully understood, and further refinement of cell culture systems and animal models is an urgent priority. While the current HCV drug pipeline contains an ever-expanding roster of promising compounds, few have moved into advanced clinical trials.
These antiviral agents could bring about a paradigm shift in HCV treatment over the next decade, potentially supplanting current combination therapy with pegylated interferon and ribavirin. Yet dramatic improvements in the efficacy and tolerability of HCV treatment are unlikely to reach the market for several years. Furthermore, most observers anticipate that the development of an effective preventative vaccine for HCV will require decades of research.
HCV prevention, screening, care, and treatment have attracted a growing constituency of advocates, including people with hepatitis C and activists working on HIV, harm reduction and substance abuse, and prisoner health. This volume of the report aims to broaden the advocacy agenda to include advocacy for basic research and drug development. The following chapters provide a foundation for understanding current issues and research priorities in HCV virology, immunology, and drug and vaccine development.
Current changes in how research is conceived and conducted provide a range of opportunities for advocacy:
- The National Institutes of Health (NIH) unveiled a new initiative, the NIH Roadmap, intended to accelerate biomedical and translational research through new forms of collaboration. Yet NIH has entered a phase of relatively flat funding, following a five-year period during which Congress doubled the NIH budget. Funding for HCV research in fiscal year 2005 is estimated at 130 million. Flat funding will limit the pace of new advances and discoveries in HCV research.
- Within NIH, the National Institute of Diabetes and Digestive and Kidney Diseases created a Liver Disease Research Branch that encompasses research on HCV within the institute. The Liver Disease Research Branch is developing an Action Plan for Liver Disease Research that attempts to coordinate and prioritize liver disease research across NIH. The Action Plan has been soliciting comments from the research community and the public.
- The Food and Drugs Administration (FDA) has launched a 'Critical Path' initiative to accelerate drug development by stimulating research on scientific barriers to assessing the efficacy and safety of new drugs. FDA intends to identify and prioritize a list of opportunities for targeted research and collaboration between government and industry. FDA is soliciting comments on potential areas of focus.
- As new classes of HCV drugs -- particularly protease and polymerase inhibitors -- begin moving into clinical trials, FDA can also take a leadership role in providing guidance to industry on trial design, study populations, and conditions for accelerated approval. Advocates can work with FDA and industry to speed the development, testing, and approval of safe and effective new HCV drugs.
- New international research initiatives are stimulating novel research into liver disease and therapies. The Human Liver Proteome Project, spearheaded by China and coordinated by the Human Proteome Organization, aims to map the interactions of proteins in healthy and diseased livers. The Gates Foundation's 'Grand Challenges in Global Health' initiative will fund innovative research projects in areas including preventative and therapeutic vaccines, with HCV listed as a priority area. On a smaller scale, the Canadian Network for Vaccines and Immunotherapeutics (CANVAC) coordinates HCV vaccine research, and the European Commission funds the HepCVax collaborative project to research and develop preventative and therapeutic vaccines for HCV. The European Union has also funded the European Network for Hepatitis C Virus Envelope Glycoprotein Research consortium (ENHCV) to study the structure and function of HCV envelope proteins for the development of new HCV drugs. Finally, HIV vaccine research offers provocative models for effective collaboration and coordination of HCV vaccine research efforts, including the incipient Global HIV Vaccine Enterprise and the Neutralizing Antibody Consortium, led by the International AIDS Vaccine Initiative.
- Future advances in HCV basic research and drug and vaccine development will require creative partnerships between government, industry, academia, and community. Basic and clinical research will mutually benefit from further integration, as occurs within the NIH-funded Hepatitis C Cooperative Research Centers. The science points to a new era of innovation and discovery; this vision can only be realized through increased leadership, resources, and advocacy.
- Support and intensify research into the molecular biology of HCV.
- Support and intensify research into immune response, persistence and pathogenesis.
- Increase funding and coordination of research.
- Support refinement of in vitro and animal models.
- Promote drug development efforts that study safety and efficacy in real-world populations.
- Initiate partnerships between industry, government, academia, and community.
I have relied on the generosity of several researchers who provided me copies of their work, answered questions, provided comments, or otherwise encouraged and stimulated my thinking on HCV research: Carol Brosgart, Kyong-Mi Chang, Nick Crispe, Gregory Dore, Rika Draenert, Brian Edlin, Bin Gao, Jay Hoofnagle, Lennox Jeffers, Leslye Johnson, Ronald Jubin, Margaret Koziel, Diane Lucas, John McHutchison, Shruti Mehta, Marion Peters, Barbara Rehermann, Charles Rice, Benedikt Sas, Kenneth Sherman, Sharon Stancliff, Mark Sulkowski, Andrew Talal, David Thomas, and Francesca Torriani.
I'd also like to thank my editors for their diligence, Lei Chou for his graphics and design work, Jules Levin for providing valuable information and perspective on HCV drug development, and Richard Jefferys for many helpful conversations about immune responses.
Finally, I am indebted to Tracy Swan for not only inviting me to work on this project, but also for the continued dialogue and feedback, the comments and insights into the structure and content of my chapters, and especially for her support and collaboration, which has enriched and inspired my work.