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Harold Margolis, MD: "Viral Hepatitis - A National Perspective: Closing the Gaps"

Harold S Margolis, MD, is Director of the Division of Viral Hepatitis, National Center for Infectious Diseases, Centers for Disease Control and Prevention. He is also the Director of the World Health Organization Collaborating Center for Research and Reference in Viral Hepatitis. Dr. Margolis earned his degree in medicine from the University of Arizona College of Medicine and completed his pediatric residency training at the University of Colorado. He is currently a Fellow in the American Academy of Pediatrics. He joined the CDC in 1975, where a substantial portion of his work has been devoted to research in developing and evaluating methods to prevent viral hepatitis. He is author or co-author of more than 150 manuscripts or chapters on viral hepatitis.

1. Viral Hepatitis - A National Perspective: Closing the Gaps

I really want to thank the NVHR organizing committee for getting us here today and giving me the opportunity to talk to you about a number of issues including where we think we ought to be heading in terms of eliminating and preventing this scourge that has occurred in the United States and globally. Yes I come from the CDC perspective, but hopefully I will offer a national perspective in terms of where I think we ought to be going - and I really bring this from other government agencies, the NIH, the FDA, HRSA, all of the state and local health departments and agencies that are currently trying to deal with these diseases and infections, from all of you from advocacy groups in terms of what you have been doing, as well as from academia, people who have been putting together data and information that I will present today. I have also had the wonderful opportunity to work with my colleagues in my own division, people who have put together much of this information, which I then have the opportunity to present to you - we have our debates and discussions and hopefully use this to build direction. What I am going to try to do this morning is give you a framework - I am not going to include everything, I don't have enough time. Yes, I have certain biases - I bring the bias of prevention, but I hope what I'll show you is that my view of prevention is all the way from primary prevention to treatment and care and all of the pieces that go into eliminating these diseases, these infections, as well as eliminating the pain and suffering that they produce in the populations that we serve. I am very much driven by an evidence-based foundation, and I hope that as we as a group work together over the years that we always use this as our underpinning. Yes, we then have to become practical, to turn this into practice, but we always seem to do best if we have something that underpins it and that we can go back to and say, "yes, this is the best information." But, it's also important that we figure out the gaps, both in information as well as where we are in terms of implementation. The other thing I would like to bring this morning is that I think we have taken a new view, and I can tell you that personally I have taken a new view. Since yesterday, I have been talking about elimination, prevention, and control of viral hepatitis, and I have come to the point where we now look at this as an entity, as almost a single entity. But it is extremely important that we continue to work on each of the agents, so that we get better vaccines and better treatments - because they don't cross, these are different problems. They have their own life and their own way of approaching things, and we have to figure that out in order to take care of them. But when we bring them together in terms of prevention, I think that is a new perspective that the NVHR and those of us working in the field have begun to take. So I think that is something else I would like to bring.

2. Disease Burden from Viral Hepatitis

I am data driven, so I am going to start with disease burden. These are the things that you already know. Lots of infections unfortunately still go on. Here in the data from 2001, you see that almost 100,000 people were infected with hepatitis A, 100,000 people were infected with hepatitis B, and 25-30,000 people were infected with hepatitis C. So, disease burden in terms of what is still going on is quite substantial. These numbers represent at least a 50% reduction from what you would see if you go back 10 years earlier, in 1990. People with chronic infections, again - large numbers. These numbers remain fairly stable, although some people might argue that for hepatitis B we haven't revised the numbers, and that is kind of a gap looking at our current data. There are a fairly large number of deaths occurring; with about 12-15,000 people dying from what we believe is viral hepatitis-related chronic liver disease.

3. Age of Infection - Viral Hepatitis

These are also diseases that occur at all ages, and I put this cartoon up here with the little pluses and the different ages, to show that yes there are some differences between the different viruses, but this is one of those diseases that is not just a childhood disease or just an adult disease; it is occurring everywhere, and this causes some of the complexity in terms of prevention, but it raises a number of opportunities. Again, they are unfortunately diseases of all ages.

4. What Will It Take to Eliminate Viral Hepatitis?

So, the task I was given this morning is to say: "So, what is it going to take to eliminate these diseases as a national health problem?"

5. Prevention and Control Activities

I figured I'd start with the issue of prevention, and maybe put the definitions of some terms up here - this is public health 101. Primary prevention is no new infections. That's the thing that we all strive for, and is the most important. But remember that, as I showed you before, we still have a number of people in the United States that are chronically infected, and so we've got to deal with people who have already acquired an infection. And that starts dealing with the issue of secondary prevention - and what do I mean by that? Well, that is the person, and I will use hepatitis B as an example, who is chronically infected, and you want to prevent him from transmitting it to others. The easiest way with that disease is that you are vaccinating the people in their household and their sexual or close contacts. So that is secondary prevention - with hepatitis C it is making sure that you are not transmitting to others, which is a hard task, but something we need to be thinking about. And lastly, is tertiary prevention, and that is really medical evaluation and appropriate treatment, which may take on the form of anti-virals, or may take on the form of liver wellness, making sure that we don't further injure an already somewhat compromised liver. So that is how I use prevention, and this theme that you are going to see through the rest of my presentation, is that this is what we ought to be thinking about.

6. Where Are We Today?

So, where are we today? Now I am going to give you some data. We use numbers, and yes you are going to see numbers that come primarily from CDC-derived information. I will give you summaries at the end of "ABC's" that tell us what we know and where we are, or where I think we are, and summarize a lot of perspectives - and where I think there are gaps.

7. Hepatitis A Incidence, 1980-2002

So, hepatitis A: hepatitis A is actually the kind of thing we like to see - many people may not realize, but we have had almost a stellar success. You get a vaccine out there and this disease starts to go away. You may argue that we had all these cycles up and it is just one of the downturns that naturally occur. But what has happened is that hepatitis A has fallen below any of the historic lows that have occurred when it was naturally circulating, and there have been studies done that show that this is being driven by immunization. This yellow line up here that occurs on several slides is the Healthy People 2010 target. We have actually done better than the target. But even with rates of about 2 per 100,000 population, this still means that we are getting reported upwards of 10,000 cases. As I showed you earlier that still represents almost 90,000 infected people, and one of the problems with viral hepatitis is that many infections are asymptomatic, and zero is not always zero. That is going to become a problem as we get farther into control, but I think we can all deal with that, and again that is part of figuring out how best to approach these diseases.

8. Recommendations for Routine Hepatitis A Vaccination of Children

Hepatitis A is different in that our immunization strategy across the country was actually regionally based. Why was it regionally based? Well, it was because these states in red and yellow are states where the highest rates of disease had occurred for many, many years. They are primarily in the west and that is where it is recommended that all children be vaccinated - and in fact there have been fairly high rates of immunization that have gone on there.

9. Hepatitis A Incidence, 1987-1997 - Geographical Distribution

If you look at these two maps, the one in the upper corner and all these red and yellow areas, you can see that these were counties that had very high rates of infection during the decade from 87-97. And since immunization, if you look at that 2000 now, both of those have melted away. We have seen tremendous decreases in these high rate areas, and that will still go on as long as we immunize.

10. Hepatitis A Incidence - American Indians/Alaskan Natives

We've also seen tremendous decreases in special populations, and the population in the United States that had the highest rate of hepatitis A was the American Indian/Alaskan native population. And as you can see here, they had a rate of hepatitis A that was almost 5 times that of the general US population. The first recommendations that came out soon after the vaccine was licensed was to vaccinate aggressively in this population. Then we moved to wider recommendations. And actually what has happened now is the incidence, the number of new infections in the American Indian/Alaskan native population is lower than the general US population. So again, a success story. It shows that if you that if you put prevention efforts in the right places, you can effect change.

11. Hepatitis A Vaccination - Adults at Increased Risk of Infection

There are other groups that have been recommended for vaccination; and in hepatitis A, most of the disease does not occur in these groups, but they play an important role in transmission communities. This includes people who travel to countries who have high rates of the disease, as well as men who have sex with men, injection and non-injection drug users, persons who receive clotting factor concentrates, and persons with chronic liver disease. Unfortunately, we have not done very well in these populations.

12. Hepatitis A Incidence - By Age Group

If you look today at what we call age-specific incidence, who is getting these infections, we see that the children who once had the highest rate of hepatitis A, now have the lowest rate of hepatitis A, because that is where we are vaccinating. What we now see is that adults are the group who are continuing with this disease, and most of the outbreaks and clusters that we see in the US are adults.

13. Hepatitis A - What Do the Numbers Tell Us?

So where are we? Well, this is a primary prevention disease. There are no chronic infections, so those secondary and tertiary terms don't count in terms of this disease, as part of the viral hepatitis spectrum. I think we are doing pretty well in terms of the children in the higher rate states - I put "OK" up there, we actually don't have good data in terms of vaccination coverage, but some of the surveys that have been done have shown that we are doing pretty well, but we need to keep after it. In special populations we have done very well, as I have shown with the American Indian/Alaskan native population. And should we move as the advisory committee on immunization practices suggested three-four years ago, in their 1999 recommendations - that we go to vaccinating all children, that this become a universal vaccine - well, there were some technical issues, and hopefully soon, at least we will have the technical issues taken care of in terms of an immunization schedule, and then the issue is, will we have our recommendation. But with adults, and I have tried to show you the data, we have done a very poor job. And you are going to see that adult immunization, for all diseases that go across the whole age spectrum, we have not done well with adults. So there is a gap and this is something we need to begin to address.

14. Incidence of Acute Hepatitis B, 1980-2001

Hepatitis B - what's been happening there? Well over all, disease rates are going down: there has been about a 67% decline in over all recorded disease incidence.

15. Hepatitis B Incidence, Children, 1990-2001

The greatest decline, which has been almost over 90%, has been in children less than 19 years of age. Again, that's where we have our major immunization program, and it is truly a program that has all of the components, including vaccine purchase and financing. And now we are getting down to the point where we are almost at zero. The goal for 2010 is actually to see only 2 reported cases per 100,000 and I actually think we will do better than that. But then there comes this issue of is zero really zero because of asymptomatic infection, but again there are ways to look at that. In terms of strategy at this point, we have done pretty well in this area.

16. Effectiveness of Infant Hepatitis B Immunization

And to show you how well we have done (because there are special populations in the US that have very high rates of hepatitis B, Alaskan native populations, and Asian/Pacific Islander population): ... There have been studies that have been done recently that looked at chronic infection before vaccinations, and this was in Alaskan natives, in Hawaiian school children (Hawaii not having an ethnic racial majority, but having a wide distribution of racial and ethnic groups, predominantly Asian and Pacific Islander). And among children born to Asian immigrants in the US, there were studies back in the late 80's that showed that almost 7% of these children had chronic infection. And if you look now, since childhood immunization has been implemented, and some of these data have been published (the Alaska data have been published, but the Hawaiian and the Asian immigrant data are new data that have been presented at a number of meetings) you can see that there has been elimination of transmission in Alaska. It looks like chronic infections are gone, they just don't occur anymore. And in these populations there has been again, almost a 90% reduction in chronic infections, and people have actually gone back to look at, who are those children that get infected. Yes, sometimes there has been a lapse in the system, but again, there has been a tremendous effect in terms of our childhood hepatitis B immunization program.

17. Hepatitis B Incidence, By Age

We haven't done very well with adults, and these are again incidence data, looking at what has happened over the last decade. And what you see is in the 19-39 year olds and in persons 40 years and older, things have been going down, not as much in the older age group (and people say, when you get older you are not at risk or hepatitis B, but no, in fact you are). Over the last 3-4 years we have seen a plateau, and actually in the over 40 group we are seeing an increase in infections and in disease, and it says that we are not doing too well.

18. Hepatitis B in Adults, 19-24 Years of Age, by Race and Ethnicity

We also see, if one looks at adults, and I just take this as one age-group snap shot, that there are racial disparities in who gets hepatitis B in this country. Whites and Hispanic have the lower disease incidence, and again you can see this in all age groups. Asian/Pacific Islanders have an incidence that is almost 2 fold higher (this is American Indians, and does not include Alaskan natives because they are really not having disease). And the African American population has always, and continues to have, disease rates that are higher than Hispanics and whites. The Asian/Pacific Islander rates have actually been coming down over the last decade. Again, this is a snapshot in 2001, and it points out that there are disparities, and there are a number of reasons for them, but again, it is harder for some of the issues we need to deal with, in terms of trying to eliminate the burden of this disease.

19. Missed Opportunities for Hepatitis B Vaccination - STD Clinics of Corrections Health

We also know that there are places where people could have been vaccinated; back 10-12 years ago we said: "It is probably pretty hard to reach higher risk populations - they don't come in for health care, we may not be able to vaccinate them." But we have looked over the last decade at where people with different risk factors, the risk for hepatitis B being multiple heterosexual partners, men who have sex with men, or injection drug users - we see that actually these people have been cared for in venues where they could have been vaccinated. We have had recommendations for 20 years that say you should vaccinate here - this is in the STD clinics or in the corrections health setting. So, almost 50% of new hepatitis B infections could have been prevented because these people were seen in a place where they could have been vaccinated. So again, I think we have a better sense of how we can achieve some of our prevention targets.

20. Hepatitis B Vaccination Coverage

So what explains all of this? Well, the obvious thing is that it is immunization coverage, and in this somewhat complex slide, let me just walk you through the age groups. If you look at children, our immunization coverage now is almost 90%. That is our 2010 goal - that is where we want to be, we think we should be able to get over 90%, but that is a good target, and it looks like we are achieving it. This really isn't a decline - this is just the older-age group. These are the kids born at the time the recommendations were made, in late 90-91. So, we kind of have to catch them here as they come into the adolescent period, and there are a number of school entry laws in various states that are helping us to achieve coverage. So, over all, there is about a 70% coverage in adolescents and in young children. The problem is that these older adolescents, who have missed the health care system , or have missed the immunization system, are going to go forward. Some of them will get caught in college, because some of the colleges now require hepatitis B vaccine for matriculation. But unfortunately, most of them are going to go out into the adult world unprotected. That brings us back to what I have been pointing out, which is we need to vaccinate adults, and we especially need to vaccinate high-risk adults, and again, part of a prevention strategy that hasn't really taken legs yet, in terms of making it happen.

21. Hepatitis B - What Do the Numbers Tell Us?

So what is my take on this, in terms of trying to put it into different categories? (And yes, I have not presented any data on treatment issues, but I will talk about it here using this slide.) In terms of primary prevention, I think we are doing very well - the data show that we are doing very well in terms of primary prevention in young children. In adolescents we are doing pretty well. There is plenty of room for improvement, but we have the mechanisms and the programs in place to do it. In adults, we are not doing well at all - really quite poor in terms of that's where the disease is, that is where our problems still exist. What about secondary prevention; the issue of preventing transmission from infected people, people who have chronic hepatitis B, to others? Well, we don't have very good data, in fact we have very little data, but we do have some data from one program, and that is from pregnant women who are screened to identify whether they are chronically infected. That has been a program that has been in place for almost a decade now. And what we have seen is that because there is a program, the household and sexual contacts of those women are being vaccinated, and we are seeing that in households, there are fewer and fewer of them to be vaccinated, because we have been catching up - we have been finding these people. Now, we don't have much information about the rest of them - the 1.25 million people out there with chronic infections. And in fact, only this last year did chronic hepatitis B infection become a reportable condition. About 25 states now have databases, but we actually don't know how well they are following these people up to see whether they are being vaccinated or counseled. That gets us to the last part, tertiary prevention - treatment, or even medical evaluation for treatment. Frankly, we have no national numbers on this in terms of how well we are doing, and I think we know that a number of new treatments have real potential in terms of prevention of cirrhosis and primary hepatocellular carcinoma in people with chronic infection and that is an area that needs a lot more work. So, I think we have some good information in the area of primary prevention, but we are really lacking information in terms of how well we are doing in secondary and tertiary prevention.

22. Hepatitis C Virus Prevalence, 1988-1994

So now, what about hepatitis C? These are numbers you have seen before, in terms of age specific prevalence, and now these numbers are almost a decade old, in terms of the ages; the actual numbers that are there, and the proportions, we don't think have changed, but this whole cohort has aged almost a decade. And we don't have good information on the number of new infections, other than that incidence data that I showed you, which are based on best estimates in these younger age groups. And so there are some relative data gaps, but we think this group is aging and the NHANES (National Health and Nutrition Examination Study) from which these were derived - those data are accruing. The NHANES is done a little differently now, but eventually we should have data to look at how this group has moved in terms of age, and if it is moving in the same way that we thought it would.

23. Incidence of Reported Acute Hepatitis C, 1982-2001

More important is the issue of incidence, and there has been a dramatic drop in incidence of hepatitis C - and most of this data come from our sentinel county study of acute viral hepatitis, through which we really had the only information from back in the 80s and early 90s. But now you see that nationally reported data from that states is matching our sentinel estimates. So I think we have reasonable indicators of what is happening nationally, and this is what translates into the 25-35,000 new infections a year. We actually don't know what has caused all of this decline; we have some ideas. It was not the fact that blood screening came into play, but probably had to do with dynamics of hepatitis C virus infection in injection drug user populations, which is where most of this disease is acquired.

24. Risk of Hepatitis C Virus Infection Among Injection Drug Users

Let me show you a little bit about what we think has happened in the injection drug users, since that is the population that accounts for almost 2/3 of the infections. If you look at a number of studies that were done, some back in the 80s in Baltimore, and then a family of studies that have been done in New York and Chicago looking at relatively young injection drug users and looking at hepatitis C based on the duration of their injection drug use - If you go back to the Baltimore group what you saw was that people acquired their infection very rapidly: within 6 months to a year of initiating drug use, almost all drug users were infected. But if you look at what's been happening now in the late 90's, and probably what is going on now, is that you see, for instance, in Chicago, and this is a bit more of a non-urban population, that acquisition of infection takes longer. Unfortunately, after 6-7 years, 60-70% of these people are infected. If you look in New York, in Harlem, or in parts of the Lower East Side of New York, again you see that acquisition occurs at a relatively steady state, but there are windows of opportunity in terms of prevention, and that probably people in these populations are doing something to protect themselves. The problem is that it may not be that they can protect themselves all of the time. We need to do things differently, or figure out new ways to prevent this infection, remembering that this is not a vaccine preventable disease.

25. Burden of Chronic Infection With Hepatitis Viruses Among Released Inmates

Another place where hepatitis C occurs is in our incarcerated populations in the U.S, and these are some data from a table in a recent publication from the CDC, in an MMWR. If you look at people with chronic hepatitis C, and this is this lower line, you can see that almost 40% of people who are released from prisons every year have chronic hepatitis C. So a large proportion of the release population that are coming back into the community are infected. The same is actually true for hepatitis B for chronic infection, where about 15% of that population has been incarcerated. So again, this is another one of our special populations and our special needs, I think, for hepatitis C prevention in terms of all of its forms.

26. Outcome of Medical Referral, Hepatitis C Virus-positive Injection Drug Users

And then lastly comes the issue of, do people really get treatment? Do they really get medical evaluation? Somebody has a positive HCV test, do they get somewhere where they can get followed up? And these are some data from San Diego looking at injection drug users who were found (actually from San Diego, Portland and New York City) found to be HCV positive. Over here is the proportion of people (and remember that this is just a small pilot study) who kept an appointment for a medical evaluation. And this is not a prepaid evaluation - this is finding what is available in the community. And you see the range is about 50% to as low as 25%. So this would suggest that we are not getting people to the medical care that they need.

27. Hepatitis C - What Do the Numbers Tell Us?

So what is my score sheet for hepatitis C? Well, primary prevention right now I would say is still relatively poor. We haven't changed that incidence over the last decade. Secondary prevention, I think the data suggest that it needs improvement, but those data you see from those injection drug-use population suggest that we have changed transmission patterns in those populations, but they are not sustained. So, we have got a lot more to do. In terms of tertiary prevention, while we do not have national data, some of the data from these high risk populations would again suggest that these people are not getting to medical care, treatment, and medical evaluation in order to prevent further liver disease.

28. Prevention and Treatment of Viral Hepatitis

So, where do we go from here? Well, I would say that we have a lot of recommendations out there, and I have just listed these to tell us what we should do to prevent hepatitis A, to prevent hepatitis B, and to prevent hepatitis C.

29. Prevention and Treatment of Viral Hepatitis - Special Settings

We also have recommendations for a number of special populations and special settings, so these are recommendations from groups like the CDC, the NIH, professional advisory groups. So there is really an evidence-based underpinning for much of what we are doing at this time.

30. No National Strategy for Viral Hepatitis Prevention and Control

But what we don't have is a national strategy. What do I mean by that? I mean: How do we put this all together?

31. National Hepatitis C Prevention Strategy

There is a national strategy for hepatitis C prevention - and yes, this was developed by CDC almost 4 years ago. It wasn't really well vetted for a number of reasons that were kind of the expediency of the time. But, what goes around this national strategy are things about communication, issues around how we put prevention programs at the local level - and that includes not just health departments, but clinical care settings, how advocacy groups are involved and patient support groups are involved. It defines issues around surveillance and evaluation and it defines issues of the need for additional research. We don't have all of the answers. But this doesn't exist for hepatitis A or for hepatitis B, or for all of these being put together as a single entity.

32. Examples - What Should a National Strategy Address?

So, what are some of the things that a national strategy ought to address? Again, this is putting aside at least points for discussion for the rest of our time here. Hopefully what this does is trigger you to say "yeah, I agree with him" or "no, I disagree with him" or "gee, he left this out or didn't think about it." This is for discussion - this is, to start, a series of examples. First, we need to go back to our recommendations, and ask do we need new ones? Do we need to revise ones that we have, and this is in all of the areas of immunization, screening, diagnosis, medical management, treatment. I know there are some people in this room thinking, "oh my gosh, not another set of recommendations!" But, some of these need to be looked at, and the question is are we at the right place, do we have the right sets of these at this time? We need to talk about implementation - and yes, I wear a public sector hat, but I feel - and I think we at CDC feel - very strongly that there should be no differentiation between public and private sector in terms of how we make these things happen. And addressing issues of health systems guidelines, how you integrate these activities into existing clinical and public health programs is something that needs to be addressed. We need roadmaps for this. Practice guidelines - this is becoming more and more of a way of life for those of us in the clinical sector, when we are practicing. Recommendations are just that - they are recommendations. But when you start developing practice guidelines, that takes it to a different level. Engaging groups of all levels, in terms of how is it that we ought to be doing things, is something that has been an evolution in terms of medical care and public health practice. Education - both the provider as well as the public. As we have all seen in the area of viral hepatitis, most people don't know the alphabet. They don't know A from B from C, they don't know what the issues are and getting out better education is a key issue in terms of implementation. Clearly there is a need for additional research and evaluation - figure out what has been working. Much of what I have shown you today has been a lot of things that have worked. So let's figure out what has worked, what has made it work, and how we can apply it to the areas where we see the gaps. Issues around health services delivery - how do we really deal with very large populations for which you are not going to have a specialist taking care of every one of those patients, and providing both the clinical support as well as all of the support that is needed in order to get through treatment. We heard from Mr. Simpson last night that these are difficult, and we need a system that begins to address this. And then there is a tremendous need for behavioral research. We have vaccines out there and yet we have a lot of people who don't want to be vaccinated. What is it that makes people not want to be vaccinated? And we know from a research standpoint, we have never addressed that issue. That is just one example of the behavioral research. And then we have the other aspects of behavioral research that are needed in terms of a very difficult issue with these diseases and infections, which has to do with drug use. And at the bottom I put resources. Obviously that's been a bit unspoken, though it was spoken very well last night. We need to figure out how to get the resources. And it is not all just money, and not all just new money - but we need to get the resources to address these issues. Again, those are some of the things that at least need to be laid out in the strategies - and if you have a roadmap of where you are headed, and those of you who work in communities know that it is much easier to take that, looking for resources.

33. What Will it Take to Eliminate Viral Hepatitis as a National Health Problem?

So where do I think we are headed? Well, I think it's this roundtable that is what it will take to get us to eliminate viral hepatitis as a national disease problem. I don't think any of us individually are going to be able to do it. I can sure tell you that we at CDC can't do it. And I don't think any of the other parts of the federal side of this equation can do it individually. Hopefully working together we can come up with a better roadmap. Thank you.