NIH CLINICAL CENTER GRAND ROUNDS
Episode 2010-02
Time: 1:12:37
Recorded January 13, 2010
"Treating Chronic Hepatitis B and C." The speaker is Dr. Jenny Heathcote, professor of medicine and Francis Family Chair in Hepatology, University of Toronto. She also heads the Patient-Based Clinical Research Division at Toronto Western Research Institute.
ANNOUNCER: Discussing Outstanding Science of the Past, Present and Future - this is NIH Clinical Center Grand Rounds.
(Music establishes, goes under VO)
ANNOUNCER: Greetings and welcome to NIH Clinical Center Grand Rounds, recorded January 13, 2010. This is a special, "Contemporary Clinical Medicine, Great Teachers" Grand Rounds, with Dr. Jenny Heathcote, professor of medicine and Francis Family Chair in Hepatology, University of Toronto. She also heads the Patient-Based Clinical Research Division at Toronto Western Research Institute. Her topic, "Treating Chronic Hepatitis B and C."
We take you to the Lipsett Ampitheater at the NIH Clinical Center in Bethesda, Maryland for today's presentation.
HEATHCOTE: Thank you very much. I do have a lot of bad points but we'll leave those until later. So it really is a great honor to come here and be asked to speak to, I gather you are a mixed audience, both clinicians and Ph.D.s and different specialties. And I was asked to talk about treatment of viral hepatitis and I have tried to make the talk as relevant as I can to general internal medicine. So we're not going to go through the minutiae of what percentage, et cetera, et cetera. But really sort of try to convey a story.
First of all, of course we always have to make this financial relationship slide and you'll see that I have had financial only relationships with virtually any company that makes drugs for viral hepatitis. Yes, I am going to in my presentation discuss some of those drugs. So I was also told that I have to give the key points of the talk at the beginning. So if you want to leave after this, that's just fine. And I thought, well, there's a good point, antiviral therapy prevents liver failure in cirrhosis and improves survival. That's a pretty good point. But there's a bad point. Inappropriate use of all antiviral therapy promotes viral resistance. What I didn't add would be deterioration of liver disease.
The third point is not ugly, or it is to some, but it's really reality, that both preventive and therapeutic strategies need to be implemented to accomplish eradication of hepatitis B and C. And there are very few of us who implement those two things simultaneously. So I am referring to viral hepatitis as the alphabet soup of viral hepatitis but I'm actually only going to be talking about hepatitis B and C. You all know about hepatitis A. An acute infection that can be permanent and there's long lasting immunity and you don't get obviously infected again. B, again, can be an acute infection generally in adults and maybe good long lasting immunity. But unfortunately if you acquire hepatitis B as a neonate or toddler you're likely to get a chronic infection, cirrhosis and/or liver cancer in 40%. Hepatitis C is the newer virus on the block so to speak. This is a short-lived infection in most, particularly when infected as children and we now know that clearance of this virus is associated with specific SNPs of the interferon lambda gene. You and I are more used to chronic infection, because 50 to 80% of people infected with hepatitis C get a chronic infection and cirrhosis and liver cancer develop in 20 to 30% within 20, 25 years. If you live longer than that the rate is going to be higher. So genotype -- virus D requires simultaneous infection with hepatitis B, gives rise to more severe liver disease and we don't see too much of that in North America.
Now, recently viral hepatitis E has been described, it's probably transmitted from animals, it's water borne, it gives rise to to acute infection only. But if the patient is pregnant it carries with it a 20% mortality rate. Let's get to the prevalence of hepatitis B worldwide. You may think you're off the hook in North America but I will demonstrate that you're not. And you can see that in China, South Africa, and some parts of South America, greater than 8% in China, some places 20%, are infected chronically with hepatitis B. Similarly in South Africa and parts of South America, and here we are thinking we're fine, less than 2% in North America. So I live in Toronto. There are 1 million Chinese who live in Toronto. I see a lot of hepatitis B and so will you if you work with new immigrants. I want to briefly just go over the natural history of this disease, as beautifully described here by Anna Lok, who is actually head of our NIH hepatitis B consortium.
And this is the natural history of what happens if you acquire this infection at birth. If the mother is positive, and the mother is E positive, a protein secreted, crosses the placenta and probably tolerates the Thymus of that infant. So when the infant is born and becomes infected with hepatitis B, they do not recognize that virus, there's no hepatitis, very high DNA and E positive. This is referred to as the immune tolerant state. What happens subsequently is that at various stages, that Thymus begins to recognize all the T-cells, the virus as foreign, controls the viral load, this gives rise to hepatitis because the virus itself as you can see is not hepatotoxic, it's the immune response to the virus that causes the hepatitis.
And what you hope to happen is the disease will become inactive with detectable DNA, normal ALT and the patient will have lost this E antigen and all you'll be able to detect is E antibody. This is a good state.
Unfortunately, at least one-third of individuals who have gone into this inactive state become HBV positive again. But curiously most remain anti-E because there's been a mutation in the gene which prevents the formation of E, even though they clearly have detectable virus. So there are two active phases. The immune clearance E positive disease and the reactivation E negative disease which is characterized by actually a very weak immune response.
So what can we learn from this spontaneous E sero conversion? Firstly that in 60%, it leads to the good state of inactive. This is best achieved at a younger age, obviously the less hepatitis that occurs before, the less cirrhosis develops. In at least 50% of those in this inactive phase, over 25 years they will actually lose HBsAg. Why is that a good thing? HBsAg loss is associated with a decreased risk of liver cancer and presumably also cirrhosis and particularly if lost before the age of 50. Hence the loss is the best surrogate marker for outcome of chronic hepatitis B. It is a surrogate but fortunately generally the patients are going to live longer certainly than I am so I cannot wait for there to look at survival so we use this as a surrogate marker.
Let's show what happens to people if they don't get treated. This is a fabulous paper written by a friend of mine from Verona. He and I have seen chronic hepatitis B since we were first able to describe it, that's back in 1971 when the test came out. Now, therapy for hepatitis B of course was not developed until much later, so she had 59 patients whom she had followed for 25 years who had never been treated.
So this is what would happen if you couldn't treat your patient. If they went into the inactive phase you can see they were probably just as good as anybody their age. If they had HBV E antigen negative hepatitis or they went back to being E positive, you can see their survival at 25 years is only 60% and if they remain with E negative hepatitis for 25 years, their survival is awful. So that is what will happen if you do not treat a negative hepatitis or E positive hepatitis.
So what therapies do we have? Well, I started my North American career at Stanford where Tom Merigan was head of infectious diseases, fabulous guy. He was the first to use interferons, realizing to get rid of this virus your best off if you can generate a potent immune response. Indeed they were very successful because they act as an immune modulator and antiviral. But now we're into an era of pills so with the advent of all the antivirals developed for fighting HIV along with that has been the benefit of antivirals being developed to treat hepatitis B either nucleotide or nucleotide analogs. What you need to realize, that these are very, very potent antivirals but they do not have any immune effect. I think you'll see as I describe, the difference in the outcome of these two treatments is really based on that particular difference. Now, for the most part we use monotherapy and we still need to know whether or not he would be better off with dual therapy, either interferon plus a nuke or two nukes together.
So this is what's been so exciting for me, I have been in the field of hepatitis B since '71 when I came to do my M.D. thesis with Sheila Shallack. Nowadays we know treatment prevents liver failure, it prevents liver disease progression, promotes surface antigen loss, prevents reactivation with immunosuppressive therapy. Maybe it reduces liver cancer but none of the studies have been long enough to really show that. And overall it reduces the mortality of chronic hepatitis B.
What I hope to show you in the next short while is how from 2000 to 2009 there's been a revolution in our management of oral hepatitis. This is just part of the revolution that has it pertains to hepatitis B. This is a paper that a group of us from Canada put together where shortly after Lamivudine was license sentenced in 1998, we treated 35 patients who actually had a decompensated hepatitis B on the waiting list for a transplant. We weren't really keen on doing transplants, you'll see why in a moment, for doing that in those days. Within nine months, of being put on Lamivudine, the bilirubin went up, albumin went up.. The iodine went down and 22 of the 35 patients could be taken off the transplant list. Isn't that a miracle? It was wonderful to be around at that time. So at much the same time another study started, a randomized control trial of Lamivudine, in individuals with advanced cirrhosis, mostly cirrhotic and this was conducted in Taiwan. You can see at 36 months it was quite clear that the outcome is deterioration according to a two-fold rise in child pew score and the placebo was very, very much higher than what happened to individuals on Lamivudine. This too was a miracle.
However, unfortunately many patients developed mutations. Resistance. You can see this was really quite alarming, by 36 months, so for these reasons, this study was stopped at this stage, one because it was obviously not right to treat people with nothing and that they did very much better as long as they didn't develop resistance. So now I want to go through, and these are the only figures I'm really going to show, about what we know about potent antivirals. Lamivudine isn't but we have two drugs now Tecavir and Tenofovir that are potent, percolated and standard interferon. Our surrogate marker of good outcomes. i.e. HVSEG loss. With the more potent antivirals not the Lamivudine you see 8% loss of surface antigen if you stick to being on this pill for three years. With percolated interferon and interferon it doesn't matter which you have, with one year of treatment you will get 7% up to surface antigen loss and five years after one year of treatment you can have anything between 11 and 25%. Why such a range? That is because there are different genotypes and there are genotypes differently responsive to interferon. So if you're European and genotype A, you'll do very well. If you are southern European a genotype D you do rather badly. And if you're an Asian with B or C, somewhere in the middle. What I want you to note, this is E antigen positive hepatitis but the story is different in E antigen negative hepatitis. Potent antivirals for one year up to three years have never been seen to be associated with surface antigen loss. Whereas percolated interferon used for E negative hepatitis is associated when you're off treatment for a year or off treatment for five years, 5 or 12% surface antigen loss. So you look at this and personally I wonder why we don't use interferon. When I do use interferon, I use interferon in those that have particularly sensitive genotypes.
But you can count the number of physicians in North America using interferon on one, maybe two hands. Why? Well because pills are so much easier to take. It's easier for the patient, easier for the physician. But what you have to remember is yes, they're easy to use, but that they are also easy to abuse. The patient and physician needs to know what they're doing if they're using nucleotide analogs. So this is a very exciting slide. This comes from Hong Kong. They see a lot of hepatitis B and George Lao looked at patients with lymphoma and hepatitis B and it's increased in chronic hepatitis B and chemotherapy. We knew from Anna Lok's work in 1991, that if you started somebody on chemotherapy, that about 50% particularly when you stop the chemotherapy and they return with the normal immune response, this reactivates the pre-initially inactive hepatitis B. What George did is to randomize 30 patients into either being put on Lamivudine prior to starting the chemotherapy or being put on Lamivudine once they saw a rise in the viral load. And so you will see that here quite distinctly that there is no reactivation in these 15 patients on pre-treatment Lamivudine, and despite adding Lamivudine, as soon as there was a rise in DNA you couldn't control the virus quick enough with Lamivudine and there was a significant difference in the rate of reactivation of hepatitis B.
So apart from chemotherapy what are the other immunosuppressive therapies that may reactivate a silent hepatitis B? And remember, these patients never have any symptoms. So unless you test them for hepatitis B, you won't even know. And steroids, a steroid sensitive element in the virus, and any time you change the immune response. So the commonest natural change in the immune response comes post delivery. And I have actually seen people clear surface antigen in the postpartum period.
And now the rheumatologists and gastroenterologists are using anti-TNF for management of various diseases that they look after. This targeted immune therapy may also be responsible for reactivation hepatitis B. I doubt whether there are very many rheumatologists or gastroenterologists that screen their patients and ask them will not put screening hepatitis B on their guidelines. We're trying to change that. I don't know if there are any oncologists in the audience. It's rare but when it occurs it's often fatal. In certain situations just showing evidence of prior infection, anti-HBC don't have to necessarily have surface antigen. Organ or stem cell recipients, these patients too reactivate the hepatitis B. Why? Because even if you acquire acute hepatitis B and clear it, the template for the virus stays in the hepatocytes life-long.
So you could have had hepatitis B, I remember a patient who had it as a child in Italy. He later had in life had a renal transplant and two years into his renal transplant he developed hepatitis B. I said how come? He never had it before. He did but he was immune with natural immunity. And Jay Hoofnagle who I believe is in the audience wrote a nice review of Retuximab and how Retuximab in fact this particular targeted immunotherapy can also reactivate surface antigen in somebody who is just anti-HBC positive, which the anti-TNS don't seem to do. And similarly, as you might expect, you may see reactivation in individuals with HIV, many of whom have prior exposure to hepatitis B. So I would like to think that this highlights the need to screen patient whose will have any of these therapies for hepatitis B and certainly in our population in Toronto, where so many come from countries where hepatitis B is present. It seems to be mandated to me. The important thing is to remember, these patients don't know they're infected, they have no symptoms, the only way we know they're infected is by testing them.
So liver transplants started in the late '60s. Here I have some data from 1985 onwards when we had a program in Toronto and here you can see the survival of individuals with hepatitis B. And by 1995 we had said forget this. This is just not right to have a 30% survival post transplant at ten years. We stopped transplanting hepatitis B. Then Lamivudine came along and we have more potent drugs and here you see a 90% ten year survival which is as good if not better than other individuals having a transplant.
Now the outcome of hepatitis B is considerably better than the outcome of hepatitis C, who need a liver transplant.
So what about the effect of creatinine on liver cancer. I can't answer because the study numbers are too small and the duration is probably too short. So there's no good data.
So should we treat everyone with hepatitis B? We don't have the answer for this. But people thought they had when they read this paper in the New England journal back in 2002. This is an amazing study that was started, it's a population study in Taiwan. They invited nearly 50,000 individuals in villages to enter this study for long term follow-up for possible hepatitis B. First of all I want you to note they're all men. They do have women in Taiwan but they didn't test them. They only enrolled a quarter. So if you think about it, if you ask you're in a village, to go in a study for hepatitis B and you never heard about it, you feel perfectly well, what are you going to say? No, I have got better things to do with my life.
If your uncle or your mother died of hepatoma and you knew it was hepatitis B, do you think you would go into the study? You bet you would. So there is a tremendous recruitment bias. But nevertheless when individuals were tested with E and anti E at baseline and followed for ten years, the relative risk of liver cancer in those people who nine years prior were E antigen positive was 60.Those who were E antigen negative at baseline still had a significant relative risk. Look at this, 13.5. It was only in those who weren't infected. They had a large percentage of patients who were not infected for which there was no increased risk of liver cancer. This scared the pants off everybody and they said my goodness we have to suppress this virus, this is bad news, you get cirrhosis and I'll discuss with you in a moment whether I think that's right or wrong. Let's see who did get liver cancer, the older the patients became, the more likely they were to have liver cancer.
So we have this study taking some assumptions. They didn't have HBV DNA measurements but it's reasonable to assume that those who are E positive had a much higher HBV DNA level than those E antigen negative. That's generally the case. And probably the increasing rate of liver cancer with age is likely because there was no treatment so far more of those who had had ongoing hepatitis for 60 plus years actually had cirrhosis. And this next slide which comes from Hong Kong, this is from a population of clinic patients so not nearly as valid as a population-based study, did show that in fact the greatest relative risk attributable to liver cancer is indeed cirrhosis. Much less HBV DNA and actually a little bit more with regards to men. So maybe there was some sense to studying men in Taiwan but I doubt this was really their reason. So there are a lot of unanswered questions. And one of the questions we have seeing the high DNA or E antigen positive status should I say seems to have such a bad outcome in terms of liver cancer, should we treat those immune tolerant people with unbelievably high DNA levels, normal ALT but high DNA, or should we treat those young women who are immune tolerant who are about to give birth because then they're going to produce another immune tolerant individual? You all know that we can actually vaccinate those babies to prevent transmission but in those mothers with very high viral load break-through is not unusual.
And again, the next big question, should we use dual therapy or not? We don't know the answers to these and one of the projects in the NIH consortium is actually to look at the outcome of treating individuals who are immune tolerant compared. We think it's a legitimate to do a control study. So we don't know whether to treat people of high viral load of normal liver enzymes.
Next question, should we treat individuals with deckable DNA but minimal disease? And if so, should we treat those who are E positive or those who are E negative. Again, I think we have an answer for these but we do not have an answer for mild grumbling E negative hepatitis B with minimal liver injury at the time you do the biopsy. So that is going to be another study in our NIH protocol to do a randomized placebo control trial. That is completely legitimate because we don't know whether we're actually enhancing the outcome. But I think we have the answer to E positive disease because this recent paper here has shown that in individuals who clear virus, who sero convert after the age of 40, this is their rate of cirrhosis, 42%. Whereas those who clear their virus at a much younger age, less than 30, you've got a chance of cirrhosis of 3.7%. So if you have a patient who say 32, in fact, I wouldn't wait that long with a grumbling E antigen positive hepatitis. It's obvious that it's better to treat before they get cirrhosis.
So generally I wait one or two years, if they haven't spontaneously sero converted then I think it's worthwhile treating them regardless of their viral load.
So this all sounds very exciting, except as I said they're easy to use and easy to abuse if you use oral therapies. I'm focusing on oral therapies because those are the drugs that most of the individuals are using in the community and there are only a few strange people like myself using interferon.
This is the first drug. This is the nightmare of all nucleotide, nucleotide analogs that there will be resistance developed. You can see at four years of Lamivudine, we were seeing with the study in chronic, severe, advanced liver disease, that resistance is really very high. The drugs have got more potent. You can see now we have two very potent drugs and Tenofivor, no resistance seen in ITT analysis at three years and in Tecavir, 1.5%. Clearly these are the safest drugs to use in terms of preventing resistance. There's probably very little place for Lamivudine except for prophylaxis in patients requiring chemotherapy. So we know that interferon is stopped at a year.
What about stopping the oral therapies. Can we stop them? This is a study recently published from Korea. These are in individuals who have been treated with Lamivudine, and they have sero converted. What you will see is if they had the Lamivudine stopped within 12 months of that sero conversion, they relapsed back to active E positive disease. But if you maintained the drug for at least a year after that sero conversion, the relapse rate was only 10%. The figure for relapse using interferon is about the same. But this is what happens when you treat someone with E negative hepatitis. This is with a very, very potent drug in Tekavir. So you get good control at the end of treatment and you see by 24 weeks of follow-up and Tekavir and Lamivudine there's no difference. Virtually all those patients have relapsed. Of course, because they have a deficient immune response, as I said right at the beginning.
Whereas the E positive patients do have some immune response to the virus. This is missing an E negative hepatitis. So the likelihood is we're going to have to treat people life-long who have E negative hepatitis. So you better be damn sure they needed the treatment in the first place.
So does potential life-long therapy, antiviral therapy improved the survival of chronic hepatitis B? This is a recent study published by the Dutch. Now, the Dutch have a very huge number of immigrants and they know a lot about hepatitis B. They have a lot of clinical data. They're very, very well organized country with regards to clinical research. So what they did was to apply a knock-off model to their patients who either had an active chronic hepatitis B or they were inactive cirrhosis, or they had cirrhosis, and they have shown the natural history of what happens without treatment at all, and not surprisingly the death rate is significantly higher in those who have cirrhosis. But it's creeping up there in those with an active hepatitis at baseline. The degree of improvement in survival in fact depends on whether you use high resistant profile drug or a low resistance profile drug. So clearly the low resistant drug is this improvement so you can see there's a significant change predicted with a knock-off model using clinic-based data that treatment will improve survival. That is part of the miracle.
To summarize, hepatitis has a complicated history. One message to get across to you, it's not just HBV DNA, it's much more than that and it's the severity of disease you need to appreciate because liver failure can be eliminated by antiviral therapy in those with significant liver disease and improves survival. There's an unproven benefit of treatment on liver cancer and we have no idea whether there's a benefit to treating patients with mild disease. That we need to learn. If you have an individual whom you find is hepatitis B positive the path of the disease is very dynamic in this case. Therefore, anyone who has hepatitis B requires life long monitoring because their story can change any time.
So now I'm going to move on to the other virus that everybody has heard about. And of course I notice a picture of Harvey Alter on the way to this talk. Harvey got the Lasker award for discovering the hepatitis C virus in 1989. That was a great highlight for any hepatologist. Now we have prevalence data that the countries that are scarlet, this is Mongolia, this is Egypt, have levels of virus prevalence of greater than 10%. You can see in the United States, it's about 1.2%, and in Canada, it's about 1%. So you have 2%, two in every hundred patients have hepatitis C. Again, they won't have any symptoms so you won't know unless you screen for them. So who should you perhaps consider screening? So worldwide, the most common way of acquiring hepatitis C is by inadvertent medical exposure. You and I know that that's entirely fixable. So where does this occur is this you might think it's in the developing world, it's in rural areas, but let me tell you in the United States you can acquire this just by parental alternate treatments, by quacks who have no idea about viral transmission or sterilization. This happens every year with another outbreak. And blood transfusions in the developing world because for instance, Vietnam, there's so many people infected they don't actually screen for this virus. You and I know in North America it's injection drug users who are at the greatest risk of acquiring infection, they only need one injection from that person they shared a needle with to get infected. It may be one slightly drunken teenager.
So this is a disease particularly in the homeless and in jails, up to 60% are infected with hepatitis C. Now, more recently, this is a blood to blood transmission virus. More recently there have been reported outbreaks of acute hepatitis C in HIV-positive men who have sex with men. As a clinician we need to recognize acute hepatitis C. Because that is completely curable. What about the natural history? This is my own diagram and it's not based at least up here on too many figures.
How many times do you have to get exposed to get acute hepatitis? Nobody knows problem t-cell function as to whether you have acquired hepatitis C in the past, and got rid of it. Let's start off with 100 patients with acute hepatitis C, most of whom have no idea that they have it. Most in North America have other things to worry about not Hep C. If you follow the patients over 10 to 20 years, a minimum of 50% will develop chronic infection and depending on things like, again, immunogenetics, escape, mutants, age, all this sort of thing, up to 80% will develop chronic hepatitis C. This was well described previously from the NIH with the blood transfusion studies that showed there was a high rate of chronic hepatitis C. Now, again, over 10 to 20 years one-third will develop cirrhosis. And 5 to 10, that's two-thirds, will develop fatal liver disease. And the longer you live the more the process goes in this direction.
So the determinants of disease severity, once again, men do very badly with hepatitis. Both B and C. Women get it with autoimmune liver disease so it's all equal in the end. Acquisition, over 50, alcohol. Now, this is not that much alcohol. This is three drinks, two. How many people do you know who drink two or three drinks a day. It's totally socially acceptable but this will make your liver disease much worse if you have underlying Hep C. Immunosuppression, for instance, HIV, disease is worse, and what we have recently discovered, obesity leads to much more rapid hepatitis C progression. The one good news you can give your patient is that coffee now well shown is good for hepatitis C. If you come away with one message for your patients today, drink more coffee. Now, peglated interferon are the standard of care as of 2010 for the treatment of hepatitis C. And I just want to spend a minute or two going through the various different pathways of viral response to treatment so that you can follow what I'm saying thereafter. So here you are at baseline with a high viral load. You start treatment and there are some who rapidly go to undetectable virus. Sometimes within a week. If they do this within the first four weeks, these individuals are called rapid viralogic responders. Nearly all of them, not quite, but nearly all of them will have a sustained viralogic response so you want to work hard on those people keeping on their treatment. There are others that are a bit slower undetectable. This patient is undetectable not by four weeks but they are described as having an early viralogic response. As you can see, they too also have a good chance of an SVR but not quite as good. Because it's the duration of undetectable virus that determines whether or not you have a sustained loss of virus off treatment.
So you can see these individuals who are very slow, yes, they were negative at the end of treatment, but they have been positive all the way through and of course they relapse straight away. Then you'll see other patients don't turn a hair when you give them treatment. They are called null responders.
And we're mostly genotype one in North America, and 6 to 15% of individuals are null responders. So it's important to understand RVR, EVR and SVR. So again, what are the benefits of sustained viralogic response? All these of course we have to explain to the patient. Well, first of all, it is a cure unless they get reinfected. Because there is no long-lasting immunity, there is immunity but no long-lasting antibodies to hepatitis C. So the benefits of treatment again, if you treat patients with cirrhosis you prevent liver failure. The great thing is if you manage to get rid of the virus before they need a liver transplant, most often for liver cancer, this disease will not recur in the transplanted liver. I mentioned to you earlier the outcome post transplant hepatitis C is considerably worse, in fact, is getting increasingly worse post transplant. Because therefore, we need to work on treating these groups. There are a number of diseases associated with hepatitis C infection, non-Hodgkin's lymphoma, all the renal complications, porphyria cutanea tarda and type 2 diabetes. One study showed us clearly there's a marked increase in type 2 diabetes with hepatitis C. How many people know of this connection? Certainly the diabetologists don't. This is remarkable and again, improves survival. So you don't get resistance to interferon and ribovarin so why not just treat everybody? Surely it's better to not have this virus.
Well, as you know, there are a lot of side effects, and patients with hepatitis C develop really severe side effects. Way more than patients with hepatitis B. One because they have to have ribovarin as well but two, because they have a lot of co-morbidities which interact with this drug that make it just impossible for them to take. It's also expensive and perhaps we shouldn't be treating elderly patients. Because the tolerability is there but also they may have co-morbidities. But that's arguable.
So this is a study that I did with a young resident from Holland and a number of other Europeans.
We put about 500 cirrhotic data and we followed the patients to eight years and you can see in those who achieved an SVR, no liver failure. And those who didn't, non-responders got liver failure. You'll see liver cancer was not eliminated in those with SVR. So we're now going to do a 15 year study of the same population and see whether it's just because we haven't followed them for long enough that we saw a significant benefit. This is a study from France. France as you know has the best healthcare system in the world we're told, and I believe it. They have fabulous, huge databases of the patients all across France. Again they have developed a knock off model from their clinic-based patients whose were treated or not treated. They have looked at hepatitis C related morbidity in those treated with abnormal liver enzymes and those treated with completely normal enzymes. Even in this group you'll see there is a slight benefit to treatment. In this group you can see a very marked benefit to treatment. What about factors we know to influence response to treatment? Because if we can alter them we would like to enhance responsiveness. As with everything, irreversible factors in Hep C, genotype, baseline viral load, can't do anything about old age, we'd like to. And cirrhosis. If you have already got cirrhosis, there's nothing much we can do about it. And then the new kid on the block, this is really very, very exciting. Is the genetics.
Now, many years ago I had this patient and I asked him what he did. He said I work on gene expression. I said what's that? I'm just a clinical hepatologist. So he explained and I said that would be interesting in the liver. So we got a grant from CIHR and looked at it. And what we did was to look at patients pre-treatment, it took forever to publish this because we had to wait and look what the correlation was between the gene expression in those who responded subsequently or those who didn't. And I think to anyone who isn't green, red, color blind have no idea why they don't put this yellow and blue.
So much better. But anyway, over on this side you'll see there are a lot more up-regulated genes. And to our complete surprise these are all the non-responders. These are all the responders. These up-regulated genes were interferon sensitive genes. I remember sitting with a Ph.D. surgeon who did the actual lab work here. Trying to work out why if you had interferon genes up-regulated could you not respond to interferon? It just didn't seem logical to us. We still don't know exactly why but you can see these are the up regulated-genes which we confirm with real time PCR, and of them are interferon sensitive genes.
This is latest thing, a slide from a former fellow here. He said you have to show this slide, it's interferon, Lambda interferon mania. Because within one month in Nature there were four papers on certain SNPs of the IL-28B, the gene for interferon Lambda that seem to be associated with responsiveness and viral clearness. This is a paper from the Japanese group who looked at GWA in just null responders. Their number of null responders and found as you can see there are two SNPs way out here in chromosome 19 that appear to be elevated. Or not elevated, appear to be in much higher frequency in these null responders. What we don't know is what they do, we don't know what their functionality is and we done know whether they're up regulated or down regulated but this is the most obvious association you'll see with the GWAs.
And before that, the first paper was from analysis of a big trial of comparing two interferons. Which was always a waste of time, but they didn't waste time because they collected DNA in these patients. So they were the first to report these various SNPs of interferon Lambda, you can see that if they have the CC homologous that they have a much higher rate of SVR. So clearly these SNPs are associated with response to treatment, and it doesn't matter whether they are European American, African American, Hispanic or any combination thereof. Which is all of these. They're clearly associated with response -- but why? We have no answer to this. This is an analysis they looked at the odds ratios for predicting response to treatment. Here we have our old markers that I mentioned before, baseline viral load, baseline fibrosis and it's quite that this SNP trumps the prediction of response in individuals of all difference ethnicities. So this is very, very exciting but we're only just at the beginning. We need to actually know what its function is. You might ask what role does interferon Lambda have in hepatitis C? We know that we treat hepatitis C with interferon alpha and it goes through certain receptors and pathways. Interferon Lambda has different receptors, both of these interferons actually go through the eventual pathway, exactly the same pathway. So perhaps interferon Lambda is important in viral clearance. This is a small study of a cell culture that replicates hepatitis C. You can see that if you give interferon Lambda, and if you give interferon alpha, both lead to H 4 and HCV RNA, so they're both important in viral clearance and hepatitis C.
Now, this is the fifth paper in Nature. And I think this is also very exciting. So David Thomas in Baltimore, you may know that has been running this incredible program with those who live in the street in Baltimore, and many of them have HIV, he's head of ID at Baltimore and Hopkins. And they have HIV and also Hep C and B. They have collected obviously serum all the way along so they know the pattern of recurrent acute hepatitis C, those that have become chronic, and those that don't. You can easily through genetic testing with buccal swabs. You don't have to have a load of lymphocytes. They too have shown that this CC SNP is associated with spontaneous clearance of acute hepatitis C. This tells us something about the functionality but clearly this interferon Lambda SNP. And there maybe others closer to the gene are important in viral clearance. This is going to lead to a lot of very exciting work. But I'm not a geneticist, as you can tell. I am a clinician and I have been working on potentially reversible factors that we can change today. So everywhere bigger is better, isn't that it?
So if you gave high-dose ribovarin, maybe you could improve the SVR rate. So these individuals are given high dose ribovarin 15-milligrams per kilogram with EPO and they manage a 49% SVR. These patients given EPO but lower dose ribavarin, you can see poor outcome in terms of SVR. So if you can support the hematological complications then high dose ribavarin may improve the outcome in genotype 1 patients. And if you are a slow responder, and remember, I mentioned EVR, these patients don't even have negative virus at 12 weeks. But they have had a significant fall-in virus in the first 12 weeks. These patients are randomized to have the standard of care 48 weeks of treatment, or to have 72 weeks of treatment because as I said, they were rather slow responders. No big surprise. It's the duration of undetectable virus which determines chance of SVR, there's a significant improvement in outcome. In those who received 72 weeks of therapy, because there was much lower relapse rate. However, very few patients can tolerate 72 weeks. So this is an interesting paper.
I mentioned earlier that diabetes is very common in hepatitis C. And insulin resistant pre-dates that.
So these authors looked at reversible factors which affect the rapid viralogic response. RVR is what we want to achieve because we can pretty well cure all of those. They looked at insulin resistance as measured by the HOMA and they look at the drug of fact in the liver. They found that you can see a marked difference in the rate of RVR if you had no resistance compared to if you did and similarly, a marked difference in the chance of getting achieving an RVR if you had no fat or if you had greater than 5% fat. In fact, before this paper came out, this Spanish group had shown if you had a HOMA value greater than four, your chance of achieving the same viralogic response as you can see is significantly lower than those who are not insulin resistant. So we know that insulin resistance is one of the factors that govern response to antiviral therapy.
So our question was can you get rid of insulin resistance? So I had there's another one before it.
So the same Spanish group tried metformin, an insulin sensitizer, and you can see this did not help the SVR rate. It's a rather too small sample size and if it could have been much larger perhaps you would have seen a difference but in this study there's in benefit to metformin. But this is the study.
This is what a fellow of mine has just done, a very, very precise study. Just looking at 12 patients, all obese, all non-cirrhotic who had hepatitis C, that were treatment naive. At baseline they were all insulin resistant, 100%. We gave them dietary advice as to what to eat that would do them best in terms of weight loss and exercise. This wasn't a treadmill, this is having a pedometer and just making sure they hit 10,000 steps a day. As you can see they did do it and their degree of insulin resistance fell. They had intense monitoring here. Then we let them alone and the insulin resistance continued to fall. This wasn't a horrible diet. This wasn't excessive exercise. This is clearly perfectly doable. What we don't know is whether they're going to improve their chance of therapy. That may be a study that we'll do in the future. But it may not. Why? Because certainly we have new drugs, none of them are licensed.
So here we have the hepatitis C polyprotein and here we have the various enzymes which splice that protein. Here we have the various drugs against protease inhibitor and polymerase, nukes and non-nukes against the NS-3 protease enzyme. If we can inhibit these enzymes we can presumably reduce viral replication. So this is the first kid on the block so to speak, a protease inhibitor Telaprevir, you might have seen the papers in the New England journal. In the phase 2 study you can see they treated patients either with standard of care, Telaprevir monotherapy or Telaprevir with interferon. You can see the fallen viral load is considerably greater if you add to the cocktail or if you give to it them on their own. You can see at two weeks you see a rise in viral load. What is happening is you're getting more drug resistant mutations, which are probably all present at baseline. But you're just enhancing them by giving them Telaprevir pressure. And now you can see that actually Telaprevir and peglated interferon are synergistic.
So there have been two studies. The first is published one is treating naive patients with Telaprevir and those that received it for 12 weeks and interferon and ribavirin were up at 69% SVR, considerably better than most other studies for genotype 1. The interesting thing is that you will see there's no ribavirin. You can see even though you have the same duration you have a much lower SVR rate. So for some reason ribavirin is essential. There's no benefit of longer treatment. This is the study we hope to be published. And this is looking at prior non-responders. Unfortunately when people send you patients and non-responders you find for the most part they haven't done the RNA repeatedly so you can't describe what kind of non-responder they were, whether null or slow. We will have the answer to that in about a year from now. So in these prior non-responders, close to 40% were able to achieve an SVR if they had the same treatment again but with Telapovir added. You can see prior relapses we're up much higher than prior break through, so overall a 51% SVR rate in patient whose are non-responders. My clinic is full of non-responders.
So this is going to be a very busy time for us and it's very exciting for the patients. But people would like to get rid of the interferon ribavirin that makes hep C tolerated very poorly. This is a very exciting, 14 day phase 2 study of combining a protease and polymerase inhibitor and you can see that with bigger doses you can actually have sustained viral suppression by quite a degree with no obvious apparent resistance as yet. Of course we're all waiting for the longer study which interestingly is being done in New Zealand.
Finally I want to mention this is another author from the NIH, this is Jake Leang's student.
What they have done is to identify the connection between hepatitis C proteins and hepatitis C interacting human proteins. Because this is another way of perhaps attacking the virus. Not by attacking the virus and getting resistance, but by targeting proteins, cell proteins to inhibit various stages of hepatitis C viral replication. So you can see from this number of proteins that clearly we have a lot of work to do. Or at least Jake does.
So now just to summarize, what have I said about hepatitis C? Now in 2010 all we can do is to try to improve SVR rates, cure rates, by weight-based dosing, optimize reversible factors like the HOMA. And to reduce the risk of cirrhosis which is alcohol and obesity. This is all sort of standard of care in the clinic. But the future is very, very exciting. I showed you the small molecule direct antivirals appear to be able to increase the rate of SVR. But they do at a cost because there is resistance. And this suggestion by trait that we could attack this virus by targeting cellular factors necessary for viral replication is actually for real. I have actually done one of the trials with the site fill-in inhibitors and it's published as a phase 2 study and it really does have an effect of increasing the SVR rate.
So you have all been very patient to sit through this entire talk. What is the major message that I want to get across to you? First of all that I have had the most wonderful career in hepatology. I did my thesis on who got hepatitis B and how. I have seen how devastating this disease is. Between 2000 and 2009 I have seen liver failure prevented and survival improve in both hepatitis B and C. Now, what is there left to do with the younger hepatologists? Between the next decade? Well, a huge challenge, and it's a particularly huge challenge I'm afraid in this country, is accessing treatment. Currently only 15% of patients with chronic hepatitis in the United States are treated. The goals, to reiterate. If we want to eradicate hepatitis C, not only do we have to decrease transmission as I suggested all those treatable fixable factors of inadvertent medical exposure, but we need to increase treatment. And only if you do both do we have any chance of reducing the viral pool as close to negative as we would like. For hepatitis B, it's so much easier. Yet we still haven't done it in much of the world. That is, to enforce hepatitis B vaccination at birth. Then we would completely eradicate hepatitis B. So it's been a very exciting 30 plus years of research for me, and I hope that I have been able to share some of those really exciting highlights with you and that you're able to make some of what I said relevant to your particular clinical practice. I thank you very much.
ANNOUNCER: You've been listening to NIH Clinical Center Grand Rounds recorded January 13, 2010. This was a special"Contemporary Clinical Medicine, Great Teachers" Grand Rounds, featuring Dr. Jenny Heathcote, professor of medicine and Francis Family Chair in Hepatology, University of Toronto. She also heads the Patient-Based Clinical Research Division at Toronto Western Research Institute. Her topic was "Treating Chronic Hepatitis B and C." You can see a closed-captioned videocast of this lecture by logging onto http://videocast.nih.gov -- click the "Past Events" link -- or by clicking the "View Videocast" link on the podcast homepage at www.cc.nih.gov/podcast. The NIH CLINICAL CENTER GRAND ROUNDS podcast is a presentation of the NIH Clinical Center, Office of Communications, Patient Recruitment and Public Liaison. For more information about clinical research going on every day at the NIH Clinical Center, log on to http://clinicalcenter.nih.gov. From America's Clinical Research Hospital, this has been NIH CLINICAL CENTER GRAND ROUNDS. In Bethesda, Maryland, I'm Bill Schmalfeldt at the National Institutes of Health, an agency of the United States Department of Health and Human Services.
