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Hillel Tobias, MD, FACS: "What is the impact of hepatitis B in the US?"

Dr. Hillel Tobias was a keynote speaker at the B Informed Educational Forum Program held in New York on September 23, 2004. He is the Professor of Medicine at the New York University School of Medicine and Medical Director of the Liver Transplant Service at the New York University Medical Center. In addition, he is Chief Executive Officer and Medical Director of the Mary Lea Johnson Richards Research Institute, Inc.

His research interests are primarily devoted to the treatment of hepatitis, a subject on which he has authored or coauthored numerous articles. He is a Fellow of the American College of Physicians and a member of the Medical Advisory Board of the American Liver Foundation. He is coauthor of a recent publication in Clinical Gastroenterology and Hepatology entitled “A Treatment Algorithm for the Management of Chronic Hepatitis B Virus Infection in the United States.” Dr. Tobias is also a director of the “Asian American Hepatitis B Project” a major program for the study and treatment of hepatitis B in the Asian communities of New York City, which is funded by a $4.5 million dollar grant from the New York City Council.

Dr. Tobias earned his MD at Washington University School of Medicine in St. Louis, Missouri and his Ph.D. in liver physiology at the University of London, England. After graduation from medical school, he completed his internship and medical residency at the New York University service of Bellevue Hospital. His postgraduate fellowships were served at the Royal Free Hospital, London, and the Mount Sinai Hospital in New York.

1. What is the impact of hepatitis B in the US?

I think there's more and more interest and concern and emphasis on hepatitis B evolving currently. To follow up on the question of why people have been hung up on hepatitis C one concept is that the incidence of hepatitis C in the United States has been judged to be over four million people and the incidence of hepatitis B has been estimated at 1.25 million. There’s been some increased interest [in C] because the incidence is three times that of hepatitis B. Hepatitis B is a much larger worldwide problem than hepatitis C and is an incredibly important problem because of the high incidence of mortality from liver cancer which is a major cause of death across the world and one of the leading lethal cancers across the world. Hepatitis B is of increasing concern in the United States and there’s going to be increased concentration on it. One of the reasons is the Asian population, which is a big reservoir of hepatitis B, has increased tremendously in the United States. The estimate of 1.25 million people is probably underestimated. We have some data from very preliminary surveys that were done in Chinatown where we found as many as twenty-five percent of the population is infected with hepatitis B which actually interestingly enough is higher than the estimate for the infection in China itself. So, this is an increasing public health concern in the metropolitan areas. Its going to be the classical problem in the United States. In the major population centers on both coasts where the Asian population has increased significantly in the last few years, this is turning out to be a major problem. And you know how it goes in the United States, as the Asian population increases, obviously their importance as voters increases and I think the interests in this world [hepatitis B] will increase. The other point that Dr. London made is really that hepatitis C, in terms of increased incidence, is really a disappearing disease. Hepatitis C is basically going to run itself out of existence in the next twenty years because the main source of it was blood transfusions which are now tested and excluded and the number of new cases of hepatitis C has dropped from like hundreds and hundreds of thousands a year is now down to less than twenty thousand new cases a year year which really takes away from it as a new public health problem as an infectious disease. Of course, the reason that hepatitis C has garnered so much interest is that hepatitis C is a disease which evolves over twenty-five or thirty years. So the incidence of new cases of the disease has dropped incredibly and this will not be a public health problem in the future. Right now were seeing all the sequela of the people who contracted this twenty-five years ago and they are the ones who are developing cirrhosis, liver cancer, etc. and that’s the leading cause of liver transplant in the United States. Its sort of split between alcohol and hepatitis C. But this will diminish, well at first it will peak because there is still the people that contracted this before 1992. So if you think about it, in twenty-five years the peak of the problems from hepatitis C will peak around 2012 - 2020, but then it will be over. And then is when hepatitis B will be coming into its own and the number of these cases will be increasing. This disease is much more easily transmitted sexually than hepatitis C which is essentially non-transmissible sexually. So we haven’t eradicated the reservoir of the people here [in US] and you'll see that in order to eradicate this reservoir, were going to have many more extensive means.

2. What is the difference between acute and chronic HBV infection?

I thought we'd talk about acute and chronic hepatitis B, the disease characteristics, and the clinical management. First, I thought I'd show you a picture of the hepatitis B virus. The hepatitis B virus is well every virus is its own special case. But this one is actually like a spherical kind of virus. It’s a DNA virus and that becomes very important because DNA is what’s in your cells and associated with your multiplication. So this is a virus that once you catch it, it grabs itself into the cell nucleus and becomes part of your own DNA and your liver. It has a virus inside and then it has a protein coat around it.

3. What are the characteristics of the HBV virus?

This virus can be seen under the electron microscope. You know if somebody has active hepatitis B and when you look in their blood under an electron microscope, you can actually see the viral particles because by the time the protein gets wrapped around the DNA essential part of it, you get to something that’s actually visible under an electron microscope. Because each virus has its own special structure that allows it to get into cells and attracts itself to the liver cells.

4. What is the most common method of transmission for the HBV virus?

So the big reservoir is the Asian population which transmits it from mother to child the others are secondary and of course in other less developed countries as well as developed countries, sexual transmission can play a major role. So this is not a disease that’s going to play itself out over the next few years, but will continue to be a problem.

5. What is the progression of the viral cell?

Once the virus gets into the body through body fluids it then settles into the liver cell where it replicates in the liver cell and winds up essentially killing the liver cell that it invaded but before it does, it releases multiple viral particles into the liver and that little diagram in the right corner there shows you that after a while the liver cells become very populated with the virus. Because of the size of this virus you can even actually see evidence of it under a light microscope. If you take a piece of liver from someone who has hepatitis, you can see the majority of the cells in the liver are infected and that of course leads to the complications of the disease.

6. What are the characteristics of a healthy liver?

This is the diagram of a healthy liver and is made up of cells in a skeletal structure of fibrous tissue. In the normal liver, the cells are in between the fibrous tissue - which you can barely see in this slide - which is the psuedostructure of the cells are based in. When the virus attacks the liver you get inflammation the same as you would get a sore on your hand with inflammatory cells. The inflammatory cells are an immune reaction to the virus and stimulate the production of scar tissue and this is where the problem comes in. So, first you get a killing of the liver cells from the acute hepatitis and if you get all your liver cells knocked out, you get what’s called fulminant hepatic failure and you die. Fortunately this doesn’t happen very often. The average Western person is able to mount an immune response because they get the disease in adulthood. Their liver blood tests or liver enzyme tests will go up, and then the body’s immune reaction will overcome the virus and eventually it will get better. By definition most people get better within four to six months. And these people are getting over acute hepatitis. They have malaise, fatigue; you know they really feel crummy because fatigue is a major aspect clinically of liver disease. They may turn yellow but they don’t have to. But they get over it over a period of months - and that’s a classic immune competent adult. After the six months is over and all their liver tests are back to normal, you can test their blood and see the virus is gone from their blood.

7. What is and what causes fibrosis of the liver?

While people are actively infected, we have very excellent means now for measuring the virus in the blood and we can tell you at any given moment whether you have the hepatitis virus in your blood or not and these people clear the virus and then they become immune and they can't have hepatitis B again. But the people who are not able to clear the virus wind up with development of a lot of scar tissue and these scars are what start to spread around the liver. The inflammation sites, the scar tissue, is called fibrosis. Hepatic fibrosis is the overgrowth of connective tissue within the liver which restricts the liver's ability to function normally and the scar tissue basically as the virus remains and continues to eat away at the liver cells; the liver cells are replaced with scar tissue. And finally you wind up with more scars and not enough liver cells and then you wind up with cirrhosis.

8. What is and what causes cirrhosis of the liver?

What cirrhosis is, characteristically, if you looked at a cirrhotic liver there is widespread fibrosis and nodule formation. The reason it looks so nodular is that of the liver cells trying to overcome the scar tissue. So they wind up with these little nodules because there’s scarring all around and the liver cells are trying to regenerate and grow out of this and at the point where they really can’t do this, that is cirrhosis of the liver you can see there’s only a few liver cells and a lot of scar tissue. The whole liver looks like that and then you get that gross appearance of that nodular situation. Once people have cirrhosis of the liver they develop liver cancer. The presence of the virus and the cirrhosis predispose to liver cancer.

9. How does liver cancer develop from HBV?

Hepatitis B is sort of a double whammy when it comes to liver cancer. In hepatitis C, you can’t get liver cancer until you get cirrhosis because what happens is you get the scar tissue as a result of the inflammation and then the liver cells are sort of trying desperately to re-grow and as they try to re-grow, they lose their control mechanism and they take off like crazy and develop and become cancer in hepatitis C and in hepatitis B and cirrhosis. But in addition, hepatitis B, because it’s a DNA virus, can on its own right unleash development of cancer modify the DNA and the liver cells and cause the patient to develop cancer without going through the stage of cirrhosis. So you have this double pronged tendency to liver cancer. Its not uncommon to see a 32-year old Asian person present with liver cancer who has no evidence of cirrhosis and in a sense never sick a day of life had no idea he had liver disease until he got a pain on his right side and was diagnosed with cancer. This is not true of other situations because for the most part in the world, hepatitis C and other reasons, alcohol, any other reasons, the cirrhosis comes first and the liver cancer comes afterwards as an aberration of the cirrhosis. But in this case, you get a lot of these young people who just having had the virus embedded in their own DNA their own DNA and liver cells gets modified to develop cancer.

10. What is the progression of untreated chronic HBV?

This is the background of the clinical situation: you get the acute infection which ranges from mild infection from people who don’t know they had it to more severe actually acute infections. There are a few people who get hepatitis B acutely and just die. We have done over the years many liver transplants of people who presented with this fulminant hepatic failure meaning they got hepatitis B and for whatever reason in their body, it just destroyed their whole liver and they needed a liver transplant. On the other hand, many people don’t even know they have the infection and there are others that are just transiently ill. Then there are the ones that go on to more severe chronic liver disease, fibrosis, cirrhosis. As the scar tissue overtakes the liver, you get liver failure, cancer, and death.

11. What is the progression of acute HBV infection?

I think this just reviews what I basically told you that the liver becomes acutely infected. The virus replicates, causes inflammation cell death. If the liver and the body clear the virus, you get a resolved acute hepatitis B. If the virus stays around and does not clear in several months, you develop a chronic infection.

12. Who is at risk for chronic hepatitis B?

The people who develop hepatitis B in adulthood when you’re immune competent, have less than a ten percent risk of developing chronic liver disease. If you contract hepatitis B at birth or early infancy when you’re immunononcompetent, you have a ninety percent risk of developing chronic hepatitis. And chronic hepatitis is the step between acute hepatitis and cirrhosis. Vertical transmission causes an extremely high rate of chronic hepatitis B and liver cancer in the Asian population. The incidence of chronic infection in China is estimated at twenty percent but in some preliminary work we did in Chinatown, we found that it was over twenty percent. This is a major number. One of five or more people in this community are infected with hepatitis B. Among Chinese males in the United States, hepatitis B and liver cancer are a major, major source of mortality.

13. What are the consequences of chronic HBV infection?

The hepatitis B virus can stay in the liver quiescently, indefinitely and cause no further inflammation in some people. Those people are called carriers. Although they are asymptomatic, carriers remain at risk for liver cancer and are capable of transmitting the disease. So a lot of the people walking around will have normal liver enzyme tests but could be carrying the virus. They are a little bit of a time bomb for themselves and for the rest of the population. A lot of these people who developed or acquired hepatitis at birth walk around with huge viral counts of like fifteen million viral particles per cc of blood and you can imagine the potential infectivity of a patient like that to their wife, to their family, or other contacts. The virus may continue to aggressively replicate and cause continuing damage leading to fibrosis, cirrhosis, and a high rate of cancer in part of the population and then you have the other part that are carriers. But it’s constantly switching over. So a person could by an asymptomatic carrier, particularly again in the Asian population and then suddenly for an assortment of reasons, the virus starts to attack the liver and they go from being what they thought was an asymptomatic carrier to someone at risk for more disease.

14. Are there treatment options for advanced liver damage due to chronic HBV infection?

I think this diagram allows an overall picture of hepatitis B progression. You start with the acute infection and go into the chronic infection. Generally thirty percent of chronically infected individuals will go on to cirrhosis. Cirrhosis leads to liver failure. Patients who get cirrhosis of their liver, twenty-three percent of these patients within five years basically die of liver failure and development of liver cancer. The graph shows that HBV is the sixth leading cause of liver transplantation in the United States at the moment and its rising very rapidly. One of the former problems with liver transplantation in hepatitis B was that the hepatitis B came back in the new liver because the virus settled in other cells in the body and reappeared in the liver. But we’ve overcome that problem now and we can successfully transplant people with hepatitis B liver failure because we have new drugs to suppress the virus in the new liver and the patients with hepatitis B work out extremely well and are much more successful than the hepatitis C patients in terms of liver transplantation.

15. How do the hepatitis B therapies work?

The treatment of hepatitis B is certainly a subject of a lot of debate or discussion and a lot of success at the moment. Over the last several years, there’s been tremendous breakthroughs in the treatment of hepatitis B. Hepatitis B is a DNA virus and it gets insinuated into the DNA of the host liver or the patients liver. It is extremely hard, once it’s settled in, to get rid of hepatitis B. So eradication of the virus totally from the body is very difficult. But the breakthrough is in the concept of how to deal with this disease. We now understand that it’s really not necessary to get rid of the virus but rather if we can suppress the replication of the virus we can prevent a development of the sequela. There are increasingly good statistics that show that the natural history of the disease is related to the active replication of the virus so we were looking for drugs that would suppress the viral replication. You can measure the viral level in the blood in most people who are infected. Now, remember that the virus replicates in the liver so in order to get viral particles measurable in the blood, especially with our new sensitive methods you must have the virus replicating in the liver to such an extent that its replicating fast enough to kill off so many liver cells or so many viruses that they’re now spilling over into the blood. If the virus was replicating very slowly, it would just go along slowly in the liver and it would affect a couple of liver cells and they would die and some would regenerate and then they would affect some other liver cells, but you wouldn’t find it in the blood. But if the virus is replicating very quickly, you find that it gets spilled out into the blood. We’ve found that if we can suppress the replication of the virus in the blood, we can significantly reduce if not eradicate the progression of the disease and that’s been the objective of the therapies. Suppression of viral replication leads to less inflammation, less fibrosis, less scarring, and a lower incidence of liver cancer. Total viral suppression and/or eradication essentially can prevent these problems of the sequela of hepatitis B.

16. What should a community hepatitis B program look like?

In the last few slides we talk about how we can manage this disease in the world and in the community. In the vertical transmission that occurs in the Asian population, the mother has hepatitis B and when the child is born he/she catches the disease in the birth canal from the exposure to the blood and the child is then born with hepatitis B. A significant number of these people are born with hepatitis B that they’ve contracted in their immune incompetent state so it goes on to chronicity. This is really the core or the source of hepatitis B in the world for the most part even though it’s not in the Western countries where campaigns have been undertaken to inoculate the infant at birth to stop this vertical transmission. Taiwan is a classic example where programs were started because if you can inoculate the infant at birth, you can prevent eighty-five percent of this vertical transmission. So, ideally you want to go out and inoculate everyone born to a hepatitis B mother in the entire world. But if you stop to think about 350 million people, 175 million are women, this is a big project especially in underdeveloped countries. That’s what we sort of have to aim for. The other thing is that every child in the world should really be immunized against hepatitis B if they haven’t already contracted it from their mother. And you’d be surprised the number of people in the United States that aren’t immunized against hepatitis B. I'm always surprised with the number of dentists for example that aren’t immunized against hepatitis B because you think they’d be at high risk, but that’s the way it goes. We need a massive immunization program. That’s the way you’re really going to attack this disease. But you first have to find out who is immune and who is not immune because some people are naturally immune because they had an asymptomatic case of hepatitis B early in their life. And some people are already infected, so there’s no point in immunizing them. That was the basis of our program that we're going to undertake in Chinatown and the Asian population of New York. Try and test the population and see how many people need to be immunized and how were going to effectively immunize those who are either not infected or not immune. I put in the last bullet on this, adult populations especially in high risk groups such as Asian communities should be mass screened for hepatitis B infection, chronic hepatitis, cirrhosis, and liver cancer to find people who are sick and also to find people who need to be immunized.

17. What is needed to manage hepatitis B worldwide?

Any patient with evidence of ongoing active hepatitis B viral replication as shown by significant elevations in their viral level in their blood should be treated to suppress the replication. Any patient with evidence of ongoing chronic hepatitis or cirrhosis secondary to hepatitis B certainly needs to be treated. The key is an antiviral therapy can prevent progression of disease and transmission to others. All patients with chronic hepatitis B infections should be monitored for cirrhosis developing, liver cell cancer developing. So you really have to monitor these patients, which is a major public expense. For example, our project in Chinatown is a large reservoir of people who come from rural areas of China recently; are basically below economic strata; and are unfamiliar with Western medicine or afraid of actually confiding in any public hospital or public health facility. So this is a problem here in the United States and its even more of a problem in underdeveloped areas around the world because all of these patients have to be monitored for development of liver cancer. As Dr. London pointed out, in New York if you develop liver cancer, you’ve got a fighting chance because we have a great program for it at NYU and there are various ways of treating it and it’s a manageable condition, but that’s not adaptable to mass populations. If you have liver cancer in rural China or in Africa and all those other places where hepatitis B is rampant, that’s it. There’s really not any effective therapy.

18. What drug therapies are currently in development for treatment of HBV?

The last slide is about looking ahead. I've talked to you about the importance of immunizations and the importance of inoculating infants and Asian and population and preventing maternal transmission. From the point of view of blood supply, we’ve cleaned that up and that’s not really a source. As we pointed out, dialysis units have been cleaned up and that’s not a source. IV drug abuse, you do what you can do with that, but that’s not really a major source in the United States fortunately at the moment. In terms of drug therapies, there are currently three licensed drugs in the United States now. One is lamivudine, which is called Epivir, which is a very effective drug, easy to take, relatively cheap, but developed resistance in the end of two to three years in two-thirds of the people who are resistant to it. The second drug is Adefovir, called Hepsera, which is the newer drug that seems to have an extremely low incidence of resistance. Its a little more expensive. It’s been studied lets say for up to five years. There has been an occasional case of drug resistance that’s come up after two to three years of therapy. it goes out over five to ten years, there may be further. The third drug is Interferon. So I think these points we’ve made, new and better treatments and immunization. Interferon is an immune stimulant. Its the treatment for hepatitis C because hepatitis C is an RNA virus and the kind of oral drugs that work for hepatitis B don’t work for C. Interferon is a drug that stimulates the body’s immune system to fight the virus as opposed to inhibiting the replication of the virus. It’s a very difficult drug to take since you have to take it by injection. It has many, many side effects and its incredibly expensive. So it hasn’t been a popular drug up to now and really the evidence that it works hasn’t been very strong. Because it’s an immune booster, it tends to work in patients who are immune competent to begin with. The big problem with hepatitis B is the chronicity in people who are immunoincompetent who got it when they were a baby and their own immune system couldn’t overcome it - that’s why they’re chronic. So the question is whether Interferon can stimulate these people to stimulate them to overcome the virus on their own by taking the Interferon injections. We’ve all been kind of pessimistic about Interferon. In addition, its extremely expensive. There’s another drug therapy called Entecavir which is about to be approved by the FDA and there are at least a half a dozen others on the horizon. The antiviral treatment may wind up being a combination of these drugs in the same way you treat HIV. Fortunately you’re probably going to need two or three and not a whole armamentarium. You may have to take the drugs for the rest of your life, but by taking one or two pills a day it may help prevent you from getting liver failure and cancer.