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“The only thing necessary for these diseases to the triumph is for good people and governments to do nothing.”

    

The Hepatitis Report:

   A Critical Review of the Research and

   Treatment of Hepatitis C Virus (Hepatitis C Virus) and

   Hepatitis & HIV Coinfection

   by Michael Marco and Jeffrey Schouten, M.D.

 

   Version 1.0

   July 2000

 

 

   Credits & Acknowledgments

   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. mikemarco@aol.com

 

   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.

 

    

 

 

                .....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.

 

                            This report is dedicated to the memory of

 

                                     Michael Wright

                                      (1953 - 1992)

 

                                          &

 

                                       Bill Thorne

                                      (1963 - 1999)

 

 

    Table of Contents

                                                                                

         Foreword

         Introduction

         Epidemiology, Modes of Transmission, & Risk Factors for Hepatitis C Virus Infection

         Pathogenesis, Viral Dynamics, & Immunologic Response of Hepatitis C Virus

         Natural History, Clinical Manifestations, and Prognostic Indicators of Disease Progression & Survival

         of Hepatitis C Virus Infection

         Diagnosis of Hepatitis C Virus Infection

         Treatment of Hepatitis C Virus Infection: The Interferon Story

         Experimental Treatments & New Areas of Research for Hepatitis C Virus Infection

         Hepatitis and HIV Coinfection

         Current Opinions & Controversies in Hepatitis C Virus Infection

         Research & Policy Recommendations

         Clinician's Response

    

 

 

 

 

   Forward

   by Marion Peters, M.D.

 

   This TAG report on hepatitis C virus (Hepatitis C Virus) is comprehensive and will bring you completely up to date. It runs

   the gamut of Hepatitis C Virus 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 Hepatitis C Virus, 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 Hepatitis C Virus 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 Hepatitis C Virus 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 Hepatitis C Virus 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. Hepatitis C Virus 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 Hepatitis C Virus in response to HIV therapy is largely

   unknown. Viral dynamics of Hepatitis C Virus is in its infancy, compared to that of HIV. Markers of response to Hepatitis C Virus 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 Hepatitis C Virus 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. This

   results in ease of treatment as well as an apparent higher response rate, including a surprisingly high rate in

   cirrhotics (<10% in all studies before pegylated IFN). We may need to look carefully at these studies when

   they are published but early reports are very encouraging. Side effects are not much different from those of

   daily dose interferon although there may be some populations in whom dose finding is necessary before

   putting patients on long- acting weekly IFN. Newer therapies aimed at the virus itself have been slow in

   coming but are clearly the next line of drugs. In particular, ribozymes may be the next "breakthrough" in this

   area. Immunomodulators have been generally less promising with the exception of IL-10 as an anti-fibrotic.

 

   I would recommend this report highly to those who want to be fully informed about the area. Those who need

   full references; those who may not have the time or inclination to gather the oldest and the latest information;

   and those who need to delve more deeply into particular areas of this fascinating field will find this report

   useful. Many scientists and clinicians have worked with Michael Marco to address specific areas of their

   expertise. It is a testament to them and to Michael that he has produced this informative but easily readable

   document. Not all of the statements in this report have been validated. You will not agree with all of them. But

   you will be stimulated to learn more and to keep abreast of new developments after reading these all

   encompassing chapters. You may not concur with all of the TAG policy recommendations but you will be

   forced to re-evaluate and think about many important issues surrounding Hepatitis C Virus. Good luck and enjoy.

 

   Marion Peters is Professor of Medicine and Chief of Hepatology Research, at the University of California,

   San Francisco.

 

    

 

 

 

 

   Introduction

   by Michael Marco

 

                Clearly the problem of Hepatitis C Virus will require a responsible partnership of public and private

                organizations....If we are to make progress against this perplexing epidemic, careful

                and disinterested voices must prevail1.

 

       Despite the wide publicity about hepatitis C in the media, and the numerous

       educational conferences and publications in the medical literature, and the

       dissemination of the NIH consensus statement on hepatitis C, there are significant

       deficits in the knowledge of primary care physicians regarding hepatitis C2.

 

   My appreciation of and desire to study hepatitis C virus (Hepatitis C Virus) research is something new. It started off as

   mere curiosity during my research of AIDS-related opportunistic infections (OIs) when I thought about adding

   a short chapter on Hepatitis C Virus to TAG's OI Report because it was well know that many individuals with HIV are also

   coinfected Hepatitis C Virus. Approximately two years later, it seems laughable that one could simply write a "short

   chapter" on Hepatitis C Virus. It has become apparent to me that there is a need for a thorough study, review, and critical

   analysis of Hepatitis C Virus research.

 

   Many AIDS treatment advocates have critically analyzed the numerous facets of HIV clinical and basic

   research with great aplomb. They have produced a wealth of patient-readable HIV treatment information so

   that people with HIV/AIDS can become experts in understanding their virus. In my two years of researching

   Hepatitis C Virus, I found that there were only a few Hepatitis C Virus treatment advocates, yet none had created one text that

   contained a complete overview of the virus, analyzed the research, and offered important and sound Hepatitis C Virus

   treatment information as well as policy recommendations to move the field of Hepatitis C Virus research forward. Since I

   have been well trained and mentored in researching and writing such documents on HIV-related

   complications, I felt I would initiate TAG's Hepatitis Project and write a report on Hepatitis C Virus, as well as on hepatitis

   and HIV coinfection. People with Hepatitis C Virus deserve the same tools as those with HIV so that they can become

   experts about their virus.

 

   I quickly realized that people with Hepatitis C Virus were not the only ones who needed to become experts. I found that

   many primary care physicians lack a complete breath of knowledge of the epidemiology and clinical

   management of Hepatitis C Virus. This was blatantly obvious in the 1999 Hepatology article, "Current Practice Patterns of

   Primary Care Physicians in the Management of Patients with Hepatitis C" by Shehab and colleagues from

   Anna Lok's group at the University of Michigan.2 In a survey of over 400 primary care physicians from the

   Detroit area, 20% and 8%, respectively, considered blood transfusion in 1994 and casual household contact

   as significant risk factors for Hepatitis C Virus; 43% overestimated the likelihood of a sustained response to a course of

   interferon therapy, while 29% had no idea what the sustained response rate was; 38% would not a refer an

   Hepatitis C Virus antibody-positive patient to a gastroenterologist even though they had no experience in treating Hepatitis C Virus

   patients on their own. Another study by Villano and colleagues from Johns Hopkins found that a majority of

   the intravenous-drug-using patients in their natural history cohort tested Hepatitis C Virus antibody-positive their first time

   on study yet were under the care of clinic or primary care physicians.3 This striking lack of awareness by

   health care providers about Hepatitis C Virus epidemiology, risk factors, and clinical management is unacceptable. Let us

   hope that this report gets into the hands of the physicians and patients who need it.

 

   I also wrote the report in an attempt to quell the mass hysteria about Hepatitis C Virus created by major weekly news

   magazines as well as by the obnoxious "get tested, get treated" Hepatitis C Virus advertising campaign of a greedy

   pharmaceutical company. The push to immediately treat everyone who tests positive for Hepatitis C Virus made my blood

   boil, because that is often the same message given to those who initially test positive for HIV. For HIV, we

   have only clinical endpoint studies documenting a survival advantage to starting potent, combination

   antiretroviral therapy before a patient's CD4 count drops below 200 cell/m3, yet with both viruses, we still

   have not fully answered the question, When should one initiate antiviral therapy? (i.e., "When to start?").

 

   This Hepatitis C Virus report attempts to answer that question and documents what we know and what we don't know

   about the epidemiology, natural history, diagnosis, and treatment of Hepatitis C Virus. After an exhaustive analysis of

   peer-reviewed articles, over 40 researchers, clinicians, primary care physicians, government heath

   administrators, industry representatives, and patients with viral hepatitis were interviewed. Research and

   treatment policy recommendations have been issued and will need to be implemented in order to carefully

   find answers to the many basic and clinical science questions in Hepatitis C Virus research.

 

   This large report–which will grow still larger in version 2.0 to include an analysis of the research and

   treatment of hepatitis viruses A and B (HAV and HBV)–is a collaborative effort. Jeffrey Schouten was a great

   partner who worked with me over these two years, and he wrote selected Hepatitis C Virus chapters and the section on

   hepatitis and HIV coinfection. Expert hepatitis researchers, including Marion Peters, Thierry Poynard, Teresa

   Wright, Jay Hoofnagle, Leonard Seeff, and Douglas Dieterich went out of their way in varying capacities to

   help me, an AIDS treatment advocate they had never met.

 

   More collaborative and concentrated efforts on the part of industry, physicians, government, and the hepatitis

   community alike are needed if we are to effectively challenge, overcome, and cure Hepatitis C Virus.

 

   1 The Lancet. Making sense of hepatitis [editorial]. Lancet 352:1485, 1998.

   2 Shehab T, Sonnad SS, Jeffries M, et al. Current practice patters of primary care physicians in the management of patients with

   hepatitis C. Hepatology 30:794-800, 1999.

   3 Villano SA, Vlahov D, Nelson KE, et al. Persistence of viremia and the importance of long-term follow-up after acute hepatitis C

   infection. Hepatology 29:908-14, 1999.

 

    

 

 

 

 

   Epidemiology, Modes of Transmission,

   & Risk Factors for Hepatitis C Virus (Hepatitis C Virus) Infection

   by Michael Marco

 

        My opinion is that we just can't tell for sure about some of this because we are bad at

        measuring human behavior.

                                              ——Davis Thomas, e-mail correspondence

 

   Background

   During the 1970s and 1980s, no one knew what was causing hepatitis in certain individuals who had received

   blood transfusions. Screening tests for hepatitis A (HAV) and hepatitis B (HBV) in the mid-1970s revealed

   that about 25% of these cases of transfusion-associated hepatitis (TAH) were linked to hepatitis B but no

   hepatitis A. The remaining 75% of TAH cases, by default, were termed non-A-non-B hepatitis (NANBH) (H.

   Alter 1999). Ten to twenty percent of individuals who had received multiple blood transfusions (or used

   plasma products) developed NANBH, with a relative risk of 0.45% per unit transfused (Donahue 1992).

 

   Because primary infection was usually asymptomatic or, at worst, mild, clinicians did not initially consider

   NANBH to be a very serious disease. It was soon recognized, however, that the seemingly benign NANBH

   could develop into a chronic hepatitis with markedly elevated liver enzymes. Sometimes the hepatitis

   resulted in cirrhosis.

 

   According to the National Institutes of Health’s (NIH) Harvey Alter, attitudes to NANBH changed in the late

   1980s:

 

        The NANBH agent remained a virologic enigma....until researchers at the Chiron Corporation

        used an ambitious molecular approach on large volumes of high-titer infectious chimpanzee

        plasma from the Centers for Disease Control and Prevention (CDC). They extracted RNA,

        cloned it into an expression vector, and screened the expressed product with presumed

        immune sera. A single positive clone was found in the millions screened, and, within a year,

        the entire genome was sequenced and the agent was identified as a novel flavivirus the

        hepatitis C virus (Hepatitis C Virus). (HJ Alter 1999).

 

   In 1988 Choo and colleagues characterized the hepatitis C virus (Hepatitis C Virus), and shortly thereafter, an antibody

   test was developed to detect infection (Choo 1989; Kuo 1989). When NIH researchers performed Hepatitis C Virus

   assays on archived blood samples, it was determined that 70% to 90% of NANBH cases were actually Hepatitis C Virus

   infections.

 

   Prevalence of Hepatitis C Virus Infection in the United States (U.S.)

   Hepatitis C Virus is considered the most common blood-borne infection and is one of the leading causes for liver

   transplantation among adults in the U.S. After the Hepatitis C Virus antibody test became available, epidemiology studies

   were performed to ascertain the incidence of the infection. The original studies, however, were considered

   flawed because they were conducted with first-time blood donors, individuals who had already been screened

   for risk factors such as infectious diseases.

 

   A recently published study by Miriam Alter and colleagues from the Centers for Disease Control and

   Prevention (CDC) reported that an estimated four million persons nationwide are Hepatitis C Virus- antibody-positive

   (ab+), indicating exposure to the virus. Roughly three-quarters of these have detectable Hepatitis C Virus RNA, indicating

   chronic infection (MJ Alter, 1999b). These data hail from the CDC’s third National Health and Nutrition

   Examination Study (NHANES III), conducted between 1988 and 1994, and involving a sample of almost

   40,000 persons between the ages of 2 and 89 years.

 

   Out of this group, 21,241 individuals agreed to be both interviewed and tested for antibodies to Hepatitis C Virus; of these,

   1.8% were found to be Hepatitis C Virus-antibody-positive. For the entire U.S., this corresponds to approximately 3.9

   million residents infected with Hepatitis C Virus. Below is a breakdown of the prevalence of Hepatitis C Virus-antibody-positivity

   classified by race or ethnic group and gender.

 

   Prevalence of Antibody to Hepatitis C Virus (Anti-Hepatitis C Virus)

   According to Race or Ethnic Group & Gender in NHANES III

 

       Characteristic

                     No. Tested

                                  Prevalence (%) of

                                 Anti-Hepatitis C Virus+ (95% CI)

                                                     Estimated No. Infected Nationwide

                                                                (95% CI)

     All Subjects

                     21,241

                               1.8 (1.5-2.3)

                                                    3,875,000 (3,102,000-4,840,000)

     Race/Ethnic Group

     Non-Hispanic White

                     7,965

                               1.5 (1.1-2.0)

                                                    2,359,000 (1,774,000-3,137,000)

     Non-Hispanic Black

                     6,119

                               3.2 (2.6--4.0)*

                                                    762,000 (609,000-953,000)

     Mexican Americans

                     6,268

                               2.1 (1.7-2.6)

                                                    261,000 (210,000-323,000)

     Other

                     889

                               2.9 (1.4-5.8)

                                                    493,000 (245,000-993,000)

     Gender

     Male

                     10,076

                               2.5 (2.0-3.2)**

                                                    2,586,000 (2,012,000-3,323,000)

     Female

                     11,165

                               1.2 (0.9--1.6)

                                                    1,289,000 (967,000-1,717,000)

 

 

   * P<0.05 for comparison with non-Hispanic whites (MJ Alter 1999b)

   ** P<0.05

 

   Hepatitis C Virus Prevalence in Blood Donors in Southern Europe

   Several large Hepatitis C Virus epidemiology studies have been published in Italy, France, and Spain. Below is a

   breakdown of anti-Hepatitis C Virus prevelance in selected studies that have been conducted since the early 1990s.

 

   Hepatitis C Virus Incidence Rates in Six Large Southern European Cohorts

 

            N =

                 Anti-Hepatitis C Virus +

                               Country (Study)

          173,038

                 0.63%

                           France (Anuelles 1992)

          60,960

                 0.69%

                           France (Aymard 1993)

          30,231

                 1.2%

                           Spain (Esteban 1991)

          46,741

                 1.12%