A Critical Review of the Research and Treatment of Hepatitis C Virus (HCV) and Hepatitis & HIV Coinfection The Hepatitis Report July 9-14, 2000 by Michael Marco and Jeffrey Schouten, M.D. From Treatment Action Group July 14, 2000 Credits & Acknowledgments By Michael Marco and Jeffrey Schouten Michael Marco is Director of Treatment Action Group's (TAG) Infections and Oncology ProJect, the author of TAG's The OI Report, The KS Project Report, The Lymphoma Project Report, and editor of TAG's The Wasting Report. He is a member of the NIH Office Of AIDS Research's Therapeutics Research Working Group, the National Cancer Institute's AIDS Malignancies Working Group and AIDS Malignancies Consortium, the USPHS/IDSA Prevention of Opportunistic Infections Working Group and a consultant to the FDA's Oncologic Drug Advisory Committee. [email protected] Jeffrey Schouten, M.D., Attorney at LaW, Clinical Assistant Professor of Surgery, University of Washington (UW) is an HIV primary care provider at UW's HarborvieW Medical Center and Vice-Chair of Washington's Governor's Advisory Council on HIV/AIDS. He is also a member of the Adult AIDS Clinical Trials Group's (AACTG) Community Constituency Group, Executive Committee and Scientific Agenda Steering Committee. Additionally, he is a member of the NCI's AIDS Malignancy Consortium, the Conference on Retroviruses and Opportunistic Infections Planning Committee, and Publications Editor for the Seattle Treatment Education ProJect (STEP). The Treatment Action Group (TAG) fights to find a cure for AIDS and to ensure that all people living With HIV receive the necessary treatment, care, and information they need to save their lives. TAG focuses on the AIDS research effort, both public and private, the drug development process, and our nation's health care delivery systems. We meet With researchers, industry, and government officials, and resort When necessary to acts of civil disobedience, or to acts of Congress. We strive to develop the scientific and political expertise needed to transform policy. TAG is committed to Working for and With all communities affected by HIV. Acknowledgments First thanks go to the board, staff, consultants, volunteers, and donors of TAG. Special thanks go out to Robert Huff for line-editing of the report, to Andrea Dailey for her forceful and exacting copy-edits, and to board member Lynda Dee of AIDS Action Baltimore, Whose generous gift enabled us to print this report. Tremendous thanks goes out to my chief clinical editor, Marion Peters, for her many hours of editing, mentoring, laughter and writing the Foreword. Likewise, thanks to Thierry Poynard for his keen insight and generosity in writing The Clinician's View. Thanks to Jay Hoofnagle, Leonard Seeff, Teresa Wright and Douglas Dieterich for helpful instruction and going out of their Way to assist me in my research. I must thank the many others Who alloWed me to intervieW them or made contributions to this proJect, including: Yves Benhamou, Clifford Brass, Megan Briggs, Massimo Colombo, LaWrence "Bopper" Deyton, Lorna Dove, Juan Esteban, Judith Fradkin, Jaime Guardia, Roy "Trip" Gulick, Bart Henderson, Joseph Hoffmann, Leslye Johnson, Michael Joyner, Christine Katlama, Brian Klein, David Kleiner, Thomas Kresina, Jay Lalezari, James Learned, Alexandra Levine, Karen Lindsay, Anna Lok, Jules Levin, Patrick Marcellin, Henry Masur, Cindy Mays, Donny Moss, Alison Murray, Chris Papas, Billy Pick, Robert Purcell, Stephen Rossi, Mark SulkoWski, Norah Terrault, David Thomas, Richard Whitley, and Kevin Young. Finally, thanks go out to David Berry, Todd Goodale, Kurt Fulton, Mark Harrington, Rick Leeds, Donna Masini, and Jeffrey Rindler for their support, guidance and fellowship. If you Would like more information about TAG, contact us at: Treatment Action Group 350 Seventh Ave., Ste. #1603 New York, New York 10036 ( T) 212.972.9022 / (F) 212.971.9019 Internet: http://WWW.treatmentactiongroup.org First distribution: XIII International AIDS Conference, Durban, South Africa, 9-14 July 2000. This report is dedicated to the memory of Michael Wright (1953 - 1992) & Bill Thorne (1963 - 1999) "The disease generally progresses at a snail's pace, requiring the passage of 3 to 4 decades, in most instances, to reach recognizable serious endpoints. It therefore represents a daunting task for the clinical investigator, feW of Whom are Willing to devote their research careers to this exhaustive form of investigation." -- LB Seeff, Hepatology 1997; 26:21S-28S. "Because of the ageing phenomena, all [natural history] studies Which do not take into account both the age at infection and the duration of infection are meaningless." -- T Poynard, e-mail correspondence, 23 June 2000. "The patient who has a liver disease wants (or needs) to know about the natural history of the disorder so as to plan for the future. The patient should be informed regarding the likely consequences, important milestones, maJor complications, and available therapies, all given With a large measure of compassion and sensitivity." -- WC Maddrey, AASLD, Postgraduate Course, 1999. "Physicians and patients must carefully Weigh the risks (Which are clinically significant in the case of treatment With interferon alfa-2b and ribavirin), the benefits (moderate in this instance), and the cost (substantial in this instance) of any treatment option for a disease that has emerged as an important public health problem." -- TJ Liang, N Engl J Med 1999; 340:1207. Foreword By Marion Peters, M.D. July 9-14, 2000 This TAG report on hepatitis C virus (HCV) is comprehensive and Will bring you completely up to date. It runs the gamut of HCV infection With areas of interest for the clinician, allied health care worker and educated patient. It contains information about epidemiology, natural history, diagnosis, pathogenesis and treatment. It is certainly an enormous task to undertake but the authors have been largely very successful. Many of the chapters contain the earliest literature in the area and are current to last month's abstracts. It may be difficult for some of us to read an abstract With the same conviction of fact, as abstracts have not been peer reviewed rigorously, nor is all the data usually available at the time presentation. HoWever, in a fast moving field such as HCV, it alloWs the reader to knoW what is "hot" and where the field is heading. We are clearly told what data and trials are peer reviewed, which are confirmed by other investigators and Which appear to be "outside the envelope" but interesting none the less. This report is generally superbly referenced and will be of great value to you. The natural history chapter reminds us that not all patients inexorably deteriorate to end- stage liver disease, liver transplantation or death. It is clear that for the large number of years that We have been folloWing patients, some clinicians see the slowest rates of progression Whilst others see HCV as "the evil empire". Patients need to knoW the facts, not colored by drug company hype, or physician preference and this report provides these facts. Only by knowing that not all patients progress, can individuals patients decide Whether treatment for them is noW or in the future. The epidemiology, risk factors and modes of transmission are Well outlined With perhaps an overabundance of information. You can skim it or dive in for the total immersion, Whichever is your preference. This is an excellent chapter With clear tables, explaining the high rate of transmission in IVDU patients and the loW sexual transmission rate. The diagnosis of HCV is often complex With multiple tests and the confusion of liver biopsy evaluation. Once again the authors have used excellent available reviews and references to present readable current state-of-the-art information. The reader must be cautioned that this area is not Well regulated and HCV RNA tests are changing rapidly. In addition, When tests are performed in the hospital setting or the community, often a different laboratory is used at different times (the pressures of managed care). In these cases, one cannot extrapolate from one bDNA to another PCR or even from one PCR to another. Therefore, it is critical that patients and clinicians not put excessive Weight on small (less than one log) changes. HCV RNA Will change little from patient to patient but a lot from test to test. The area of co-infection with HIV is the youngest in the field and is a moving target. Large cohort studies are lacking and treatment trials are small in number and patient size. This is an area that is receiving a large amount of attention; treatment trials are underWay and more hepatologists are becoming involved Working side-by-side With infectious disease specialists. The role of HCV in response to HIV therapy is largely unknoWn. Viral dynamics of HCV is in its infancy, compared to that of HIV. Markers of response to HCV have included genotype, age of acquisition, gender, viral load and amount of fibrosis on liver biopsy. Early studies suggest that these may be superceded by viral dynamics: those With rapid response to interferon therapy are more likely to achieve a sustained response versus those who are sloW responders. Only time Will tell if this sWeeping statement is correct. The chapters on experimental therapies and current treatment are excellent. Once again We are reminded that at best only half of HCV patients respond to current therapies. But only half may need therapy in the long term. Unfortunately clinicians cannot determine which patients will progress to fibrosis and end-stage liver disease and so most patients are treated especially if they have some scarring Without cirrhosis. This is an area that requires intensive research from clinical, epidemiological and immunological aspects. Interferon remains the mainstay of therapy with pegylated IFNs providing exciting new advances. By combining IFN to polyethylene glycol, IFN remains in the circulation longer and thus only Weekly dosing is required.