FOOD AND DRUG ADMINISTRATION

CENTER FOR DRUG EVALUATION AND RESEARCH

PEDIATRIC SUBCOMMITTEE

OF THE

ANTI-INFECTIVE DRUGS ADVISORY COMMITTEE

8:20 a.m.

Monday, April 23, 2001

Food and Drug Administration

ACS Conference Room, Room 1066

5630 Fishers Lane

Rockville, Maryland 20857

ATTENDEES

SUBCOMMITTEE MEMBERS:

P. JOAN CHESNEY, M.D., Chair

Professor of Pediatrics

Department of Pediatrics

University of Tennessee College of Medicine

50 North Dunlap

Memphis, Tennessee 38103

JAYNE E. PETERSON, R.PH., J.D., Executive Secretary

Advisors and Consultants Staff (HFD-21)

Center for Drug Evaluation and Research

Food and Drug Administration

5600 Fishers Lane

Rockville, Maryland 20857

JUDITH O'FALLON, PH.D.

Director, Cancer Center Statistics Unit

Plummer #4

Mayo Clinic

200 First Street, S.W.

Rochester, Minnesota 55905

SGE CONSULTANTS:

DAVID DANFORD, M.D.

Associate Professor of Pediatrics

University of Nebraska Medical Center

Pediatric Cardiology

600 South 42nd Street

Omaha, Nebraska 68198-216

KATHRYN EDWARDS, M.D.

Professor of Pediatrics

Vanderbilt University

1161 21st Avenue South

7th Medical Center North

Nashville, Tennessee 37232

ROBERT FINK, M.D.

Pulmonary Medicine

Children's National Medical Center

111 Michigan Avenue, N.W.

Washington, D.C. 20010

ATTENDEES (Continued)

SGE CONSULTANTS: (Continued)

SUSAN FUCHS, M.D.

Children's Memorial Medical Center

Division of Pediatric Emergency Medicine

2300 Children's Plaza, No. 62

Chicago, Illinois 60614

RICHARD GORMAN, M.D., FAAP

Pediatric Partners

9051 Baltimore National Pike

Ellicott City, Maryland 21042-3927

F. BLAINE HOLLINGER, M.D.

Professor of Medicine, Virology & Epidemiology

Baylor College of Medicine

One Baylor Plaza

Houston, Texas 77030

MARK HUDAK, M.D.

Professor and Chief

Division of Neonatology

Department of Pediatrics

University of Florida at Jacksonville

Health Sciences Center

653-1 West 8th Street

Jacksonville, Florida 32209

NAOMI LUBAN, M.D.

Vice Chairman

Department of Laboratory Medicine

Director, Transfusion Medicine/Quality Assurance

Children's National Medical Center

111 Michigan Avenue, N.W.

Washington, D.C. 20010-2970

ROBERT NELSON, M.D., PH.D.

Department of Anesthesia and Critical Care Medicine

The Children's Hospital of Philadelphia

34th Street and Civic Center Boulevard

Philadelphia, Pennsylvania 19104-4399

ATTENDEES (Continued)

SGE CONSULTANTS: (Continued)

KEITH RODVOLD, PHARM.D., Consumer Representative

Professor, Department of Pharmacy Practice

University of Illinois at Chicago

College of Pharmacy M/C 886

833 South Wood Street, Room 164

Chicago, Illinois 60612-7230

VICTOR SANTANA, M.D.

Associate Professor

Department of Hematology/Oncology

St. Jude's Children's Research Hospital

332 North Lauderdale

Memphis, Tennessee 38101

STANLEY SZEFLER, M.D.

National Jewish Center

Division of Clinical Pharmacology

1400 Jackson Street

Goodman Building, Room 926

Denver, Colorado 80206

GUESTS AND GUEST SPEAKERS:

WILLIAM BALISTRERI, M.D.

Children's Hospital Medical Center

Division of Gastroenterology

3333 Burnet Avenue, OSB 4

Cincinnati, Ohio 45229

MAUREEN JONAS, M.D.

Division of Gastroenterology-Hunnewell Ground

Children's Hospital

300 Longwood Avenue

Boston, Massachusetts 02115

RALPH KAUFFMAN, M.D.

Representing American Academy of Pediatrics

Director, Medical Research

Professor of Pediatrics and Pharmacology

The Children's Mercy Hospital

University of Missouri at Kansas City

2401 Gillham Road

Kansas City, Missouri 64108

ATTENDEES (Continued)

GUESTS AND GUEST SPEAKERS: (Continued)

KAREN LINDSAY, M.D.

University of Southern California

Keck School of Medicine

1355 San Pablo Street, Suite 128

Los Angeles, California 90033

BARBARA REHERMANN, M.D.

Liver Disease Section, DDB

National Institutes of Diabetes and

Digestive and Kidney Diseases

National Institutes of Health

Building 10, Room 9B16

10 Center Drive MSC 1800

Bethesda, Maryland 20892-1800

KATHLEEN SCHWARZ, M.D.

Johns Hopkins University

School of Medicine

Division of Pediatric Gastroenterology and Nutrition

Brady 320, 600 North Wolfe Street

Baltimore, Maryland 21287

LEONARD SEEFF, M.D.

National Institutes of Diabetes and

Digestive and Kidney Diseases

National Institutes of Health

31 Center Drive, Room 9A18

Bethesda, Maryland 20892

STEVEN SPIELBERG, M.D., PH.D.

Representing Pharmaceutical Research and

Manufacturers Association

Janssen Research Foundation

1125 Trenton-Harbourton Road

Titusville, New Jersey 08560-0200

ATTENDEES (Continued)

FOOD AND DRUG ADMINISTRATION STAFF:

RUSSELL FLEISCHER, PA-C, MPH

Senior Clinical Analyst

Division of Antiviral Drug Products

Center for Drug Evaluation and Research

DIANNE MURPHY, M.D.

Associate Director of Pediatrics

Center for Drug Evaluation and Research

KAREN WEISS, M.D.

Director

Division of Clinical Trial Design and Analysis

Office of Therapeutics Research and Review

Center for Biologics Evaluation and Research

JAY SIEGEL, M.D.

Center for Biologics Evaluation and Research

C O N T E N T S

ISSUE: TREATMENT OF CHRONIC HEPATITIS C IN CHILDREN

AGENDA ITEM PAGE

CONFLICT OF INTEREST STATEMENT

by Ms. Jayne Peterson 10

INTRODUCTION TO THE MEETING

by Dr. Dianne Murphy 14

REVIEW OF MEETING AGENDA/BACKGROUND

INFORMATION AND OVERVIEW

by Mr. Russell Fleischer 16

VIROLOGY AND IMMUNOLOGY OF HEPATITIS C

by Dr. Barbara Rehermann 20

NATURAL HISTORY OF HEPATITIS C IN THE ADULT POPULATION

by Dr. Leonard Seeff 33

HEPATITIS C IN CHILDREN

by Dr. Maureen Jonas 56

PEDIATRIC DRUG DEVELOPMENT: OVERVIEW OF FDA INITIATIVES

by Dr. Karen Weiss 81

OPEN PUBLIC HEARING 92

QUESTIONS FROM THE SUBCOMMITTEE 92

SUBCOMMITTEE DISCUSSION OF THE ISSUES/QUESTIONS 151

AGENCY UPDATE TO THE SUBCOMMITTEE

by Dr. Dianne Murphy 278

P R O C E E D I N G S

(8:20 a.m.)

DR. CHESNEY: Good morning. Just getting last minute instructions here. The microphones that you have in front of you are a little different than we've had before. Be sure please to push the top button to speak, and also introduce yourselves. As you know, this is all being recorded and that makes it easier for the individual recording.

We'll start with introductions and let's start here with Dr. Weiss.

DR. WEISS: Karen Weiss, from the Division of Clinical Trial Design and Analysis, Center for Biologics, at FDA.

MR. FLEISCHER: Russ Fleischer, Division of Antiviral Drug Products in the Center for Drugs, FDA.

DR. RODVOLD: Keith Rodvold, University of Illinois, Chicago.

DR. FUCHS: Susan Fuchs, Children's Memorial Hospital, Chicago.

DR. DANFORD: David Danford, joint section of pediatric cardiology, University of Nebraska Medical Center, Creighton University in Omaha.

DR. EDWARDS: Kathy Edwards, Department of Pediatrics, Vanderbilt University.

DR. SANTANA: Victor Santana, Department of Hematology, Oncology, St. Jude's Children's Research Hospital in Memphis, Tennessee.

DR. SZEFLER: Stan Szefler, Department of Pediatrics at the University of Colorado.

DR. NELSON: Robert Nelson, Department of Anesthesiology and Critical Care Medicine at the Children's Hospital, Philadelphia.

DR. HOLLINGER: I'm Blaine Hollinger, from Baylor College of Medicine in Houston, Texas.

DR. O'FALLON: Judith O'Fallon, Cancer Center Statistics, Mayo Clinic, Rochester, Minnesota.

DR. FINK: Bob Fink, pediatric pulmonology, Children's National Medical Center and George Washington University, Washington, D.C.

MS. PETERSON: I'm Jayne Peterson with the FDA. I'm the Executive Secretary of the subcommittee

DR. CHESNEY: Dr. Chesney, the University of Tennessee, Department of Pediatrics and St. Jude Children's Research Hospital.

DR. LUBAN: Naomi Luban, Department of Hematology and Pathology, Children's Hospital, Washington, D.C. and George Washington University.

DR. GORMAN: Rich Gorman, Ambulatory Pediatrics, Ellicott City.

DR. HUDAK: Mark Hudak, neonatology, University of Florida, Jacksonville.

DR. KAUFFMAN: Ralph Kauffman, Children's Mercy Hospital, Kansas City, Missouri, University of Missouri.

DR. SPIELBERG: Steven Spielberg, Pediatric Drug Development, Janssen Research Foundation, representing PhRMA.

DR. JONAS: Maureen Jonas, Children's Hospital and Harvard Medical School, Boston.

DR. SEEFF: Leonard Seeff, NIDDK/NIH.

DR. LINDSAY: Karen Lindsay from the Department of Medicine, Division of Gastroenterology and Liver Disease from the University of Southern California in Los Angeles.

DR. SCHWARZ: Kathy Schwarz, Division of Pediatric Gastroenterology and Nutrition, Johns Hopkins, Baltimore, Maryland.

DR. REHERMANN: Barbara Rehermann, NIDDK/NIH.

DR. CHESNEY: And next we'll have the conflict of interest statement from Jayne Peterson.

MS. PETERSON: The following announcement addresses the issue of conflict of interest with regard to this meeting and is made a part of the record to preclude even the appearance of such at this meeting.

Since the issues to be discussed by the subcommittee at this meeting will not have a unique impact on any particular firm or product, but rather may have widespread implications with respect to an entire class of products, in accordance with 18 U.S.C., section 208(b), waivers have been granted to all members and consultants who have reported interests in any pharmaceutical and biological companies.

A copy of these waiver statements may be obtained by submitting a written request to the FDA's Freedom of Information Office, Room 12A-30 of the Parklawn Building.

With respect to FDA's invited guests, there are reported affiliations which we believe should be made public to allow the participants to objectively evaluate their comments.

Ralph Kauffman, M.D., would like to disclose that he has contracts and/or grants from Bristol Myers Squibb, and he is a researcher for Bristol Myers Squibb, Janssen, and Merck. In addition, he has received consulting fees from Johnson & Johnson, McNeil Consumer Products, and Purdue Pharma, and he's a scientific adviser to McNeil Consumer Products and Purdue Pharma.

Steven Spielberg, M.D., would like to disclose that he is a full-time employee of Janssen Research Foundation.

William Balistreri, M.D., is a member of Roche's Safety Review Board.

Maureen Jonas, M.D., is an investigator at Harvard University for a multi-center pediatric Rebetron trial funded by the Schering-Plough Research Institute. Dr. Jonas is also a consultant to Schering-Plough Research Institute. She consults with medical care providers about hepatitis, not necessarily related to treatment or use of Schering products.

Karen Lindsay, M.D., has contracts and/or grants with Schering-Plough Corporation, Glaxo-SmithKline, and Hoffman LaRoche, and receives speaker's fees from Schering-Plough.

Leonard Seeff, M.D., is employed by the Veterans Administration Medical Center in Washington, D.C., and the National Institutes of Diabetes and Digestive and Kidney Diseases at the National Institutes of Health. He's an investigator in the Glaxo-SmithKline-sponsored multi-center trial of lamuvidine for the use in treatment of hepatitis B. As part of his federal duties, he's an investigator in a study of transfusion-associated hepatitis and a study of hepatitis in injection drug users.

In the event that the discussions involve any other products or firms not already on the agenda for which an FDA participant has a financial interest, the participants are aware of the need to exclude themselves from such involvement, and their exclusion will be noted for the record. With respect to all other participants, we ask in the interest of fairness that they address any current or previous involvement with any firm whose products they may wish to comment upon.

Thank you.

DR. CHESNEY: Thank you, Jayne.

We have a fascinating day ahead looking at issues of treatment in children with chronic hepatitis C, and I think this has been somewhat precipitated by the introduction of the polyethylene glycol interferon, and the FDA has given us a long list of questions to address.

I see this meeting also as very important, given that as everybody here knows, FDAMA is up for renewal January 1st, and particularly the pediatric exclusivity portion of FDAMA is of concern. Let me put it that way. I think the committee is very interested at this point in knowing what we can do to support the FDA as the hearings, I understand, begin next month in Congress. We look forward to hearing Dr. Murphy's comments at the end of the day as to anything further that we can do, again to support the FDA.

So, Dr. Murphy is going to start us off this morning.

DR. MURPHY: My job is to welcome you, and one of the most important things you can do for children and for the pediatric activities of the FDA is what you're doing, which is take time out of your busy schedules and come here and discuss with us the very important questions that we have about how to approach clinical trials in children in a way that's scientifically grounded and ethically based, because if we make a mistake here, it could have tremendous impact. So, again, thank all of you for taking time to come here.

I wanted to particularly take a moment to address the Pediatric Subcommittee because today is your two-year anniversary. This is your fourth meeting. And I wanted to just remind you of how much you have accomplished in a very short period of time. You have participated in providing some advice and guidance to us in some very important scientific and ethical areas.

As you will see when I do my update later, you've provided guidance to the FDA in whether we should develop products for sleep disorders in children.

You have provided guidance in our approaches to the development of neuropsychiatric oncology products.

And particularly important has been the guidance that you have provided us in the ethical arena, in which you have developed some consensus points, which are available now on the Web, concerning the conduct of trials involving children who will not derive direct benefit, and recommended at the same meeting that Subpart D be adopted by FDA. I wanted to let you know that that happened last week in the form of an interim rule, and I'll give you a little more follow-up on that later

You provided some important discussion on the use of placebo-controlled trials in children, and I'm going to provide you today, at the end of the day, the draft of the consensus points that we think we have at this point, and provide an opportunity for the committee to continue to provide feedback on that.

As you've heard, today we've asked you to come now and discuss for us both scientific and ethical issues in two very important areas that have long-term implications, as I think is clear to most everybody here. That is, the scientific and ethical issues in the development of products to treat hepatitis C in children. Should we? If so, when and how? And the same for the development of products to treat a need in children who have received neurologic injury and are unable to communicate with us. The areas of concern being both ethical and endpoint assessment.

So, you have a tremendous set of tasks before you over the next two days, and we really do look forward to your discussion. Thank you.

DR. CHESNEY: Thank you. Our first speaker is Russell Fleischer, who is going to give us a review of the agenda and some background information and overview.

MR. FLEISCHER: Good morning. On behalf of the Division of Clinical Trial Design Analysis in the Center for Biologics and the Division of Antiviral Drug Products in the Center for Drugs, I'd like to welcome you today. I think this is going to be an interesting discussion of a number of issues related to the development of treatments for children with hepatitis C infection.

It really represents a joint effort because both of our divisions are responsible for product development -- us for the antivirals and the Center for Biologics for biologics. As you know, there is a drug combination with biologics available for adults.

So, my job is to try to set the stage for what we're going to talk about today, and so why are we were? We're here to engage in a public discussion and to obtain your guidance and advice on the development of treatments for pediatric patients with chronic hepatitis C infection.

I'd also like to take the opportunity to thank the guests who've come who are going to present and who are here at the table to talk with you, because I believe they will provide a significant amount of background information that will help this committee's discussions.

So, although the number of pediatric patients with chronic hepatitis C infection is relatively small, we know there's substantial interest in treating them. This interest stems from information suggesting that they exhibit a number of characteristics that seem to be possibly predictive of a good response in adults, which is milder liver inflammation, less frequent cirrhosis, lower viral load levels, and shorter duration of infection.

Also, since chronic hepatitis C virus is currently the primary indication for liver transplantation in the United States, it's been postulated that if we treat children in childhood, we might possibly reduce the risk of progression to end-stage liver disease later in life.

We anticipate that there will be use of both drugs and drug-biologic combinations to treat hepatitis C, even in the absence of labeling. Thus, the labeling of these treatments would likely represent a meaningful therapeutic advance since there are none currently approved for this population.

There are concerns, however, about these therapies, and about treating children with chronic hepatitis C. We know that most of the patients with chronic hepatitis C virus infection are relatively healthy, they typically feel well. The disease is insidious. It can take as long as 30 years to progress to end stage liver disease. The currently approved therapies are quite toxic, and they also have some specific concerns to children, which is that we don't really know what the long-term impact of these treatments would be, such as on growth and development.

The currently approved treatments yield relatively poor antiviral response, depending on the type of the disease the person has. It can be as much as 50 percent of the patients who are subjected to treatment who will not respond. What we really don't know, though, is, if we treat a child today, or we treat anybody today, will we ultimately translate that into reducing the rates of end-stage liver disease, and potentially hepatocellular carcinoma later on in life.

So, the questions and the issues we're interested in having some discussion on are the need for an optimal timing of studies during drug development. Can we extrapolate that the course of chronic hepatitis C virus infection and the response to treatment are the same or similar between adults and pediatric patients?

If yes, are there some pediatric patients whose disease is somehow different so that extrapolation would not be appropriate?

How can pediatric patients whose HCV infection might warrant treatment be identified?

What study designs would optimize the collection of safety, pharmacokinetic, and activity data?

Is there a need for additional studies of interferon-based therapies?

And very importantly, what approaches can be used to maximize the collection of long-term follow-up information on pediatric patients?

Then if there's time, hopefully, if you have any specific recommendations for additional research that you believe might help us better understand chronic hepatitis C virus infection in the pediatric population, we would welcome them.

This morning we're going to hear from Dr. Barbara Rehermann from the NIDDK, who will provide an overview of the immune response and some virologic information about hepatitis C.

She'll be followed by Dr. Leonard Seeff and Dr. Maureen Jonas, who will give us, I guess you can consider them, state-of-the-art talks for adults and pediatrics, respectively.

Dr. Karen Weiss will discuss some of the regulatory issues concerning our pediatric initiatives and how they apply to today's discussion.

Then we've got a couple of questions for you to discuss.

I just want to take this opportunity to thank the other members of the planning committee who put this meeting on. The left column is the Center for Drugs. The right column is the Center for Biologics. And I just want to thank them.

DR. CHESNEY: Thank you. Dr. Rehermann is going to speak to us next on the virology and immunology of hepatitis C.

DR. REHERMANN: Good morning. I was asked to give an overview on the virology and immunology of hepatitis C virus infection. Hepatitis C virus causes clinically inapparent onset of infection in the majority of patients. For this virus infection, it's characteristic that the majority proceeds to chronic infection, with moderate hepatitis, mild hepatitis over the years, but can develop into liver cirrhosis. Hepatitis C virus infection is the leading cause for liver transplantation in the U.S., with more than 4 million people infected, and also hepatocellular carcinoma as an end-stage complication of cirrhosis.

A minority of patients can recover, and it is not known which factors contribute to recovery. It has to be said, to address children's infection, that in contrast to hepatitis B virus infection, where most children are neonates that are infected proceed to chronic hepatitis, there's a surprisingly high number of children that recover after hepatitis C virus infection. This seemed to be unusual, and to date it's not known whether this is immunologically mediated or whether other factors play a role.

Hepatitis C virus is an RNA virus consisting of 9,000 nucleotides and is translated into a single polyprotein that consists of several structural and nonstructural proteins. The structural proteins form the virus core and envelope, and the nonstructural proteins are important for viral replication and amplification inside the cells.

To this virus, neutralizing antibodies have been reported, and they're mainly targeted against the viral envelope proteins, E1 and E2, that are indicated in red on the left side of the slides. Cellular immune responses recognize all viral proteins, structural and nonstructural, but we believe that an immune response against the nonstructural proteins is especially important because these are expressed early in infected cells, and T cells that might recognize these nonstructural proteins may be able to eliminate virus-infected cells before new viruses are released.

Hepatitis C virus is present in several genotypes. Up to six have been described worldwide, and also in any individual patient, there is a wide variety of quasispecies present in any patient at any given time point. So, the virus has the ability to mutate and to escape from any protecting immune response.

In the U.S., genotype 1a and 1b are the most predominant, also in northern Europe.

Some determinants for the outcome of the infection are certainly the virus itself, the genotype that infects the patients, the quaispecies distribution, the mutation rate, also the viral inoculate size. Then in terms of the host, the age at the time of infection is important.

The host determines the innate immune response. This is mediated by cells and antibodies that can neutralize the virus immediately, without being induced in the lymph nodes, and then the humoral immune response, the antibodies, and the cellular immune response. The last two points are ones I would like to address in this talk.

This is a graphic description of the immune response to hepatitis C virus. In the left lower side, you'll see the liver, and the liver is the main organ in which the hepatitis C virus replicates. It has its own immune system, natural killer and natural killer T cells are the cells that are most present in the liver. These cells may mediate an innate immune response.

However, to date, the innate immune response has not been very well defined in the liver, and it's difficult to study because we cannot isolate sufficient cells from liver biopsies, for example. So, this will probably remain an unknown for the next years.

Hepatitis C virus then induces specific T cells in the lymph nodes, probably also in the bone marrow, and these are CD4 and CD8 T cells on the right-hand of the slide, that can proliferate in response to viral antigens, expand, and then migrate to the liver, recognize infected cells there, and eliminate them.

B cells are also induced, and B cells receive help by CD4 positive T helper cells that produce certain cytokines, Th2 cytokines, such as IL-4, IL-5, IL-6, IL-10.

However, in the infected cells and for the outcome of viral infection, another cytokine profile has been described to be important, and this is the Th1 cytokine profile. It's also indicated on slides on the right-hand in yellow. This is interferon gamma and TNF-alpha. So far, every patient who had recovered and had been studied had a strong T cell response, and those T cells produced interferon gamma, TNF-alpha in response to viral proteins.

There is certainly evidence for the role of both the humoral immune response and the cellular immune response. This will be reviewed in the next two slides.

For the humoral immune response, there are clinical studies that indicate that certain antibodies have been associated with resolution of acute hepatitis C virus infection. These are antibodies against a hyper-variable region, a region within the envelope protein of the virus that has been analyzed and studied by Ziebert, et al. on a single-source outbreak of hepatitis C virus infection in Germany 20 years ago by contaminated anti-D immune globulin.

Also resolution of chronic hepatitis C has been associated with antibody titers that can be measured in neutralization of binding assay. This is the best antibody test that we have so far to determine neutralization of antibodies. However, what is not known is whether the virus is neutralized prior to infecting responsible cells because there is no infectivity assay established yet. So, in tissue culture we cannot determine whether the virus infects it or not. All we can measure is whether there are antibodies that can neutralize the envelope proteins of the virus.

In the chimpanzee model, neutralization studies and also vaccine studies have been performed with the envelope proteins. Short-term neutralization has been reported, but long-term neutralization is not possible because the virus then changes its sequence and escapes from this antibody response.

In terms of the cellular immune response, resolution of infection in the absence of antibodies has been reported, for example, in hypogammaglobulinemic patients, patients that cannot synthesize antibodies against hepatitis C virus, and also in chimpanzee studies. In these chimpanzee studies, recovery has been associated with a cellular immune response and the absence of antibodies.

In summary, to summarize several clinical studies, it has become evident that in chronic viral infection a cellular immune response is detectable but weak, and antibodies against all different viral proteins have been described. In contrast, in recovered patients, the cellular immune response is much stronger than in the chronic ones, and the antibody response is weak and can even disappear.

The study on the single-source outbreak of HCV in Germany that I mentioned before describes that antibodies may disappear in recovered patients between 10 and 18 years after infection. This has been shown in up to 40 percent of the recovered patients. So, these patients cannot be diagnosed as recovered anymore because the antibody test is the current diagnostic assay.

In contrast, T cell responses, cellular immune responses in these patients persist in the peripheral blood. In recovered patients, they are targeted against all viral proteins. They're indicated there as core, NS3, NS4, and the two NS5 proteins of the virus. In chronic patients, these responses are much weaker.

This is the same as an acute hepatitis C virus infection.

Just one example for several clinical studies that describes that patients who can normalize their liver enzyme values and can recover from hepatitis C virus infection indicated by the green bars have a much stronger cellular immune response than those who develop persistently elevated liver enzymes, indicated by the orange bars. And again, the immune response is targeted against all viral proteins.

Which assays are available to study cellular immune responses? I just would like to review that because it may be important for studies in children.

There are a large variety of assays available right now. None is used for clinically diagnostic assays, so all of these assays are based in research labs and used for research studies. There are qualitative assays which measure the function of specific T cells such as proliferation, cytotoxicity, or cytokine release. And then there are new quantitative assays such as MHC Tetramer, on the left side of the slide. And then there are several that are in the middle, like ELISPOT, or Intracell, a cytokine analysis.

I'm just going to show you two examples for the Tetramer analysis and also for the ELISPOT analysis because these are the most frequently discussed assays at this time. Also, all of the functional assays on the right-hand slide are really not feasible in children because they require a large amount of blood to isolate lymphocytes and to study their function in vitro.

So, the Tetramer analysis is a specific complex of four HLA molecules, that are indicated on the left of the slide. These are depicted in the violet color. Each of these HLA molecules presents a specific HCV peptide that we know that is recognized by T cells to those T cells. This whole complex is stained with a fluorochrome, and therefore it is possible to use the complex to stain T cells that recognize the HCV peptide and then to quantitate the number by FACS analysis.

Importantly, for any given HCV peptide, the number of T cells that recognizes this peptide is very low. It has been described as .01 to .5 percent of all CD8 positive T cells in the blood. So, this is another reason that makes this assay very difficult to use in patients, especially in infants because you need a lot of lymphocytes, a lot of blood to obtain the number of T cells suitable for analysis.

The T cells that are HCV-specific are present at a much lower frequency than, for example, T cells against other viruses. In EBV infections, this can be up to 40 percent of virus-specific T cells in the blood. Even in HIV infection, up to 20 percent. In HBV infections, it's also much more. So, in general, HCV seems to avoid to induce a good cellular immune response in most cases.

However, these T cells are present in the liver. We have detected them at a 30 times higher frequency, and all of these T cells in the liver express activation markers, meaning that they are probably activated by virus-infected cells, that they can recognize these cells, lyse them, and cause liver damage, contribute to liver damage in the liver.

So, the second assay that I would like to discuss is the ELISPOT. This is a graphic description of the ELISPOT assay. For this assay, only a few lymphocytes from the blood are required. I would estimate that analysis of the T cell response against all viral proteins could be performed with 5 to 10 mls of blood so that it may be possible to do it in adults or even in children.

In the ELISPOT assay, cells are stimulated in multi-well culture plates with individual HCV proteins, and then these plates are coated with specific antibodies to T cell-derived cytokines such as interferon gamma. If a T cell is stimulated by the specific HCV antigen, it will produce interferon gamma or other cytokines. The cytokine will bind to the plate. You can then wash away the cells, and for each cytokine secreting cell you can visualize one dot in the ELISPOT culture. So, on this slide, each dot represents one cell that produces interferon gamma in that case to HCV proteins.

In the middle, we have an HCV peptide that is frequently recognized, and on the right-hand side we have a positive control, which is the cytomegalovirus peptide. So, you can see in this case there is a strong immune response against this particular HCV peptide, and it's equally as strong as the one to the CMV peptide, and much stronger than the medium control on the left-hand side of the slide. So, this is a way to quantitate the number of T cells that produce specific cytokine in response to HCV proteins.

Which studies have been performed during interferon gamma ribavirin treatment or other viral treatments? This is a study just recently published in Gastroenterology. Two groups of patients have been studied, responders to interferon ribavirin treatment and nonresponders, depicted as the strength of the T cell response, the percentage of patients with T cell reactivity against all HCV proteins.

As you can see on the left side, indicated by the green bars, the response of treatment responders increases with time of treatment. Only approximately 10 percent of the patients have HCV-specific T cell reactivity prior to treatment in chronic infection, and then this percentage increases to up to 60 percent at the end of treatment.

In contrast, in nonresponders the percentage of responses decreases. At the end of treatment, it's only 20 percent and, in the year of follow-up, decreases to zero percent.

So, it is possible by antiviral treatment not only to decrease viral load but also to increase the immune response.

In summary, I've written what is known about the cellular immune response in acute self-limited hepatitis C. We know that a vigorous, multi-specific, and sustained CD4 and CD8 T cell response is associated with recovery from hepatitis C, all studies performed in adults so far, and it needs to be maintained to ensure that viral clearance. In individual cases, it has been shown that the T cell response may decrease up to 6 months after the first negative PCR for the virus in the blood. Then the virus may reappear and the patient may still become chronic. So, this T cell response seems to be necessary to maintain for a long time after viral clearance.

After recovery from HC infections, circulating HCV-specific antibodies may decrease. I say "may" because this is not the case in every patient, and only after long-term recovery while Th1 and Tc1 cells remain detectable in the blood for decades, and Th1, Tc1 cells are the cells that produce interferon gamma as the predominant cytokine.

So, why is recovery not present in a rare percentage of patients? What may be the factors that determine viral persistence? There are a lot of possibilities right now that are being studied and discussed. The next slide may describe a few of them.

So, for example, lack or loss of neutralizing antibodies has been discussed.

The frequency of HCV specific T cells, as I mentioned, is very low and may not be high enough to clear HCV in most patients.

HCV sequence variation, quasispecies may play a role, especially because this is an RNA virus that introduces mutations in the viral genome during replication.

HCV may interfere with antigen processing. It may not be susceptible to most T cell cytokines.

Then certain HCV proteins, such as the viral core, may alter T cell-induced cell death, may change the T cell response in general.

And certain viral sequences within the viral envelope and NS5 proteins have been shown to interfere with activation with interferon-induced enzymes that then inhibit viral replication.

So, the virus has found a way to escape from a productive T cell response, even from antiviral treatment, because it may interfere with the intracellular response of host cells that respond to cytokines coming from the outside. So, by developing mutations, HCV may have developed certain ways to escape from a strong cellular immune response.

Thank you very much.

DR. CHESNEY: Thank you very much. We'll save questions until a little bit later.

Jayne tells me that Dr. Rehermann sent copies of her slides by Fed Ex and hopefully they will arrive and we'll be able to have copies before too long.

Thank you. That was very informative.

Our next speaker is Dr. Leonard Seeff, who is going to talk about the natural history of hepatitis C in the adult population.

DR. SEEFF: Good morning, everybody. Yes, indeed, I was asked to talk about the natural history, and if I have a little time, a brief summary of treatment with pegylated interferon. I may not have that time, but I'll do the best I can.

As you know, one of the most difficult issues that we face in the study of hepatitis C is trying to define its natural history, and the reasons for this are obvious to everybody. This is a disease, as you know, that when it begins, is usually silent. Upwards of 80 to 90 percent of people have no symptoms. As you've heard and as we know, there is a very high rate of progression to chronic hepatitis, and even when chronic hepatitis evolves in the first 15 to 20 years, it is by and large silent and people are identified later in the course of the disease. And if it evolves into end-stage liver disease, it takes many, many years, longer than the life of most investigators, so it's become very difficult to, in fact, identify the long-term natural history.

So, the controversy that has plagued us is as follows. Is fibrosis progression linear, and therefore advancement to end-stage liver disease and ultimately death from liver disease inevitable as long as people don't die of something else first? Or is fibrosis progression not inevitable, but may be affected by virologic, host, environmental, dietary, other extraneous factors which may limit and modify outcome. This is a struggle I guess we've had and we still don't really have the answer to that.

The sequence of events, as I think everybody knows, is as follows. If you look at the very top here, the disease begins usually silently as the initial infection. It then progresses to chronic hepatitis, which is initially presumably first minimal and then moderate. And then eventually it progresses to much more severe chronic hepatitis, namely the development of cirrhosis and/or hepatocellular carcinoma. So, this whole process may take 20 to 40, even 50 years.

So, how do you study that?

Well, as you know there have been three approaches, and the first approach, and the approach that gave us great concern were the retrospective studies, in which people began looking at individuals with severe end-stage disease, tracked them back to the beginning of their disease to determine how long it took and, of course, beginning then with fairly severe disease, identified the fact that this was an infection that evolved into serious liver disease.

More appropriately would have been to do prospective studies, and the prospective studies would have permitted us to start from the beginning of the infection and to follow through to its end. The trouble is, we can't define the beginning of the infection in most instances, and the end takes forever, so that's a problem.

More recently there have been a series of studies, so-called retrospective-prospective so-called, or nonconcurrent cohort studies -- and I'll summarize these -- which have given us a little different perspective on this infection, a little different from our initial studies, which were those data derived from the retrospective studies. I'm going to quickly summarize these as quickly as I can.

So, a quick summary of the retrospective studies, and I've listed just a few at the bottom here, a couple from Japan, from the United States, from Germany, and another one from the United States. Putting all these studies together, the number of patients that were studied was somewhere between 70 and 840. The intervals from exposure in the retrospective studies were listed as 9 to 29 years.

As you can see, there was a very high rate of development of cirrhosis; 17 to 55 percent of these studies were reported to have developed cirrhosis over a period of 20 years. I forgot to mention that in that initial slide the usual view that is held is that cirrhosis develops in about 20 percent of people at the end of about 20 years, approximately. So, here we see much higher rates of cirrhosis.

There was a high rate of development of cancer and liver-related death.

So, these studies, which were extremely important in defining the potential severity of this disease, were somewhat concerning, indicating that there was a very high rate of evolution to cirrhosis and to cancer.

As I've said many times, one of the problems with these studies is that we began with individuals who are, in many instances, were already ill, and what we missed out were those who never got to the tertiary care centers where these studies were done.

Well, what about the prospective studies? Well, I list the prospective studies here: DiBisceglie, Koretz, Mattson, Tremolada.

One of the problems with these studies is they were relatively short. They did not exceed 15 to 16 years. The number of patients studied were 61 to 135. Intervals from exposure, as you can see, was 8 to 16 years. In these studies the evolution to cirrhosis appeared to be much less; 16 percent was the top number. And the development of cancer was lower. Liver-related death was lower, but of course the problem with these studies was that they were short, and indeed, we believe that it takes 20-30 years before you end up with liver cancer.

How do you then get the information that you need in order to track the outcome?

Here are the so-called retrospective-prospective studies, and I'm going to go through each of these in turn. I think if you look at the right-hand side over here you'll see that, by and large, the development of cirrhosis in these studies, for a variety of reasons we'll talk about, seem to be lower than some of the earlier studies. Liver cancer is somewhat lower, and liver death is somewhat lower.

Let's start going through. I thought what I would do is to break them down into various types of studies that have been done.

There have been two studies involving young women. Both of these are immune globulin contaminated follow-up studies. Dr. Rehermann has mentioned the study from Germany, Dr. Wiese. I'm just going to show you one slide from each of these, reminding you that we anticipate a 20 percent rate of cirrhosis at the end of 20 years.

So, the first study from Dr. Kenny-Walsh and her group in Ireland, in which some 363 women were tracked who had, 17 years earlier, received contaminated anti-D immune globulin, came out with somewhat surprising data. This was really quite a surprise when it first came out. It showed that, indeed, 20 percent of this particular cohort had not developed cirrhosis. 2 percent showed cirrhosis. There was 10 percent with bridging, which is a serious problem, and could well evolve into cirrhosis over time. But here we have a 20-year follow-up with a lower rate of cirrhosis, and that was somewhat of a revelation.

Well, it was followed by a study from Germany, Dr. Wiese, et al. Again, this was a large number of women, 264 livery biopsies in women who, 20 years earlier, had been exposed to hepatitis C.

Here we use the Ishak Fibrosis Score, 0 to 6. 5 and 6 represent cirrhosis, 3 and 4 represents fibrosis, and less than that is very little fibrosis.

So, here again we see that almost none of them had developed cirrhosis. The numbers show a very low rate again, quite similar to the data that we saw from the Irish study. So, certainly it appeared that in young women, at least, evolution to cirrhosis at the end of 20 years was a little lower than had been anticipated.

What about studies in children, which is important over here? I don't know too many. Perhaps Dr. Jonas will tell us more about the natural history in children.

This is the one well-known report that appeared in the New England Journal from Vogt, et al. This was a study of young children who had undergone cardiac bypass surgery in the first three years of life, had been transfused, and they followed them up some 20 years later. They started off with 458 patients, and 20 years later they went back to the original samples. 14.6 percent were anti-HCV position.

What was interesting, and it's a point that again Dr. Rehermann has made, and I'll come back to that later, is that when they followed them up 20 years later, 45 percent of these youngsters were now RNA negative. They had spontaneously lost virus. That was a much higher rate of spontaneous loss than we had usually thought to be the case, which was about 15 percent.

Well, increased ALT was found in one, with congestive heart failure. Liver biopsy was done in 17. Fibrosis, 2. Both happened to have congestive heart failure. Cirrhosis in one, and this was a child with HBV, so again, there was a very low rate.

I also happen to have some data here that you might be interested in that I got from Jay Hoofnagle on Friday about a split database on pediatric liver transplantation from June 2000. This is a study that's being supported by the NIH. This is a study that covers transplant centers, 29 participating centers since 1995.

So, far they have data on 1,144 children who were listed for transplants. 12 had cirrhosis due to hepatitis C, 1 percent, and 1 had subacute hepatitis C. Of these 1,144, 706 children underwent transplant, of whom 6 had hepatitis C, or 0.8 percent, 5 with cirrhosis, and 1 with subacute hepatitis. So, transplantation in children is not very common for hepatitis C. That doesn't mean to say that 20 years later that this becomes a problem once they become adults, and that's the big issue that we face.

So, now let's go quickly to a series of studies in transfusion recipients. These are studies that I was involved with. Blaine Hollinger here has been involved helping me out with these studies, Harvey Alter, and so on. These are long-term studies. We reported the first time in 1992, and then we actually have a paper, which I say in preparation here, that was reported in Hepatology a couple of months ago.

Just a quick summary. This was a study in which we went back to five prospective studies that had been done in the 1970s in which patients were diagnosed as having hepatitis C on the basis of evolution of abnormal enzymes after transfusion. We put all the studies together. They all used, more or less, the same criteria. We have been following the individuals who developed transfusion-associated hepatitis C for the last 25 years, matching them 2 to 1 with individuals who are very carefully matched, transfusion recipients, and didn't get hepatitis C.

What's happened to them?

Well, in our first report at 18 years, all-cause mortality was no different. All-cause mortality, 41 percent versus 42 percent, and 23 years later, all-cause mortality is no different. Now that doesn't mean to say that that makes hepatitis C a benign problem because these were, after all, adults who were in their late 40s who were transfused for a reason. What this really tells you is that people who are transfused have a high risk of dying, not necessarily of viral hepatitis.

If you look at viral hepatitis on the right-hand side, it was 2 percent among the cases versus 1.3 percent among the controls, and then 23 years later it had gone from 2 to 3.1 percent, whereas the controls stayed the same. So, there is a slight increase in mortality from liver disease. These are 23 years. We have 25 years' data. It's about the same, about 3.4 percent at 25 years. It does indicate, then, that transfusions are a serous thing to receive because that's what often kills you. Many of these people have undergone cardiac bypass surgery.

What I think was interesting -- and also it speaks to the issue that Dr. Rehermann has spoken about -- is what happened to those individuals who had transfusion-associated hepatitis C, were positive, and did not in fact die? What happened to them some 25 years later?

Well, we find that 25 years later 77 percent remained viremic, antibody and viremic. But 17 percent are nonviremic, and this has been tested many times, including in Blaine Hollinger's laboratory. They are anti-HCV positive, but also in keeping with what she told us, 7 percent have lost all markers. These were people whom we saw develop hepatitis C and yet 25 years later are negative for virus and are negative for the antibody. No evidence that they'd been infected.

What this tells me is that the total number of people in this country who have been infected are, in fact, higher than the number that we have accepted now, which has come from NHANES of about 4 million people. There may be more people who have been infected and who lose all evidence of virus. Here we see 24 percent of people have lost virus and not the 15 percent that we used to think about.

In this next very complicated slide, which I won't go through in detail, what we did was we tracked each of these groups to see how many of them ended up with cirrhosis. Not all of these people were biopsied for a variety of reasons, but based on the biopsies we did do, we calculated somewhere between 15 and 17 percent of people did develop cirrhosis. So, here we are closer to the 20 percent that we had anticipated to be the case.

There's another series of studies in injection drug users. There's well-known study that comes out of Hopkins. Dave Thomas and his group have been looking at a large number of drug users. Dr. Schwarz, who has been involved in that, is doing some studies herself looking at this particular group. Let's see the data.

This is 1,667 anti-HCV-positive drug users who have been followed for a median period of 8.8 years. It turns out that 2.4 percent of them ended up with end-stage liver disease. That's not small. On the other hand, 10 times as many, 22.4 percent, died of non-liver disease. That means drug overdose, trauma, HIV, and so that more people were dying as a result of other causes than of liver disease, so that doesn't detract from the fact that liver disease is important.

I might just mention -- I don't have a slide -- I am doing a 25-year follow-up study now in a VA cooperative study that we did 25 years ago in which we studied 600 drug addicts, and we followed them now 25 years later, wanting to see what happens to hepatitis C. Well, it turns out that when we studied them initially, they were all HIV negative. Now it turns out that 60 percent have died. These were young men 25 years ago. 60 percent have died. Our control group is 6 percent, so there's a 10 times higher mortality.

And what's the cause of death? In about 80 percent it's HIV. The the original samples were negative. They came in just as HIV was evolving. Unfortunately, they lived through the period of time where treatment had not yet become effective, and they died of HIV. We're struggling, in fact, to determine what happened with hepatitis C because it's a big problem.

There's one more slide from Dave Thomas' study. When he did liver biopsies in 210 patients, 2 of them had cirrhosis.

Well, there have been a couple of interesting so-called community-acquired hepatitis C. I've learnt a little bit more now. This is a study that we did that I will quickly report on, and I didn't bring slides on this one.

We happened to come across, and people may know this, almost 9,000 blood samples that had been drawn between 1948 and 1952 at an Air Force Base in Wyoming. Dr. Ramelkamp was at this place at the time. He was an expert in strep. There was an outbreak of streptococcal infection. He drew blood from all these people, tested it for strep, sequestered the samples, sent them back to this hospital in Cleveland, and it sat there for 45 years. And we learned about it about five or six years ago and decided here was a wonderful opportunity. In fact, it's giving us an opportunity to do a number of studies which we are in the process of doing now.

But one of them was to go back and test for hepatitis C. To my knowledge, I don't know of any data that take us back to 1948 with respect to hepatitis C. But we did test, and we found using the third generation test that 34 people were positive. Now, that's not a heck of a lot. But remember, these were so-called young, healthy individuals who entered the Air Force, and you assume that they are low-risk and this is what you would expect in a blood bank.

Well, we then did the RIBA test on them, the third generation test, and it turns out that 50 percent were positive. The others were either indeterminate or negative. So, we decided to focus our attention on these 17 people. A small number, but this is the earliest, as far as I know, reported evidence that hepatitis C has been around, and I believe that hepatitis C was around since the Second World War, probably in low level. Then when the drug culture began to flourish, it probably increased, and that's why we're dealing with a big problem now.

So, what's happened to these 17 people 50 years later?

What's happened to these 17 people? 7 have died and 10 are alive. Of the 7 who have died, 1 has died of liver disease, and I'll show you what's happened to the 10.

Here are the causes of death in 6 of the 7. We could not find the data on the seventh person. One died of alcohol abuse, one of trauma, one of heart failure, another of heart disease, multiple myeloma, and one patient died of viral hepatitis and chronic liver disease 42 years from the time of the original phlebotomy.

Now what about the people who are living? This is not an updated slide. But what we have managed, of the 10 people that we know to have been infected and alive, 2 of them we cannot find. That leaves 8. One of those 8 has had a stroke and the family will not permit us to see that person. The other 7, we have seen all of them. This shows you 6 of them, and I don't have the seventh one in, but I'll quickly summarize by telling you that every one of them are still anti-HCV positive. All but 2 are RNA positive, and 1 has the highest level of RNA I have, frankly, ever seen. Almost all of them have still got abnormal enzymes. We didn't do biopsies for a variety of reasons, it was ethically not possible. So, I would love to see those but we can't do them. So, we used surrogate markers, albumin and platelets.

The only one who had low platelets was this one, of 110,000, 3.5 albumin. This happened to be a very heavy alcoholic, and so he had a huge, long history of alcohol, as well as hepatitis C. I didn't know what caused this. We have now spoken to these people, and in fact 3 of them admitted to using drugs prior to entering the Air Force in 1948. So, I think they've actually been infected for more than 50 years.

Now, this is a vignette. This hardly speaks to the whole issue of what the natural history of hepatitis C is. These were young, healthy men. It's a different story and we don't really say that this is what normally happens. But here is evidence that you can certainly live with this disease for 50 years. None of them were treated. Frankly, when I spoke to all of them, none of them have actually clinical evidence. Two of them have mild hepatomegaly. The alcoholic has splenomegaly and I think probably has cirrhosis. But this is 50 years.

So, the natural history of hepatitis C. Do all persons with HCV infection have the same long-term outcome?

I think the answer is that it is not true that everyone has the same outcome.

We've heard that age is a very important determinant.

Gender may be possible, although now some evidence suggests that that may not be the case, but I think it may play a role.

There's a very interesting story developing about African-Americans, yet to be determined. We have a big study that's coming up at the NIH to look at this whole issue about the treatment and natural history of the disease in African-Americans.

Obviously we've heard about genetics.

I believe that there's a difference in the outcome depending on how you get the disease. If you have transfusion as the basis, you have to worry about the reason for having been transfused in the first place. If you're an IV drug abuser, you have to worry about the fact that you co-infected with HCV.

Viral genotype clearly is extremely important, as we know, as far as treatment is concerned, and may play a role in outcome.

And then there are certain co-factors that I believe we still need to spend more time looking at. We know that alcohol is an important issue. Smoking may play a role, diet may play a role. Environmental factors may play a role.

I am personally intrigued by the fact that the death from hepatitis C in Japan is so much more commonly a result of liver cancer than it is in this country. I've just reviewed another paper in which there was a long-term follow-up of hepatitis C in Japan, and of those people with hepatitis C who died, 68 percent died of liver cancer. Now, that's not what we're seeing in this country, regardless of what we think. It's much higher there. The question is why.

I happen to believe that there may be environmental or dietary factors that may play a role. I don't know this, but I believe that that's an area that we may need to look at in more detail.

So, let me show you what we've done over here. Harvey Alter from the NIH and I happened to write a review article, and we tried to project a lifetime outcome based on our review of the literature. Now, this is obviously pure fantasy, but it's not pure. Nothing that we do is pure, certainly not Harvey.

So, we started off with 100 patients with acute HCV infection, and we're making the assumption that about 20 percent recover. As I'll show you and as we've already heard, it may be higher than that in some populations, leaving 80 patients with persistent infection.

We think that if you follow these people out, 30 percent will have stable chronic hepatitis, and by this we are now talking about histology. That is, if you do liver biopsies, you're going to see less than 3 out of 6 Ishak fibrosis. 40 percent, variable progression. That means individuals with bridging fibrosis, and 30 percent of this group, which is 20 percent of that, with cirrhosis. Then you treat those people, as we are now doing, and this was before we have the pegylated interferon, and this may get better. We say there's a sustained response rate of about 35 percent, or 20 patients, leading to treatment failure in 65 percent.

So, what we estimated is that there's a favorable outcome in some two-thirds of individuals, and a potentially unfavorable outcome in about a third.

Now, how do we choose these, and how do we find out who falls into which category? That's our big problem. Remember, that if we do have 4 million people, and a third of those have a potential for severe outcome, that's a lot of people, and that's why we're seeing so many people ending up in the liver transplantation, and that's the reason for our panic and concern about trying to treat these patients.

So, let me just quickly summarize the data demonstrating a higher than expected rate of spontaneous recovery. In our study, 24 percent of individuals who are transfusion-associated have spontaneously recovered. If you look at the NHANES data from Miriam Alter, 26 percent have recovered. Here are the data from leukemic children; 29 percent of her people have recovered. The Kenny-Walsh and Wiese study, the contaminated Rh immunoglobulin, 45 percent have recovered. The study from Germany, 45 percent have recovered. And in the paper that I didn't report to you from Australia, 46 percent have recovered spontaneously. The question is when and why, and that's why we pay Barbara to help us find out why they recover.

So, that finishes my talk on the natural history, and if you want me to proceed, I've got about four or five slides on treatment. If that's too late, I can come back to that.

DR. CHESNEY: You go ahead, please.

DR. SEEFF: All I'm going to tell you about are the pegylated interferon studies. I think we're all aware of the fact that we're moving into a new era, and the era is going to be pegylated for the immediate future. These slides, by the way, were made by Jay Hoofnagle for a presentation he was giving, and when I told him I was coming here, he lent them to me. They're just very brief.

The first study was reported in the New England Journal in the year 2000, an international trial using PEG-interferon alpha-2a. This was 531 patients randomly assigned to receive 180 microgram PEG-interferon weekly versus 3 to 6 million units of standard interferon three times a week for 48 weeks. The endpoint of virologic response was to reach HCV RNA negativity 24 weeks after stopping.

Here you see the striking difference between standard interferon and pegylated interferon. The top bars show you the end-of-treatment response. The lower bar shows you the sustained response. So, it was 39 percent versus 19 percent in individuals who received the PEG-interferon versus the standard interferon.

The next slide is the study which focused now its attention on individuals with cirrhosis or bridging fibrosis, and this was again an international trial, 271 patients who were assigned to receive either 90 or 180 micrograms of pegylated interferon weekly versus the 3 million units standard interferon, and again, the endpoint was loss of virus at the end of 24 weeks after stopping treatment.

Here we see that in the standard interferon, the end-of-treatment response was 14 percent. When we got to the pegylated interferon, there was no difference in the end-of-treatment response between those who received 90 and those who received 180, but there was a significantly higher rate of sustained response, 30 percent versus 15 percent versus 8 percent. So, those were the two reported studies.

There is also a large ongoing study that was reported at the AASLD meeting by Dr. Michael Manns, and I don't have the data other than in abstract form, but we took some information at the meeting and this is a summary. This is 1,530 treatment-naive patients with compensated chronic hepatitis C, with RNA in the serum and raised ALT, stratified by genotype and cirrhosis. Three arms, 48 weeks of therapy. They received either interferon alpha and ribavirin, 1 to 1.2 grams per day, PEG-interferon, 0.5 micrograms, plus ribavirin. As you can see, the dose over here, and then PEG-interferon 1.5 plus ribavirin.

Here you see the standard versus the PEG-interferon. This is the PEG-interferon 0.5 versus the PEG-interferon 1.5. There's 47 percent sustained response, 47 percent sustained response, 54 percent sustained response. It was significant at the p .01 level.

The next slide shows you what happened over here. Here is the end-of-treatment response. The end-of-treatment response appeared not to be different, but the sustained response was different. The relapse rate was much less. So, there was a significantly higher response rate among those who received the PEG-interferon 1.5.

There was obviously a dramatic difference between those with genotype 1a and 1b versus genotypes 2 and 3. As you can see, the standard went from 33 to 34 to 42 percent in the genotypes 1b, a dramatic response in genotypes 2 and 3, 80 percent plus. I think now we're reaching the point where this is virtually a curable form of hepatitis C if you have genotypes 2 and 3, and I hope that that will get better as time goes on and reach 100 percent. In fact, it may have reached that already.

What was very interesting was that body weight played a role. The higher the body weight, the less the response. As you can see, there were people who were more than 85 kilograms who had a much lower response rate. So, body weight is now important with respect to the likelihood of response to treatment, and it requires us then to consider the amount of interferon that needs to be given.

What was also interesting was an effort to look at the ribavirin dose, and they cut it, I guess at 10.6 micrograms per kilogram. Is that about 800, Karen? 800, right, okay. So, here we see that the difference between those who received lower doses, the risk of those who received slightly higher doses.

Now, what about the adverse effects? Well, here we see early discontinuation. About 14 percent of all groups had to discontinue, and there was a somewhat higher rate of dose modification in people who received the higher dose modification. So, it's obviously more effective but it does come with obvious side effects, which you will be discussing in more detail.

Let's skip this slide and just go to the final slide to show you the changes that really have taken place and are pretty remarkable, I think. We began with interferon for 6 months, 6 percent. Interferon for 12 months, 16 percent. Interferon plus ribavirin for 6 months, 34 percent. Interferon plus ribavirin for 12 months, up to 42 percent. PEG-interferon about the same, 39 percent. And PEG-interferon with ribavirin, up to 54 percent. So, clearly over the years there has been a remarkable improvement in the response rate to treatment. I guess that's where we are likely to be in the very immediate future as far as treatment is concerned.

Now, your problem is to decide what happens to children who are infected once they reach 20 and move on to 30 and 40 and 50 and 60. There's no answer to that. I guess the question is, I think we all do believe that the older you are when you're infected, the more likely the disease is to progress.

Now, what happens if you're infected at age 5 and you get to 50? Do you then assume the circumstances that occur if you're infected for the first time at 50 and progress thereon, or does this remain as a flat curve rather than one that goes up? I don't know how to answer that question, and that's a quandary that I guess this committee has to face.

Thank you.

DR. CHESNEY: Thank you very much. Very informative.

Dr. Jonas, from the Division of Gastroenterology at Children's Hospital in Boston, is going to give us all the answers about hepatitis C in children. Thank you all in advance.

DR. JONAS: Thank you all for this opportunity to share this important issue with you. I know for all of us pediatricians around the table, it's rather gratifying to hear our adult colleagues talk about weight-based dosing in medication, and maybe it's important. But eventually they caught up.

(Laughter.)

DR. JONAS: What I'm going to do in these next 20 minutes is sort of touch on some of the issues you've heard discussed on hepatitis C in children. Our data are nowhere near as mature as things you've heard from Dr. Seeff this morning, unfortunately, but maybe with this committee's help we can get some direction about how to pursue your learning what the important topics are at least.

These data I actually extracted from Dr. Alter's paper and from the NHANES data that you've heard alluded to earlier, and this is just looking at prevalence of antibody to hepatitis C by age in the United States. You can see that most cases are certainly not childhood cases. The two pediatric age groups are described here, and the prevalence of this antibody is quite low, less than .5 percent of the population have been infected or are infected with hepatitis C.

If you look at it a different way, the same data, just shown a different way, but the proportion of infected people that are in the pediatric age groups is quite small, so we're not talking about huge numbers of patients. When I tried to do the math to extrapolate this out, it came out to about 250,000 children in the United States infected with hepatitis C in this one survey alone.

Dr. Alter is quick to point out that the incidence of new cases is rapidly decreasing, and the reasons for this are not totally known. I start to think about that, and probably the incidence of new cases in children is not rapidly decreasing in parallel because I think that, as you'll hear, the most common way children will be infected now will be perinatally, and there's no reason to think that all of a sudden infected women of childbearing age will stop having children. So, I'm not sure that the general gist of decreasing incidence is pertinent to children.

So, which children are at risk? Well, these I think have been defined. Certainly children who've had recurrent blood or blood product transfusions over their lifetime, and the risks there are obviously in the pre-donor screening era, but children with hemophilia and thalassemia have prevalence rates that you see listed there: 80 percent of hemophiliacs in the pre-recombinant factor era; thalassemic children have a very high incidence.

Obviously, blood or blood product transfusion, even 1 prior to 1992, and we all have many of these children in our practices who had one blood transfusion. But certainly those who were exposed to a large amount of blood, either treatment for acute lymphoblastic leukemia, cardiac surgery, these prevalence rates are about what are quoted in the literature in more than one study, somewhere in the 4 to 10 percent range. Children who have had orthopedic surgery, care in the neonatal intensive care unit with a lot of blood exposure prior to 1992. So, obviously these children are at least 9 years of age now.

Adolescents with the high risk behaviors that allow adults to contract hepatitis C are certainly at risk.

And then I think what is the most common and important category for us to spend some time on is children born to HCV-infected women.

This is a study we actually did some number of years ago in Boston to try to get a sense of are there a bunch of kids out there infected with hepatitis C and we don't know about it, and they have no risk factors that we know about. This was at the time when we talked about a lot of adults with no risk factors, and we know now that's sort of a myth as well.

What we did is we were doing a hepatitis B vaccination study, so we had a lot of kids involved with questionnaires and blood. And they were in our adolescent clinic at Children's Hospital and they were in a local high school-based clinic. We did some serologic testing. We looked at them across the board for socioeconomic group. They were very scattered, whether they had insurance or not, and so forth.

So, I don't think in pediatrics this is a disease of kids with no risk factors and they're out there in the community and there's this big pot of them out there. But I think, on the other hand, pediatricians need to know what the risk factors are and who to test.

I want to spend a few moments on perinatal transmission because I think, as far as pediatricians in general, this is where we have to concentrate a lot of our thinking and our efforts.

I've extracted data from these papers only to include women who were HCV viremic, not just antibody positive, because people who are antibody positive but not viremic do not transmit hepatitis C to their neonates, and HIV negative for the purposes of this slide.

If you look at the early studies, it seemed a little bit high as far as percentage of transmission, but if you look at the later studies with larger numbers of women, hepatitis C-infected, HIV negative, the perinatal transmission rate seems to circle somewhere around 4 to 5 percent. I think that's probably fair.

I wanted to bring to your attention this study, however, and the next couple of papers, about about the dynamics of perinatal hepatitis C transmission because I think they're important.

This is a study reported last year also in Hepatology. In this study, 266 infants were born to hepatitis C viremic women. I will point out to you obviously all infants are antibody positive at birth because there is passive transfer of antibody. This is an IgG antibody, so testing for antibody in the infants, at least in the first year, 15 months, is not very helpful in understanding this issue.

What these investigators did was look for hepatitis C RNA at birth by sampling cord blood. 18 of the 266 were positive, indicating that there was already maybe some viremia at the time of birth, and most were negative. But if you look at 4 months of age, the vast majority of these infants had cleared hepatitis C RNA. Were they truly infected? Qas it a transient viremia? It's not really analogous, for example, to HIV, I think. But 2 remained positive.

But look here. Of all of these infants who were negative in cord blood, 6 more were positive at the age of 4 months. That gave a total of about 8 perinatally infected infants. It gives you somewhere around that 5 percent, so it makes sense. And of the 8 that were followed, all of them remained infected at 18 months.

So, the transmission may occur a little bit in utero, but probably is somewhere between birth and 4 months when this happens, or at least can be detected in the newborn. I think that's important for understanding when you talk about intervention, or when to make this diagnosis.

If you look at risk factors, which mothers transmit hepatitis C to their infants, it's been recognized a long time that co-infected mothers, HIV positive mothers, have a much higher increased incidence of transmission of hepatitis C. And importantly, it's not necessarily associated with HIV co-transmission, so their infants will get hep C infected but not HIV infected.

Looking at other sort of risk factors that might increase this, there is some data that were presented here from CDC where prolonged rupture of membranes was a risk factor increasing the likelihood, and they chose a 6-hour cutoff to make that designation. The use of internal fetal scalp monitoring makes sort of sense. Pricking the skin of the neonate with maternal blood increased the likelihood. In most studies, mode of delivery -- i.e., vaginal versus C-section -- has not been a demonstrable risk factor.

Just a word on HIV co-infected women. Perinatal hepatitis C transmission, you can see the significant increase in the likelihood of hepatitis C transmission from HIV co-infected women.

On the other hand, the Italian study that I showed you, if the HIV is very well and aggressively treated and the HIV viral load is low in these women prior to delivery, this transmission rate actually goes back down towards the 5 percent again. So, aggressive treatment of the HIV in the mothers can decrease the likelihood of perinatal hepatitis C transmission.

This is a rather intriguing study that came out last year. And I think it might give us a little bit more insight, once again, looking at perinatal hepatitis C transmission and the fact that it probably occurs around the time of birth and not before birth. They examined a large number of mother-child pairs, 441, and once again, the overall rate, 6.7 percent, pretty consistent with what I've told you from other studies. Once again, a much higher transmission rate from HIV co-infected women without concurrent HIV transmission.

Most of the newborns that were eventually proven to be infected with hepatitis C were negative by PCR testing at birth. Once again, if you examine infants at birth, this is not the way to make that diagnosis.

They looked at mode of delivery and they separated them out a little bit. Looking at vaginal delivery versus C-section, in general there was really no difference. But if you took emergency C-section and elective C-section, this is the intriguing part. There may be a difference here. You can see the odds ratio.

And the postulate was that these women, because an emergency C-section had earlier rupture of membranes, here in elective C-section the membranes are ruptured right at delivery, so maybe once again saying that there's something around after rupture of the membrane when this transmission occurs, and something for us to think about as far as prevention.

So, these are current recommendations regarding perinatal hepatitis C transmission. These may change as our knowledge increases, but right now it is not recommended that all pregnant women be tested, as they are for hepatitis B. On the other hand, targeting testing, which means that obstetricians need to know who should be tested, women obviously with a history of IV drug abuse, women with a history of blood transfusion prior to 1992, women with an unexplained ALT elevation and so forth, or as I say, any woman who requests to be tested typically should be tested.

At this point elective cesarean section to prevent hepatitis C transmission is not recommended. I think more data needs to be accumulated regarding that, but certainly there is the hint that maybe we should consider avoiding internal fetal monitoring or prolonged rupture of membranes in that setting.

A word about breast-feeding. It's very difficult to tease out the additional contribution of breast-feeding to perinatal hepatitis C transmission in most of the studies. There always are a number of women who breast-feed and some of the infants do or do not become infected. But if you look in breast milk of infected women, it's very difficult to find hepatitis C. Most studies show that it's either not there or there in very, very trivial amounts. So, at this point there are no hard data to indicate contraindication of breast-feeding that setting.

What's recommended now is that infants of hepatitis C infected women be tested after 15 months of age for the antibody because at this point maternal antibodies should be gone and an antibody is probably helpful at that time and can be pursued with further testing if positive.

Now, clinical features. How do these children look? Well, you all know that really you cannot pick them out in a crowd. Acute infection is rarely symptomatic in children, and chronic infection is even less symptomatic, I believe, than in adults. First of all, chronic fatigue, which is considered the major symptom in adults, is very difficult to assess, I think, in children. And extrahepatic manifestations, immune complex disease, kidney disease, vasculitis, dermatologic manifestations are also much less common in children than adults. So, this is an illness or a condition, if you want to say, without any symptoms. I think targeted testing and recognition is very important for those of us who want to identify and take care of these children.

Natural history. This is the hardest part, I think, as Dr. Seeff alluded to. He has some of the same questions, I think. Does fibrosis progress linearly? That's what we all worry about as hepatologists, is how much scar tissue is in their liver, because when you have fibrosis and you get cirrhosis, you start having all of the bad complications. Actually that may be a topic for discussion of the committee: Is that the only thing we care about with hepatitis C in children? But certainly from a medical point of view does fibrosis progress linearly?

What are the risk factors during childhood that may contribute to progression of disease? I think as you heard earlier, some of the risk factors in adults have been identified.

What is the role of underlying disease? Remember, these children were either transfused for an underlying condition, or what is the role of mode of acquisition? In other words, is the natural history of perinatally acquired hepatitis C different than transfusion-acquired in children?

Natural history studies we have thus far are basically cross-sectional cohort studies. People are trying to do prospective studies, but they go out a few years. As you've just heard, a few years is nothing in this disease, and we really need to do them over decades.

Looking at just a few studies of natural history transfusion acquired hepatitis C in children, I've just summarized a few of them here and I'll walk you through this slide. This is the study that Dr. Seeff alluded to that was presented in the New England Journal, cardiac surgery. But there are a few others here.

You can see that children acquired hepatitis C from transfusion in this percentage. So, here almost 50 percent of these leukemic children became infected with hep C; 15 percent after heart surgery in this German study.

But if you look at follow-up, and again look at the duration of follow-up, look at the length of time for follow-up, there is a drop-off. So, sometimes as many as a third to a half of the children are no longer infected when looked at 10 to 20 years later. What does this mean? It's very difficult to know.

I notice there are several panel members from St. Jude's. This is actually a study that was published last year from St. Jude's, and they tried to look at the importance of hepatitis C infection in their population. They looked, first of all, at children who were transfused and had died, and they were able to study 346 of them. 3.5 percent had evidence for hepatitis C infection. Then they went to look at the cause of death in these 12 children. Interestingly, one died from liver failure 9 years after his original cancer treatment, and there were two deaths from hepatocellular carcinoma, which was not their primary malignancy, 25 and 27 years later. So, of the 12 deaths in the hepatitis C group, 3 of them may have been related.

Obviously that's retrospective. It's difficult to take that information and go forward.

They looked at their transfused survivors of the 6.6 percent who were infected with hepatitis C. Of those, roughly half had undergone a liver biopsy at some point. These were all different time points after their transfusion and their cancer therapy. But all of them were abnormal. 9 percent, which is only 3 patients, had cirrhosis, and you can see 10, 20 and 30 years after treatment. So, some children who get transfusion-associated hepatitis C have a bad outcome. It's the minority, but there it is.

This is a complicated, messy slide but there's really no data on it of any importance, so it doesn't matter. But this is what there is regarding the natural history of perinatally acquired hepatitis C. There are very small studies with pretty much short duration follow-up. These things are hard to get your hands on, but you can see most children who become infected, followed for 1 to 2 to maybe 7 years, remain infected with hepatitis C. That's really all you can say from these prospective studies that have been done because we only have a few years of data.

I put on here a couple of anecdotes because they are striking anecdotes, and these are the patients I think that are going to concern all of us, that we have to deal with. They are anecdotes, but that's what I have.

These are in my practice. Two children who were perinatally infected developed cirrhosis by age 11 and 13. One has had a liver transplant. She had membranal proliferative glomerulonephritis as well. The other is now awaiting a liver transplant. She has decompensated cirrhosis. She's several years older, though. I should say she's almost 18. These children are reported in a response to an editorial describing the "benign" natural history of hepatitis C, where three perinatally infected children had decompensated cirrhosis very early in life.

I know about another anecdote -- I'm sorry to share only anecdotes with you, but that's what I have -- about an 18-year-old girl who developed this perinatally who now has hepatocellular carcinoma and cirrhosis. So, there are a few that become sick with this disease.

Just to show you that it probably is the same disease as in adults, just looking at histopathology. I didn't bring slides to show you liver biopsies, you'll be happy to know. But I will show you that if you look at the major histologic features that have been recognized in hepatitis C -- sinusoidal, lymphocytes, lymphoid aggregates, steatosis, bile duct damage, and so forth -- you'll see that if you put a few studies together, the percentages of these findings are not all that different in adult and pediatric studies.

Bridging fibrosis is only described in one of the adult studies I reported here, but is seen in children.

Then interestingly, the rate of cirrhosis. Now in adults, depending on which study you look at and where you start in the natural history, as you've heard today, it can be very uncommon if you start early, or it can be very common if you start late natural history studies. There are children in some studies with cirrhosis from hepatitis C during their pediatric years.

So, how do you interpret this? Well, I think that by saying the features are generally the same as those seen in adults, it probably is the same disease and has a very similar pathogenesis in children, if I can make that inference. And interestingly, in two of the major studies, our own included, looking at these histopathologic features, where a mathematical equation was tried to be generated, there was an association between extent of fibrosis and age and duration of infection. I don't want to say that it's linear, but there's definitely some sort of association. So, there is progression over time.

So, hepatitis C in children. Tthe natural history may be different in children infected by transfusion versus those infected perinatally, and we may need to keep that in mind if we're designing trials. It may be different according to the underlying disease by which the transfusion was indicated. I think at this point it's fair to say that the natural history of hepatitis C is benign in the first two to three decades in most instances. But a few children have very aggressive disease and we do not know the associated factors for that, and we certainly don't know anything about the third decade and beyond in children.

Now what about treatment? What do we want to do with hepatitis C therapy? Well, sustained normalization of ALT sounds good, but I think many of these children that we detect after perinatal transmission or after transfusion associated disease, 10 years later, have normal ALT already. So, that is not always an important outcome variable, I think.

I think sustained virologic response, as you've heard alluded to before, not having hepatitis C in the serum 6 months after any kind of therapy is probably the gold standard that I think is used in most studies.

Improvement in hepatohistology. We need to think about that a little bit. I've showed you that children do have fibrosis and inflammation. The scores in general are lower. We talk about histologic activity scores as numerical sort of variables, and in children they're lower. So, I think it's going to be very difficult to show changes in low numbers, in small numbers of children. Obviously, it makes medical sense to look at that as an outcome variable, making inflammation less. Obviously, we do want to decrease the long-term risk of cirrhosis and hepatocellular carcinoma, which are life-threatening to these children later in life.

What do we know about interferon monotherapy? Well, because there was no group such as this, and no laws, such as the one you're discussing, five or seven years ago, we really have no large randomized controlled trials. So, when we start talking today about newer therapies and what to compare them to, I'm going to show you a little bit of information about what we know about plain old interferon monotherapy. We have nothing of any substance that you can dig your teeth into.

The trials that have been reported that I'm going to show you have very heterogeneous patient groups. Different dosages of interferon were used, different types of interferon, and different lengths of treatment. So, it's very difficult to make definite implications from this.

Here's a potpourri of interferon monotherapy trials in children, and I'll briefly walk you through this. I didn't put all the data because, again, different doses of interferon, different lengths of therapy. You can see the kinds of patients: only transfused patients, mixed patients, leukemia patients, only thalassemia patients, not all of them were pediatric. Some of them repeated some are the same patients. It's very difficult to make a lot of sense out of the details. There's only one randomized, one control trial in all of these trials.

But I did want to point out the bottom line here, which even though the trials are all done in very different ways and the patients are all different kinds of patients, if you look at this one outcome variable, sustained virologic response, i.e., no virus in serum, 6 months after the end of therapy, you seem to get a number that's significantly higher than what is reported in adults with interferon monotherapy. This is plain old interferon, not long-acting interferon.

Again, these numbers are small and I don't want to put a lot of stock in the absolute numbers, but they are fairly consistent and probably a little bit higher than what's been seen in adults.

These authors tried to do a meta-analysis of a bunch of interferon monotherapy trials. They looked at 11 manuscripts and abstracts that included 270 treated children and 37 controls. One of the controls lost RNA over the time period of the study. They had a sustained virologic response in treated subjects overall of 35 percent, not inconsistent with what I just showed you. And just as you see in adults, a very striking difference, whether the virus was genotype 1 or non-1. Once again, though, this meta-analysis includes very few controls, very heterogeneous therapy, and they did discuss the possibility of publication bias towards success.

So, does interferon monotherapy have greater efficacy in children than in adults? I think we need to think about this as we talk about study design later on. There are reasons that it could. These children are younger at the time of therapy. They certainly may have an earlier stage of liver disease compared to adults that were originally included in the monotherapy trials. They have different modes of acquisition. Again, we talked briefly about weight and dose. We don't use a standard dose. We use a weight-based dose, or that had been used in all of these trials. So, it actually turns out to be higher for body weight than what an adult would get.

There may be lack of important co-factors that would allow interferon to be more efficacious, or it may simply be artifactual and it's not more efficacious at all because these studies were not the way we like them.

Interferon has significant side effects in children, and I'm sure we'll talk about those a little bit more.

Virtually all the children get the flu-like illness, but it's not, I would say, rate-limiting or lifestyle changing.

Neutropenia is very common but serious infection is very rare and usually well tolerated.

Weight loss and failure to gain weight is, I would say, almost universal, especially in the young school age children. We talk a lot about nutritional supplementation and very close follow-up of this. Virtually all the children regain the weight after the interferon is stopped. They actually quite rapidly in the first few months regain the weight.

I haven't talked a lot about linear growth here. There are very few data about that, and it's one of our concerns. But it really hasn't been well documented except for one or two of the studies that you have in your handout. Neuropsychiatric symptoms. Certainly, as you know, in adults interferon and depression and other psychiatric problems -- they're reported in children on interferon, but the severity and the frequency have been very difficult to characterize from the study reported to date, but certainly a concern.

Likelihood of seizures or lowering the seizure threshold in children who may have a seizure disorder already.

The treatment of very young infants I think needs to be looked at very critically and separated out. In our own institution, children were treated with alpha interferon for hemangiomas early in life. So, these are life-threatening hemangiomas. They were treated with the same kinds of doses that we talk about for hepatitis C. There was an incidence of spastic diplegia, when they were looked at after a year, year and a half of age. So, I really don't consider using this for this disease at this point early in life until we understand that a little bit better, at least.

Then, of course, we have no knowledge of very long-term side effects.

ribavirin we're going to talk a little bit about. What is the toxicity? Well, we know that in almost everyone who gets it there is some anemia, hemolytic anemia. It is most common in the first weeks of therapy, and then usually stabilizes. Most commonly the drop is less than 2 grams of hemoglobin, although very striking and dramatic drops can be seen and have been seen. It is reversible and dose-dependent. So, usually if you understand it and look for it and monitor it, it can be, I think, safely handled.

On the other hand, we know that certainly this is a teratogenic/mutagenic drug. There are issues regarding contraception that need to be discussed, and not fertility, but really pregnancy that may need to be handled.

Then obviously, what about this drug in growing children. I think not much is known about that.

Let me tell you a little bit about the trials that are ongoing for Rebetron, which is standard interferon with ribavirin in children. There are basically two studies.

The first study is a phase one dose-finding study, which has been completed, which included children, 48 weeks of therapy with both drugs and 24 weeks of follow-up. The interferon dose was 3 million units per meter squared. So, remember, some of these children will be getting more than an adult would get, if they're more than adult size. Three different doses of rhe ribavirin were used: 8, 12, and 15 milligrams per kilogram per day. Eventually the 15 milligram per kilogram dose was selected for the later study based on pharmacokinetics that were done in the fourth week, and some safety data.

The first study included 61 children, school age and early adolescent children, and there they are: 57 treatment-naive and 4 who had relapsed.

The ongoing study now is the phase III study. It's open-label. There is no control group. 48 weeks of therapy, again. 24 weeks of follow-up. All getting the same treatment: interferon, 3 million units per meter squared, three times a week, and the ribavirin. This study includes 105 children. We went down a little bit lower to age 3, and they're all treatment-naive.

Safety data from the first study. Basically the types of adverse events were similar to those seen in adults. Neutropenia has been seen. There were two of the children with depression, is my understanding. There were serious adverse events that included the depression and non-related kinds of illnesses. Most dose modification was required in 11 percent, and 3 percent discontinued the medication. I think the agency has more of this data. I think they're looking at it right now, more than I have.

If you look at response in the phase I, this is only 60 children. This was the dose-finding study, so they're getting three different doses of ribavirin, but this is what we have. Remember, again, all the kids got interferon alpha, 3 million units, three times weekly, plus one of these doses of ribavirin daily. If you look right across the board at all patients, this is the sustained virologic response rate: virus negative 6 months after therapy, overall about 38 percent. Very similar to what's been seen in adults.

Broken down by genotype, again, a significant difference between non-1 genotype, genotype 1, 31 percent, non-1. These numbers are pretty small.

There wasn't a huge amount of difference in the different doses of ribavirin, but this dose actually gave pharmacokinetic properties very similar to the standard adult dose, and had no really more significance to safety issues than the lower doses, and that's why this was chosen.

So, what are the therapy considerations for hepatitis C in childhood? Well, we really don't know the long-term natural history completely. It seems that in the first couple of decades this a benign disease, but in some children it's quite aggressive.

Which children should we treat? Well, should we use the criteria that people are now recommending for adults: moderately severe hepatitis, some fibrosis, not normal liver biopsies, or very minimal liver biopsies?

Should we treat no children because we have no randomized, double-blind, placebo-controlled trials on which to base these recommendations?

Or should we really treat all children because we think, number one, they have less severe disease, they're earlier in their infections, they may be more likely to respond to therapy, and there may be other therapeutic considerations, like getting rid of an infection which we didn't really talk about? But as far as the emotional and social issues regarding hepatitis C throughout your life, is there any value to trying to eradicate this infection, even though it hasn't caused serious chronic liver disease yet?

Thank you.

DR. CHESNEY: Thank you very much. That was superb for filling us all in.

Dr. Weiss from the FDA is going to speak to us now regarding an overview of the FDA initiatives.

DR. WEISS: Good morning. I also want to extend my welcome and appreciation to all of our additional guests who have agreed to come and share their knowledge with us.

My job is to just go over some of the initiatives the FDA has taken over the years with regard to pediatric drug development. I know for the existing standing members of this pediatric subcommittee, you've heard these types of presentations over the past few years, but hopefully this will be just a brief summary and will provide some information to our guests, who may not be as familiar with all these initiatives, which will hopefully help in addressing the questions that we have for you later on.

This is just a chronology of the various initiatives the FDA has undertaken over the years, and I'm going to go over each one of these in just a very brief type of discussion.

I might add, though, that this actually started even before FDA's involvement with the American Academy of Pediatrics, who had a significant role in, I think, shaping these initiatives. Before the mid- to late 1970s or so, the attitude for a number of different types of populations, including children, including women of childbearing potential, other types of "vulnerable" populations, was that they should not be enrolled in studies because of the concern about the risks of investigational products in these populations. There started to be a change in thinking over the years, somewhere in the 1970s, that the problem is not not putting them in trials. The problem was not putting them in trials and not understanding enough about the treatment and the response to treatment so that when products were ultimately marketed, they started to be used in certain populations without really good data to understand how to use them. That was felt to be really more of an ethical issue. Again, this started I think in 1977 with the statement from the American Academy of Pediatrics to that effect.

In 1979 the agency published a regulation that established for the first time a pediatric use subsection of the labeling. The idea of this regulation was to encourage information that would regularly contain data regarding prescription drugs in pediatric populations. The regulation specifically said that the basis for including pediatric data would include substantial evidence from adequate and well-controlled studies in the pediatric population unless that requirement was waived. The substantial evidence from adequate and well-controlled studies is our standard efficacy requirement.

Now, the problem with this 1979 regulation was that there was a waiver, and that was intended to be able to be used when other data, other than adequate and well-controlled investigations, would suffice. However, the basis for requesting or granting such waivers was unclear I think, both to the outside as well as to people within the agency, and the bottom line was that most prescription drugs continued to lack information on pediatric use. In fact, the standard default, which every pediatrician was very familiar with if you looked at labeling, was safety and efficacy below the age of 12 or 16 or whatever have not been established, despite the fact that most pediatricians developed some type of expertise and comfort level with using medications despite the lack of information in labels. Obviously, the 1979 regulations really didn't have the intended effect.

In 1992 the agency proposed new regulations, or revised regulations. These were finalized in December of 1994, and we refer to this as the 1994 rule. The citations for all of these things that I'm going to be speaking about are the last two slides in your handout. The intent of the 1994 rule was to allow a broader basis for inclusion, or to clarify a broader basis for inclusion of pediatric data in the label. It specifically said that evidence to support pediatric claims can include effectiveness data in adults and additional data such as perhaps some PK or safety data in pediatric patients, when the agency concludes that the course of the disease and the drug's effects are sufficiently similar to permit extrapolation.

That was very much a landmark kind of regulation, and it really clarified that recognizing that certain diseases were very similar and some of the difficulties of actually doing large randomized trials in pediatric populations, this would be a basis for actually including information about pediatric use in the label.

The 1994 rule called specifically for our sponsors or manufacturers of marketed drugs and biologics to review their existing data because at that time clearly there was a lot of what we call off-label use of these approved products for pediatric patients. And it called for our manufacturers to review their existing data, with the idea that perhaps there would already be a large amount of experience already out there in the community about the pediatric use of these products, and called for these manufacturers then to survey their data, to put it all together, and to submit it to the agency so that we can use that information to update labeling.

It specifically said that there would be no need to submit pediatric data if there was a belief that the disease or drug effects were not similar and if pediatric use was not otherwise adequately supported. That was somewhat vague. It specifically did not actually require the conduct of new pediatric studies for new products, or already marketed products.

So, what was the impact of the 1994 rule? The problem was that it really didn't result in more pediatric labeling, and there were some surveys that were done, as we started to format the new rule, that came out regarding the impact of the 1994 rule. There were some pediatric data that were submitted on a fraction of the approved drugs and biologicals, but not that many of them resulted in actual useful information on the labeling for pediatric use. Of the new products that were coming to market where there could be a potential use in pediatric patients, only about one-third of those products actually provided data on pediatric use. So, this rule took some steps but really didn't quite go far enough.

So, in 1997 the agency proposed again new regulations. These were finalized in December of 1998. We refer to this now as the 1998 rule. This basically required for the first time -- it was a requirement -- that new drugs and biologicals that were being studied in adult patients would then be studied also in pediatric patients for the indication being studied in adults, unless that requirement was waived. The waiver would be if it was not likely to be used in substantial numbers of pediatric patients or did not represent a meaningful advance in pediatric patients.

The rule went on to discuss some aspects of timing in pediatric studies. If studies were going to be done, when should they be done? Should they be done concurrently with the adult data? Should they lag behind? And if so, should it be during phase III of the adult studies. Should it be after post-marketing?

And that's not really a very easy question to answer. For many indications, the pediatric studies will just by necessity and practicality lag behind the adult studies. Oftentimes there is at least some phase I data generated in adults before pediatric patients are exposed to certain types of products.

But many other factors will influence the timing of the pediatric studies. The seriousness of the disease, the safety and activity profile that's been determined from adult studies, availability of the therapies, ability to develop a pediatric formulation are just some of the issues that will impact upon the timing of the pediatric studies.

What kinds of studies would be required in pediatric patients? Well, the rule did not mandate any particular type of study, and it specifically retained the language of the 1994 rule, that being, where appropriate, pediatric use can be based on extrapolation of adult efficacy data plus other types of data.

The impact of the 1998 rule. We don't have really hard numbers right now because this is just coming into play as we're reviewing all of our drug development programs with our manufacturers and reviewing licensing applications. There's clearly a greater emphasis on the need for and the timing of pediatric studies, and pediatric drug development considerations are included in the overall drug development schemes for every new product, every new indication, every new formulation, whenever that's coming before the agency. So, for every product for which there is a potential use for pediatrics, there are discussions with the manufacturers regarding when the studies are going to be done and what kinds of studies should be done.

So, that is the evolution of the regulations regarding pediatric use information for labeling.

There are a couple of other very important provisions, some of them very recent, that I just want to mention briefly.

The first, and I know the existing committee members are very familiar with FDAMA, which is the exclusivity provisions in the FDA Modernization Act. FDAMA exclusivity is available to certain drugs that are approved under section 505 of the FD&C Act. It specifically -- and it's somewhat important for some of the discussions that we have -- excludes biologics, which are approved under a different authority, and it excludes certain classes of antibiotics known as the old antibiotics.

The way exclusivity works is the manufacturer voluntarily conducts pediatric studies that are responsive to an FDA's written request. The written request would include detailed information about the kinds of studies to do, the numbers of studies to do, the types of patients to enroll, the age range of the patients, et cetera. If the manufacturer conducts studies that meet the terms of the written requests, they would be eligible to receive six months of additional marketing exclusivity or patent protection attached to whatever existing exclusivity they already have.

That's a slide that just shows the comparisons between FDAMA and the rule. Under FDAMA, they're voluntary; under the rule, it's required. Under FDAMA, the exclusivity covers the entire moiety; in the rule, the studies are only on the drug product and the indication that's being sought. FDAMA has an incentive; the rule is not an incentive in terms of a financial incentive. And FDAMA excludes old antibiotics and biologics, and under the rule, the only thing that's exempted are orphan drugs.

Impact of FDAMA. These numbers are constantly being updated in the Center for Drugs. But as of April 1, 2001, the FDA has issued 188 written requests, which cover 411 studies because each written request, of course, may include more than one study. The agency has given 28 grants of exclusivity, and 18 products have come along now with new labeling for pediatric use. The manufacturer will be able to receive exclusivity for conducting the studies, even if the studies do not result in changes to labeling, but that's part of the agreements under FDAMA.

ICH E-11 is a guidance document that was developed under the auspices of the International Conference on Harmonization, ICH. ICH is a process whereby regulatory authorities and representatives from industry from the U.S., Europe, and Japan get together to come to agreements, harmonize, on the technical requirements for drug development. ICH covers various types of manufacturing aspects, preclinical requirements, as well as clinical types of data that would be necessary for certain types of settings.

ICH E-11 was the pediatric guidance document. It was a document that has now been finalized. It's available on Web. Towards the end, I have the Web address. But it has a number of issues with respect to guidance on pediatric studies. It talks about considerations in determining the need for a program, issues to consider in pediatric formulations, in terms of timing of studies, types of studies that might be done.

Steve Spielberg, who is here at the table, was a major leader in the development of the ICH document. There are a few people as well, like Dianne Murphy, Rosemary Roberts, who couldn't be here, and I who represented the FDA, and this was a very interesting and informative process.

The Subpart D regulations. Dianne Murphy just briefly mentioned this. I think there's going to be more of an update on this, but this is our newest initiative and it was just actually available this past week, so it's extremely new.

Subpart D is our abbreviation for this regulation, but it has to do with the fact that in October of 2000 then-President Clinton signed into law the Children's Health Act. Among the things that were in that act was a directive to the Secretary of HHS to require all research involving children that was conducted, supported or regulated -- and I added that emphasis on "regulated" -- by HHS to be in compliance with Subpart D of the common rule within six months of enactment. And that meant that it had to be in place by April 17th, which is just last Tuesday.

This committee I'm sure is very familiar because some of these discussions occurred with issues regarding placebo controlled trials, but IRBs are extremely familiar with provisions for children involved in clinical research over the years. They've been following Subpart D of the common rule for quite some time now, and that has to do with issues such as level of risk and whether or not the research involves minimal risk or more than minimal risk, and the chances of direct benefit, issues that the IRB needs to consider when determining whether or not that type of research will be accrued at the institution.

That rule has been in place for HHS-conducted or supported research, but it has not actually been specifically stated for FDA-regulated research. So, the impact of this Children's Health Act and this rule was now the FDA is in compliance with these aspects of protection of human subjects for FDA-regulated research as well.

I think that's my last slide for here. The next two slides are just the different citations for the documents that I mentioned, so you can have those and refer to them if you're interested in looking at any of the websites for the documents.

Thank you very much.

DR. CHESNEY: Thank you, Dr. Weiss. If the other committee members have as many questions as I do about the presentations, we won't finish in 10 minutes, because I'm going to take 20. I would like to propose that we take a break first, and we're allowed 15 minutes for the break. So, if we could be back here at 10:30, is that acceptable to everybody?

Thank you.

(Recess.)

DR. CHESNEY: Before we start the questions, I wanted to introduce everybody to Dr. Bill Balistreri, who is sitting over here next to the famous Dr. Spielberg. Dr. Balistreri is head of Pediatric Gastroenterology, Hepatology and Nutrition at the University of Cincinnati, and recently spoke at our own grand rounds on this issue. So, we look forward to his input during the questions and discussion.

We are scheduled now to have the open public hearing. Nobody has signed up for it. Is there anybody who hasn't signed up who would like to speak at this time?

(No response.)

DR. CHESNEY: I don't see anyone. So, we will go ahead and ask members of the committee and the people who actually spoke to us, if you have questions also, to please feel free to address them to our morning speakers. Yes, Dr. Nelson.

DR. NELSON: To some extent my questions started being answered as I talked with people over the break, but let me ask it anyway to reinforce it. My question relates to how one is excluding patients with hepatitis C who would have the potential for a spontaneous recovery given, I gather, the anywhere from 25 to 46 percent chance after an acute infection to sort of have a virological clearing and loss of antibody, when one is designing an intervention study. It came up in listening to Dr. Rehermann's remarks and also, since I don't recall the inclusion and exclusion criteria for the Rebetron study, how is one being sure that you're not intervening in a situation where they would get better anyway?

DR. CHESNEY: Did you want to address that to anybody in particular?

DR. NELSON: It came up in thinking about the response on the initial question. If the cellular response predicts who not only recovers and who responds, how can you be sure you're not giving a drug and then finding that you're measuring both just those that are going to recover anyway, and it came up in thinking about the Rebetron study how one excludes children, for example, who might have a spontaneous recovery. Does that make sense?

DR. REHERMANN: Well, I think the data I showed on the interferon/ribavirin study was the treatment of chronically infected patients, and those patients who responded to treatment would have not recovered without treatment. So, the T cell response was somehow induced by the antiviral treatment or enhanced by the antiviral treatment, as we would interpret it. But without the treatment itself, the people would not have recovered.

DR. NELSON: Just given the 7 percent in one of the other talks of recovery, at what time do you decide it goes from acute to chronic?

DR. SEEFF: Well, traditionally we've said that if you could identify acute hepatitis, if they persist in it, being abnormal for 6 months, by definition we call that chronic hepatitis.

But I think you're asking a question for which there is, at this moment, no answer. I think once you develop chronic hepatitis C with HCV RNA, the likelihood of losing it is remote. I don't know when it occurs. We don't know when the 7 percent that you referred to occurred. We have the original samples from these patients. We had follow-up samples some years later, and we didn't have sequential samples to know when it occurred. My own guess is that it is going to be a spontaneous loss that's going to probably take place during the first year or fairly early on. I don't think it's going to be late, but I don't know that we have the data to support that unless Barbara has additional sequential data. I think that most of us, once we see a patient who comes in with chronic hepatitis C, the likelihood of their losing virus is pretty remote.

DR. CHESNEY: Yes.

DR. SCHWARZ: I think implicit in your question -- and it's an excellent one -- is at what