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Emmet Keeffe, MD: "Evolving Treatment Strategies for Chronic Hepatitis B"

Emmet Keeffe, M.D., the featured Keynote Speaker at the 4th Annual B Informed Patient Conference (June 2004), presents "Evolving Treatment Strategies for Chronic Hepatitis B" offering useful treatment information for both patients and healthcare providers.

The annual B Informed Patient Conference, sponsored by the Hepatitis B Foundation and the Hepatitis B Information and Support List, draws attendees from around the world and is the only conference geared specifically toward hepatitis B patients and families.

Dr. Keeffe is the Chief of Hepatology and Co-Director of the Liver Transplant Program of Stanford University, Stanford California as well as the President of the American Gastroenterological Association.

Dr. Keeffe has been very active in national organizations in his field and has held several leadership positions. He holds several editorial positions as well as several internet gastroenterology and hepatology editorial boards.

1. Introduction to Evolving Treatment Strategies for Chronic Hepatitis B

You’ve heard a little bit about the background of hepatitis B, and some of the epidemiology and what this disease is like around the world and in the US. What I’m going to focus on this morning is to talk about some of the evolution in the treatment of hepatitis B. We have come a long way, although we’re not there yet, as you’ll see as we go through this.

2. What is the prevalence rate of chronic hepatitis B in the world?

Hepatitis B has different prevalence rates, this is the number of cases in the population in different parts of the world and we were talking earlier about China where the prevalence rate averages ten percent. By the way, hepatitis C is 3 percent in China, so China has hepatitis C as well as hepatitis B. There are other parts of the world like parts of Africa and Russia where there’s an intermediate incidence, and in the US, we are a low incidence overall. About 0.3% or 0.4%, that’s 3 or 4 people per thousand. But that’s the US as a whole, if you live in the Bay Area and you practice as a physician or you live in an Asian community, your prevalence rate really parallels the country of origin. So, although the US statistics are low, it really depends on where you live.

3. How many people have chronic hepatitis B?

The large amount of carriers, most of whom are in Asia, the large number of deaths per year. There are 1.25 million carriers in the US, or 0.3% of the adult population as I alluded to. Now compare this to hepatitis C, hepatitis C is 4 million adults in America and about 2% of adult Americans, so hepatitis C gets a lot more of the press but we’re working on that to try to get more of the press interested in realizing that hepatitis B also is a major infection in the United States. The real concern is the premature mortality from cirrhosis or HCC (the abbreviation for hepatocellular carcinoma) liver cancer, that also goes by the name "hepatoma", and that ranges from 15% to 40%, or roughly a quarter of the people with chronic hepatitis B. This is in particular people who are infected early in life. We’re a little less knowledgeable about people who are Caucasian Americans infected in their adolescence or early adult life about whether these same kind of statistics really apply.

4. What is the natural history and progression of hepatitis B?

A little bit about the natural history of hepatitis B. There is the acute infection, if you’re a newborn child (born to a mother with hepatitis B) and you do not receive the hepatitis B immune globulin, or the vaccine as a young baby, there is a 90% or more chance of infection. However, probably less than 10% of adults develop chronic infection, so most adults will recover from acute hepatitis B. When it’s chronic, the concerns are over time, liver cancer and over time, cirrhosis. Now there are two kinds of cirrhosis, there is cirrhosis in which the individual has good liver function and really feels OK, can work full-time, can run a marathon, really has good liver function. And then there’s cirrhosis with liver failure or decompensation, and that in one study occurred in about a quarter over a five year period. Now if there is liver cancer, or liver failure, that may eventually lead to death. But as shown in the center here, we now are able to apply, not to everybody as we would like, but to some segment of the population, are candidates if they have a small tumor, for liver transplantation or with liver failure, can also undergo transplantation. Chronic hepatitis B is the 6th leading cause of liver transplantation in the US, so it’s not the top cause, hepatitis C and alcohol are the top causes, but it’s up there in terms of top causes for liver transplant.

5. What is the natural clearance rate of the surface and e-antigen?

Now what about if we do nothing? If we don’t have any therapy at all for hepatitis B, is there a natural clearance rate? Well there is, but it’s very low. And I have to say that I only rarely see this in my practice, but there are some very nice reports in the literature, particularly from Taiwan and China, showing that if you follow a large number of carriers, particularly older individuals, that they will actually lose the surface antigen. The surface antigen, that we abbreviate HBsAg, is really the marker of infection. When that goes away, the antibody of recovery is called the surface antibody, abbreviated Anti-HBs, occurs. But more importantly, as it relates to therapy, is there is an antigen called the “e-antigen”, which is a marker of activity of the virus. And so, it along with DNA indicates an active virus. This particularly applies to what is called the “Wild type” virus. Now the e-antigen will spontaneously convert in about 4%- 12% of carriers per year, even if we do nothing. That means the disease shuts down spontaneously. In over 5 years it’s 40%-50%, over 10 years it’s 70%-80%. These studies come from Asian countries, and also from Brian McMahon, who’s been very carefully studying Native Americans in Alaska and has published some very nice papers. This occurs more often in older individuals and those with elevated liver enzymes. The ALT, that patients sometimes called the “alt”, is the abbreviation for the alanine aminotransferase, it’s a liver enzyme. It’s simply a protein in the liver cell. When the liver is inflamed, that protein gets out of the liver cell into the blood stream, so it’s a marker of inflammation of the liver. The ALT tends to be higher in people who are converting. So some doctors, and you’ll see some guidelines that are conservative will say that if we see a new patient, and the ALT level is up to 200- 400, and the patient is e-antigen positive, that patient may be going into a spontaneous sero-conversion, they’re going to lose the e-antigen and develop the e-antibody, and they’re going to become quiet without therapy, so wait, don’t treat right away. My own philosophy, I would rather initiate therapy and accelerate sero-conversion because when the ALT is elevated, there is liver damage taking place. I would rather accelerate the process if I can. Now up to 20% who lose the e-antigen may revert back and become active, but that’s the high figure, it’s more like 5% over a lifetime. Now the one thing we’ve learned, for those of you who have hepatitis B, if you ever have a malignancy, and have to have chemotherapy, like breast cancer or colon cancer, you need to be protected with an oral agent, like lamivudine or adefovir, because while you’re having chemotherapy, there’s a high likelihood your hepatitis B will reactivate again. Now, oncologists are starting to get that message out, but it’s still not there across the community, so you should be aware of that, that’s one of the issues that will lead to the reactivation of hepatitis B.

6. What is the risk of liver cancer for someone with active chronic hepatitis B?

We also know, from studies from Taiwan, this is a publication from Dr. Yang in Taiwan, that there is a higher risk of liver cancer when the virus is active as shown in the red line. And this is the cumulative percent incidence, so this is the new development of liver cancer. It’s much higher in the e-antigen positive than the e-antigen negative, and it’s very low, of course, in people who don’t have hepatitis B, as sort of a comparison group.

7. Is the presence of hepatitis B DNA associated with increased risk of liver cancer?

And the same investigators looked at the other marker of an active virus, which is the hepatitis B virus DNA level. People were four times more likely to have liver cancer if the DNA was detectable at a high level. In this particular study, it was used at 10 to the fifth by a particular assay. So this therefore suggests, and this is only a suggestion, that maybe we can prevent the long-term risk of liver cancer if we can have a sustained suppression of the HBV DNA. Now, that’s not been proven, this is only a supposition because of these kinds of data. More and more, as we talk about treatment and we look at what’s the endpoint- we want to have a sustained suppression of the HBV DNA.

8. Is there more than one type of hepatitis B virus?

There is more than one hepatitis B virus. The one I learned about in medical school we now call the wild type. This is the usual- what we now call “e-antigen positive hepatitis B”, these are individuals that have detectable DNA, have an e-antigen and do not have an e-antibody. This is the usual wild type. Now in a survey that I participated in, in the United States, 27% have a mutation called the Precore Mutation, and 44% of United States patients with hepatitis B have another mutation called the Core Promoter. In both cases, there is no e-antigen in the blood and there is an e-antibody, but the DNA is high, so these are active viruses. And this will confuse physicians because they all learned in medical school that if the e-antigen is not present then it’s inactive, but these two are exceptions. Now we do not have commercial tests that we can check off when we see you as a patient to get this done in the laboratory, so we have to make this judgment when we see that you do not have an e-antigen, you have an e-antibody but your DNA is high, and often your liver enzymes are high as well, we then diagnose “e-antigen negative chronic hepatitis B”. When I dictate my notes so I can remember, since I have a large practice, I always say “I just saw Mrs. Smith who has e-antigen positive chronic hepatitis B or e-antigen negative chronic hepatitis B,” so I can keep track of all of my patients. Now if that weren’t confusing enough, we’ve had two therapies that have come into the market in the last few years, one is called lamivudine, it was licensed in the US in 1998, and adefovir that was licensed in 2002, and both of these drugs when given to a patient over time can cause a drug-induced mutation. The one with lamivudine is called the YMDD mutation, it occurs at a relatively high rate, at about 20% per year. It’s sort of a partial failure of the therapy when this mutation occurs. And with adefovir, there was none at one year, 2% at two years, and the latest data published in Berlin is 4% at three years. So adefovir has a lower rate of forming mutations. They have different names, this will really blow your physician out of the water if you tell him, “I’m worried, Doc, about developing the N236T mutation and the A181V”. These occur fortunately at a lower rate with adefovir. Now it turns out that you’re not born with the precore and the core promoter mutation, patients who are infected early in life are infected with the wild type. When there is a phase that occurs in early adult life of beginning immune recognition of the virus, that’s the time that the virus can mutate, and rather than going from e-antigen positive to e-antigen negative and becoming quiescent, one of these two mutations form during the time of attempted spontaneous sero-conversion.

9. What is e-antigen negative chronic hepatitis B?

So let’s review what is somewhat new to many physicians in practice, what we now simply call e-antigen negative chronic hepatitis B. They mostly harbor the two variants that I mentioned, the precore or the core promoter; they’re not acquired de novo, or all by themselves. They’re selected out during the immune clearance phase. That occurs usually in early adult life. So the wild type switches and undergoes a mutation. How do we make the diagnosis in our routine day in and day out practice? Well, we see a patient that has a negative e-antigen, a positive e-antibody, a DNA that has to be at least 10 to the fourth, so it’s a log 4 copies, ALT is usually elevated, but it may be intermittently elevated. This confuses physicians, because the first visit for a patient, the ALT may be normal. So with a normal ALT and a negative e-antigen, it looks like there’s inactive hepatitis B. That’s why it’s important that all hepatitis B patients see their physicians about twice a year to do routine blood work, because it may take serial blood work in order to make a clear diagnosis. Another thing is that with the two oral agents, sustained remission is uncommon, so what’s intimidating for patients with e-Negative chronic hepatitis B, is when you initiate therapy, it’s probably going to be long-term therapy, maybe lifetime therapy. And e-Negative also has somewhat of a more progressive course than does the wild type.

10. Are there different genotypes of the hepatitis B virus?

I want to highlight, for those of you who want to keep up with the literature, there’s an evolution now of hepatitis B virus genotypes. Let me just summarize to say that this is not something we use in day-in day-out clinical practice. This is new information, this is evolving, and we don’t have clear consensus on all the research yet. In the case of hepatitis C, genotypes are critically important, they help us make major decisions about therapy. But there are some interesting things that are coming out here. There are now seven genotypes that are classified by the letter of the alphabet. The way to remember it is that Northern Americans, the Caucasian US population are A and D and the Asian US population are B and C. These other ones are less common. One association is the B genotype appears to be less active, more slowly progressive than C, maybe because it has an earlier sero-conversion.

11. What are the demographics of hepatitis B genotypes in the US?

This is a study that I participated in with Dr. Chu, who’s a colleague of Anna Lok, at the University of Michigan, that tells you a little bit about the demographics of the United States. The blue is A, and the pink is D, and yellow and orange are B and C. So out here in the west, the centers that participated were Stanford and UCLA, so you can see we have large Asian populations in our practices out west. But if you go to the Northeast or the Southeast, you see more of genotype A, because there are more Caucasian and Hispanics that were entered into these studies.

12. Is the response to therapy related to HBV genotypes?

So this is something that may come into our routine practice, there’s beginning to be some early reports that at least in the case of interferon, in Caucasians, A responds better than D, and B responds better than C for interferon therapy. But for lamivudine therapy, there was no difference in the response rate, nor were there in the adefovir pivotal trials, so genotype did not predict response to therapy.

13. What are the phases of chronic hepatitis B?

Here’s the other thing that is confusing to our physician colleagues, which is the so-called phases of chronic hepatitis B. This was institutionalized by the NIH at a consensus conference about 5 or 6 years ago in a publication in our literature. They made the suggestion that we should try to characterize our patients who have hepatitis B virus infection into being either in the immunotolerant phase, the immunoactive phase that in our lingo we call ‘chronic hepatitis B’, or who are inactive carriers. Now how do we tell the difference? Well, sometimes it takes more than one series of tests, but immunotolerant phase are e-Positive, so they have the wild type, their DNA is high, sometimes so high that it’s very frightening to the patient and to the doctor, but the ALT is normal. So the concept here is that these are people infected at birth or early in life, when their body’s immune system was immature, and the virus was not seen as foreign. They were born with it, so the immune system doesn’t see it as some sort of foreign protein in the body, so there’s no immune reaction against the virus. For reasons that are unclear, some time in early adult life, something triggers and the immune system begins to see the virus as foreign, and that’s when the liver enzymes go up. This is the immunoactive phase, when there’s immune activity against the virus. From all of our studies with interferon, lamivudine and adefovir, our drugs are most effective when given in this phase because there’s two things going on: the body’s immune system is trying to get rid of the virus, and then we prescribe an anti-viral agent, so it’s sort of like a double hit, an active immune system and an anti-viral agent. Therapy in the immunotolerant phase has not been particularly effective in getting a sustained clearance of the virus. And it’s OK, because although this is frightening to doctors and patients sometimes, there’s really very little going on in the liver. If you do liver biopsies, which we don’t routinely do, the biopsies are normal or there’s just very minimal inflammation in the liver. Now in the phase that we call chronic hepatitis B, the e-antigen may be positive if it’s wild type, or negative if it’s one of the two mutants, DNA is high, sometimes on average a little less higher, the ALTs are elevated and patient may or may not have symptoms. Most often there’s no symptoms, but there may be some vague right upper quadrant aching that’s quite nonspecific in nature. Now if all goes well, in the wild type, in the immunoactive phase with the e-Positive, will go down to this phase and will become an inactive HBsAg carrier. Now the old lingo we used to use was “healthy carrier”, the NIH said that’s a misnomer, because these people have infection, they’re still at risk for liver cancer, and to use the word healthy is inaccurate. So the lingo now is inactive HBsAg carrier, these are e-Negative, DNA becomes low now and is typically less than 10 to the fourth so you still may have detectable DNA, but the ALT tends to be normal. These are the people that occasionally, in the Chinese and Taiwanese study, may actually lose surface antigen and have a clearance.

14. How do doctors assess chronic hepatitis B?

For the diagnosis of hepatitis B, what is typically done, and has been done for years, are we always get, when we first see a patient, these two markers. Patients have already been diagnosed when they come to a referral physician, so we already have positive surface antigen, so chronic hepatitis B is already known at that time. We measure DNA by a sophisticated assay. We all use now what’s called a Polymerase Chain Reaction which is a very accurate assay. And then we assess liver status through a liver function panel that looks at liver enzymes. We may or may not do a liver biopsy, we don’t tend to biopsy everybody with hepatitis B. We tend to use a biopsy if there is confusion in the categorization. We get an ultrasound for baseline imaging, even in young patients, and an alpha-fetoprotein.

15. What are the serological markers for hepatitis B?

These are the serological markers that are available in our laboratories. The surface antigen, now even for our physician colleagues, it’s hard to even pronounce these tests, because this is the hepatitis B surface antigen, and that’s a mouthful, so I always tell the students to just call it surface antigen- two words, easy to say. Sometimes they call it HBIG, HBsAg, it’s all hard to say, just call it surface antigen. The surface antigen is the marker of infection, it’s the first thing that appears in a person that’s infected, and by arbitrary convention, if it sticks around for more than 6 months, we call that chronic hepatitis B. So that individual, if they have gotten infected as an adult, aren’t getting rid of it, it’s become chronic. E-antigen indicates active replication except in the precore and core promoter mutants where it’s absent. The surface antibody is recovery or immunity so that if an individual had natural infection and then cleared, they will have a surface antibody. This is also the antibody that you get after your vaccination, because when you get hepatitis B vaccine, you’re vaccinated with purified surface antigen. It’s recombinant, it’s made in the laboratory, and that leads your immune system to develop a surface antibody against that surface antigen. And once in a while, to make things even more confusing, people who are chronically infected and have the surface antigen may also have the surface antibody, now that really causes a lot of confusion and happens in about 10% of individuals. It has no particular relevance; it just is a little confusing. The e-antibody we’ve already talked about generally indicates inactive virus, except in the precore. Now the core antibody is a little more confusing, because this indicates present or past infection, so that when you’re infected with hepatitis B, you will develop the surface antigen right away, and right away, you’ll develop the core antibody. If you go on to recover from hepatitis B, you will lose the surface antigen and develop the surface antibody, but the core sticks around. The core antibody comes right when you’re infected, and it sticks around for the rest of your life. People who have natural immunity will have both antibodies, the surface antibody and the core antibody. People who get the vaccine shot and are protected will only have one antibody, the surface antibody.

16. What are the AASLD Practice Guidelines for treatment of chronic hepatitis B?

General management and counseling- this comes from Anna Lok at the University of Michigan and Brian McMahon who’s in Alaska and they’ve published a guideline that was just updated a couple of months ago and what they recommend are some common sense things. These are not evidence based, we can’t prove you ought to do this, but it just makes good sense to physicians. You ought to see carriers on a regular basis, and we think every six months is a reasonable interval for follow-up. The tests that we do routinely are the liver enzymes, the ALT and AST, alpha fetoprotein, and imaging. If the patient is an inactive carrier, that’s all we do. If the enzymes increase, then we have to re-evaluate what’s going on, something has changed. If they have chronic hepatitis B though and the ALT is elevated, then we follow with a CBC. Now why a complete blood count? That’s the hemoglobin, hematocrit, white count and platelets count. Well because we know that if you’re developing scar tissue in the liver, fibrosis, that’s going to make your spleen become more active and that’s going to lower your platelets count. So we get concerned if we see a gradually falling platelets count. In our world of hepatology, in liver practices, we call the platelets count, a poor man’s liver biopsy. Because if the platelets count falls, we know there is developing hepatic fibrosis. We monitor that, as well as the liver function tests and we measure regularly the e-antigen and e-antibody.

17. Are there other counseling recommendations for someone with chronic hepatitis B?

In terms of counseling, we do a lot of things that Dr. Sam So has emphasized as well, although we didn’t really emphasize vaccination. One of my research interests that I’ve published quite a bit is that if you have underlying chronic hepatitis B or chronic hepatitis C or some other liver disease, and you get acute hepatitis A, it will be a more severe liver illness if you already have pre-existing liver disease. Therefore, the CDC now recommends hepatitis A vaccine for all people with any chronic liver disease, alcoholic liver disease, hepatitis B, hepatitis C. Now many of the Asian community that are my age, that were born in China, already have hepatitis A antibodies, about 90%-95% are already immune. So, it’s worth checking an A antibody. Hepatitis A is a very silent infection, occurs often in childhood in Asian countries and most Asians who are adults are already immune and don’t need the vaccine, but younger people are often not immune and need to be vaccinated. Alcohol- now this is just common sense, no one has studied the lower threshold. The best data is from the hepatitis C literature and we know that people who drink daily and heavily have an accelerated progression of their hepatitis C it’s probably the same for hepatitis B. People need to be counseled about infectivity, and there it’s DNA and e-antigen. 50% of sexual partners will be infected with hepatitis B. This is also not widely known- hepatitis B is far more infectious by sexual contact than HIV and more than hepatitis C. Now if you have a low DNA, then there’s a low risk of sexual spread, but you can still spread hepatitis B. All household contacts should be tested and all newborns should be vaccinated.

18. Should someone with chronic hepatitis B be screened for liver cancer?

Screening should be considered in all carriers. We know that liver cancer begins as a single lesion in most cases and the doubling time is wide, unfortunately, but it averages 6 months. That’s why the screening has been recommended every 6 months, based on this average doubling time. The alpha fetoprotein is kind of a minimal test although it has a lot of limitations and therefore is alpha fetoprotein plus ultrasound is the standard in anybody with cirrhosis, any positive family history and beyond a certain age. Many of us start earlier anyway.

19. What are the licensed treatments for chronic hepatitis B in the US?

There are three licensed therapies in the United States. One is interferon therapy and what’s licensed is Intron A, this is a Schering product at a dose of 5 MU per day or 10 MU per day three times per week over a four month period is the standard. Now it doesn’t mean that you can’t treat for six months or a year, but this has been the standard. There are a lot of studies underway looking at the pegylated interferon, the one shot a week, long acting, but they’re not licensed yet, but I’m sure they will supplant standard interferon in the future. And I would say there’s a renewed interest in interferon. The two oral agents are Epivir, 100 mg per day, licensed in 1998, and Hepsera, 10 mg per day, licensed in 2002. We don’t have time today to talk about transplant, but transplant is widely accepted and is very effective when there is decompensated liver disease or an early liver cancer that is in an area that the doctor can’t get to it, or there’s too bad of a liver disease so it’s not safe to do surgery.

20. What are the response, duration and durability for the three hepatitis B treatments?

Here’s a summary for the three drugs that are available. I’ll just go through these slowly for you one at a time. So this is, first of all, the published data in the one-year response, e-Positive, and here’s the wild type, e-Negative (precore and core promoter mutants). Now the response for the e-Positive is defined as loss of e-antigen, development of e-antibody, and a low DNA. That occurs in about 20% with interferon, 16%-18% in four different studies for lamivudine, and 12% in the Gilead adefovir studies for one year of therapy. So these are relatively low rates, and as you’ll see later, if you treat longer than a year, these numbers go up. Now the e-Negative, here there’s a different end point. They’re already e-Negative to begin with, so the end point is only the DNA. And so the DNA comes down low, and that occurs commonly with e-Negative. All of these therapies will lower the DNA level. The problem, if you skip down to the third box, is the durability. For e-Positive hepatitis B, if you treat for a year and you stop when there is loss of e-antigen, development of e-antibody, it’s durable for 80%-90%, for lamivudine it is a little lower, 60%-80%-there’s a higher relapse rate. This data was just published also in Berlin; it was 91% with Gilead for adefovir. So, you stop therapy the patients will have a persistently inactive virus. For e-Negative, it’s very very low. In other words, these patient’s DNA will always come back up again. Duration of therapy for interferon has four to six months for e-Positive. There is new information suggesting that one year of interferon therapy may actually get a fairly good sustained response rate. I think we’re going to see some renewed interest, although we use a lot of oral agents. The pegylated interferons are a little better tolerated and for those with e-Negative, we’re starting to see some better results. And for the two oral agents, we just simply treat long-term.

21. Are there other notable differences between the treatments, including side-effects?

Now the route of administration, this is subcutaneous, the other two are oral. Side effects are many, interferon causes flu-like symptoms, aching, and tiredness. It causes psychiatric and psychological changes in 30% of patients, that’s either irritability, or depression, or sleep disturbance, or all three and it can lower the blood counts. Both lamivudine and adefovir in the pivotal trials- the drug equals placebo, in other words, when they analyzed all of the side-effects, headache, stomachache, diarrhea, fever, you name it, there was no difference between people who got the drug and the dummy tablet. We all get headaches every now and then, so you have to always have that control group that gets the placebo. So these virtually have no side effects. Therefore, there’s no contraindication, except here, interferon you cannot use this in people who have serious psychiatric disease or have other auto-immune disease like rheumatoid arthritis. Now, the advantage of interferon is there is no resistance, where here it’s 20% in one year, goes up to 70% in 5 years. This is really the Achilles heal of lamivudine therapy is this resistance rate. Lower rate here. Cost, these are all expensive therapies, interferon is quite expensive. Lamivudine is about $100-$150 per month, adefovir is about $400-$450 per month, so it is three times as expensive.

22. Does the hepatitis B virus develop resistance to the anti-viral treatments?

Here are some of the comparisons of the resistance. This looks at one year of therapy with the two oral agents, the yellow is adefovir and the green is lamivudine, and resistance was zero, and 24%, 2%- 42%, 3.9%-53% and then 70%. So you can see, resistance is really one of the key issues of difference between the two drugs.

23. Are the oral treatments for hepatitis B complimentary in treating resistance? (lamivudine resistance and adefovir)

One of the beautiful things about the oral agents is they are complimentary in terms of treating resistance. In people who develop resistance with a YMDD mutation, adefovir is active against that mutation, and the flip-flop occurs. Here’s a study by Marion Peters, who’s up at UCSF, just published, she did a study and took a group of people that had development of lamivudine resistance. Now, I told you how we define that: the DNA going up one log. But in this study, they actually measure what we call sequence analysis, to absolutely confirm that this was the YMDD mutation. And then they randomized patients in a research study into either continuing lamivudine, adding adefovir to lamivudine in the green, or in the yellow, switching to adefovir. And you can see that you can just switch to adefovir, and the DNA level which is here on the ordinate goes down to the same degree. You don’t need to have both lamivudine and adefovir. When the YMDD mutation occurs, you can switch to adefovir and you will get an equally good response.

24. Are the oral treatments for hepatitis B complimentary in treating resistance? (adefovir resistance and lamivudine)

Now what about people who get adefovir and develop the N236T mutation? Here are four patients who are on adefovir, they developed a mutation as confirmed at different points, and then they got switched to lamivudine and you can see the DNA level in each case drops down. Here, one patient had the A136V mutation, it drops down. So you might say to yourself, some of you know about the world of HIV. HIV also is a virus that is very prone to mutations. So how do we treat HIV? We treat HIV with a cocktail of several different drugs. And the reason that is done is to prevent resistance. And the HIV virus is even more prone to resistance as is the hepatitis B virus. So why don’t we use lamivudine and adefovir? Well the reason we don’t is because it escalates the cost and there is no added benefit in terms of the DNA lowering or the ALT. If we could prove or research shows that two oral agents make the liver better, make the DNA lower, then that’s probably where we’ll end up going.

25. Is pegylated interferon effective in treating chronic hepatitis B?

Interferon may be having resurgence. This is the first published study by Dr. Cooksley who’s an investigator in Australia looking at pegylated interferon. Now pegylated interferon is the regular interferon molecule that is hooked to polyethylene glycol. Polyethylene glycol is a molecule that extends the blood life so that the interferon stays in the bloodstream for the whole week. So you only have to give injection once a week, rather than injection every other day, and it’s also more potent for that reason. Dr. Cooksley looked at the Roche pegylated interferon Alpha2A, and he looked at different doses because it wasn’t clear what would be the right dose. This is what we use in hepatitis C, we use 180 micrograms, and he compared that to regular standard interferon at the standard dose of TIW, that’s three times a week. He studied only the e-Positive hepatitis B.

26. What is the combined response of treatment between interferon and pegylated interferon?

Here are the results. This is a combined response. He defines that as e-antigen loss, DNA less than 10 to the fifth, and a normal ALT. That occurred in just under 30% at the two different doses of the pegylated interferon. So that’s a pretty good response rate with pegylated interferon. There are now studies underway looking at pegylated interferon plus adefovir and pegylated interferon plus lamivudine. Many of us think that’s where the future of the treatment of hepatitis B is going is to combination therapy.

27. How has the HBV treatment landscape changed?

We met a while back and looked at the treatment landscape and looked at the historical development: interferon 1992, lamivudine 1998, adefovir 2002, diagnostic progress- we only had serology back in the old days. Then we got a DNA assay although it wasn’t so accurate and now we have PCR. Therefore we have to rethink what we do.

28. Who participated in writing the HBV Treatment Algorithm?

This is a group of physicians that got together and wrote this paper. These are people who see a lot of hepatitis B patients around the country. Dr. Dieterich is in New York, Steve Han is at UCLA, Ira Jacobsen in New York, Paul Martin in L.A., Gene Schiff’s in Miami, Hillel Tobias in New York and Terry Wright in San Francisco.

29. Why was the HBV Treatment Algorithm written?

We looked at the guidelines that were published at the time and we wanted to get a clear algorithm for physicians that would try to increase awareness and also increase the aggressiveness of treatment. We sort of have a bias that there has been a certain amount of nonchalance in the Asian community. For example, people say, “well, my mom has it, my sister has it, I feel well, why should I see a doctor and consider therapy?” But also there’s been a certain nonchalance among the physician community. We’ve been more gung-ho to treat hepatitis C, but I think to a certain extent we’ve neglected being appropriately aggressive in treating hepatitis B.

30. What are the key issues with the current guidelines focused on by the Treatment Algorithm?

The issues that we looked at in putting this guideline together were that PCR was critically important. Not only in identifying active disease, but also the rebound, when resistance occurs. You can’t diagnose resistance if you’re using a hybridization assay. Some of the labs in the community still use the hybridization assay. Now how do you know that? It comes back in picograms/ml rather than in copies/ml, and is much less sensitive. The ALT, we’ve talked about that. Some of the guidelines from Dr. Lok and Dr. McMahon say, “don’t treat people unless the ALT is more than 2 times the upper limit of normal”, we feel that’s too conservative. And also, what’s a normal ALT? In our laboratories, normal ALTs are often 40, 45 and sometimes even 60. And that’s because we have become an obese country, as you know. 23% of Americans are obese. How do labs get normal values? They survey people that walk through the door, and then they develop a bell-shaped curve and do two standard cutoffs and say everything below that is normal. But the people who walk through the door to get routine blood tests, some have undiagnosed hepatitis B, or undiagnosed hepatitis C, a lot drink, and a lot of them are obese. And so the normal ALT is higher than it really ought to be, we appreciate that. And biopsy is always challenging, but we thought we needed to individualize and use selectively when needed to clarify the diagnosis.

31. What are the AASLD Treatment Guidelines for hepatitis B?

Now Dr. Anna Lok and Dr. Brian McMahon are good friends of mine I have to tell you, we do a lot of work together. But let me beat up on them a bit. They published the AASLD Guidelines (this stands for the American Association for the Study of Liver Disease) and as I said, this is the more recent reference that just came out in 2004. Here is their suggested guideline. And in the yellow are the ones that I take a little bit of exception to. They said if you have e-Positive and a DNA, and by the way, they just used greater than 10 to the fifth because this was an arbitrarily chosen value for a positive DNA. So they said, if you have the wild type, and the DNA and the ALT are less than two times normal, observe. If you have a patient that has the wild type virus, e-Positive, DNA high, and the ALT is greater than two times the upper limit of normal, so let’s say that’s 150 ALT, observe six months, treat if no sero-conversion. That’s the point I made earlier, I would rather initiate therapy because if the ALT is 150 or 200 or 300, there is active inflammation going on and I don’t know if that patient is going to sero-convert in the next three months or six months, I would rather initiate therapy. And as I said earlier, I think if an ALT is one and a half times normal, I think most people feel that’s good enough to treat. Now what about the e-Negative patients? The DNA is high, they say if the ALT is greater than two-fold, treat. We would all agree with that. But if the ALT is less than two-fold, they say observe. I would disagree with that. I think that e-Negative chronic hepatitis B is a more serious illness and these people ought to be considered for therapy. If there’s cirrhosis, treat, we would all agree with that. But if the DNA is low, observe. Many of us feel that if there is already cirrhosis even if the DNA level is 10 to the third or 10 to the fourth, that’s enough to treat because there has already been severe liver damage.

32. What are the recommendations made by the treatment Algorithm panel?

So this is our group’s proposed approach to therapy with whatever drug you choose, or you as a patient choose to take. And by the way, the decision of taking interferon, or lamivudine, or adefovir I think is a partnership decision between your doctor and yourself. We educate, we tell up the up-sides and down-side, the pros and cons and then we make a decision together. All three therapies are acceptable. I would say any elevated ALT, doesn’t need to be two-fold, or repeated flares don’t need to wait six months. DNA greater or equal to 10 to the fifth in the regular e-Positive, the wild type- but it’s been shown if you have e-Negative chronic hepatitis B, 10 to the fourth occurs in a lot of active hepatitis B- that’s enough to treat. E-Positive or negative, if you do a biopsy there ought to be moderate disease on biopsy.

33. What is the appropriate DNA level for initiating treatment of chronic hepatitis B?

This is the same author I worked with before, Dr. Chu, he did a large study in Taiwan. He looked at a large number of patients with different types of chronic hepatitis B and he showed that 1/3 of e-Negative chronic hepatitis B had DNA that was greater than 10 to the fifth , but here’s the important point- 2/3 of e-Negative that had chronic hepatitis B as well as all inactive carriers had a DNA of less than 10 to the fifth. Quite a few patients who were e-Negative who had active disease on biopsy had 10 to the fourth. So, 10 to the fourth is an adequate threshold to treat.

34. What is the treatment algorithm for patients with HBeAg positive compensated disease?

So here is the algorithm that we published in the paper. You have a patient that’s e-Positive, we look at the DNA. If the DNA is less than 10 to the fifth, then probably that patient can be followed because they have inactive disease. If the DNA is greater or equal to 10 to the fifth then we look at the ALT. If the ALT is normal, that’s probably immune tolerant, now you can consider a biopsy, but most of us would do serial laboratory testing because this is probably immune tolerant. But if the ALT is elevated, then these are candidates for either of the first line therapies.

35. What is the treatment algorithm for patients with HBeAg negative compensated disease?

What about e-Negative? First we look at the DNA. If it is low, but here we use 10 to the fourth instead of 10 to the fifth , we don’t treat, these are probably inactive carriers. If the DNA is 10 to the fourth or higher, we look at the ALT. Now here, I would consider more strongly a biopsy because these people are more likely to have active disease and we would like to define that. It’s easier if the ALT is elevated- then treat. Now here, adefovir is probably preferred, because as I said earlier, you have to use long-term therapy, so you probably want to use a drug that has a lower resistance rate.

36. What is the treatment algorithm for patients with compensated cirrhosis?

If there’s compensated cirrhosis, we look at the DNA. Equal to or less than 10 to the fourth you can either observe or treat, but greater than 10 to the fourth we all feel you should treat.

37. What is the treatment algorithm for patients with decompensated cirrhosis?

If there is decompensated cirrhosis, these people need to be considered for a liver transplantation.

38. What are the advantages and disadvantages of the current approved hepatitis B treatments?

To summarize what I’ve reviewed with you, and this is what I try to talk about with my patients, there’s advantages and disadvantages of our three therapies. I’ve only highlighted a few of them here. Interferon, and I haven’t discussed this, but there is about a 5%-8% chance with interferon you actually will lose the surface antigen, that’s higher than the other two therapies. It’s only a short duration of therapy, 4-6 months on average, it has to be given by shots and there are a lot of side effects. Both of the oral agents, they’re oral, there’s good tolerance you can use it in end stage liver disease, whether it’s cirrhosis or liver failure, and you use lamivudine in adefovir failures and adefovir in lamivudine failures. The disadvantages are that drug resistance is common, about 20% per year, where here you also have drug resistance but it’s less common. Now there are new studies from Berlin, they showed here loss of surface antigen in 2% of patients at one year, not bad. It’s not as high as interferon but it’s reasonable.

39. Are there new treatments on the horizon for treatment of chronic hepatitis B?

The other thing to be encouraged about, is that hepatitis B is actually a rich area of ongoing studies. These are abbreviations of drugs that are in various stages of study. Entecavir, that will be out by Bristol Myers Squibb will probably be on the market in about a year or a year and a half, it’s in the latest stages of study. They all have different characteristics. What encourages me is that some of my patients, when they have e-Negative chronic hepatitis B, we say we’re going to start adefovir and you’re going to have to take this for a long time, that creates an anxiety because there will be a certain amount of resistance. But I know that lamivudine is effective against the A181V mutation and I suspect that some of these agents will also be active against other mutations. So the bottom line is that we’re going to have a whole shelf-full of drugs over the next five years, and probably more use of interferon, so that there will be lots of treatment options as we go down the road.