Slide Lecture with Audio
This activity is based on a 45-minute slide lecture presented by Dr. Mark Sulkowski and Dr. Jason Smith. This program is available as read only and with accompanying audio.
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Slide 1: Welcome to “Practical Strategies to Minimize the Clinical and Economic Burden of Hepatitis C.” This program is jointly sponsored by Medical Education Collaborative and Princeton CME, and is supported by an educational grant from Schering-Plough Corporation.
Slide 2: I am Dr. Mark Sulkowski from Johns Hopkins School of Medicine in Baltimore, Maryland. I will be your presenter, along with Dr. Jason Smith, Clinical Pharmacy Specialist at the VA Greater Los Angeles Healthcare System, and the Hepatology Clinical Research Center at the David Geffen School of Medicine at UCLA, who will be presenting a case study, which will apply the data presented to a real world scenario. Please note that all faculty disclosures for this program are included in the front of your activity booklet.
Slide 3: My goal in speaking to you today is to provide a brief overview of the prevalence and clinical and economic burden of hepatitis C in the United States, as well as discuss the frequency and implications of long-term complications of hepatitis C, such as cancer and end-stage liver disease. We will also summarize the current data regarding hepatitis C treatment and apply these data to assist clinicians to maximize outcomes in hepatitis C.
Please remember that to receive continuing education credit following the conclusion of this activity, each participant must complete the post-test and evaluation form. These forms can be easily completed online for immediate receipt of credit at www.princetoncme.com.
Thank you again for joining us. Dr. Smith will now introduce the case study.
Slide 4: Thank you, Dr. Sulkowski.
Slide 5: Let’s begin with a brief history of our case study, Mr. Jones. He is a 55-year-old African American male who used heroin for a few years in his early 20s. He admits to abusing alcohol for at least 10 years. He has been intermittently sober for about 6 years, attending Alcoholics Anonymous meetings.
Slide 6: Not too long ago, he relapsed with a DUI and was ordered to participate in a 1-year court-ordered treatment program. Mandatory testing revealed hepatitis C infection. At the time of the diagnosis, he had no symptoms and no complaints, but admitted to insomnia and fatigue over the past few years. Most recently, he has been sober for 8 months.
Slide 7: His physical examination detected obesity, a palpable spleen edge, and hepatomegaly. However, there was no scleral icterus or collateral circulation.
Slide 8: As part of his pre-treatment assessment, Mr. Jones was discovered to have mild transaminitis, with an ALT of 51. His viral load, or HCV RNA as detected by PCR, indicates that he is actively replicating. He is genotype 1. A biopsy was agreed upon by Mr. Jones and his doctor, revealing stage 3 of 4 fibrosis and grade 3 of 4 inflammation.
Slide 9: Some questions we might consider—first, what risk does Mr. Jones have for disease progression, and does he need to be treated? Another question we would consider—which treatment option would be best for Mr. Jones, and what duration of therapy would be appropriate? Lastly, should he be monitored for potential treatment complications and how could those complications be minimized?
I will now turn things back over to Dr. Sulkowski for his presentation.
Slide 10: Thank you, Dr. Smith. I would like to talk about hepatitis C today, covering both the virus itself, the epidemiology, natural history, as well as treatment response. But first, I would like to review the viral pathogen.
Slide 11: Hepatitis C classification—this is a Flaviviridae virus. It is a single-stranded RNA. One of the important characteristics about this virus is its rapid rate of viral production. It is estimated that a trillion virions are produced per day from an infected person. In addition, the RNA-dependent RNA polymerase is error-prone. What that means is there are frequent mutations.
So, hepatitis C exists as a family of mutant or related viruses. This heterogeneity is found in a couple of different ways that are clinically important. The first is genotype. Hepatitis C exists as 6 major genotypes that I will review a bit later. These are related, but different viruses. In fact, they are less than 60% identical. And then, when an individual human being is infected, hepatitis C exists as multiple variants, known as quasispecies. These are related viruses that have all changed over time.
Slide 12: But what is clinically important is the hepatitis C genotype. There are 6 genotypes in the world and surveys suggest, in the United States, genotype 1 accounts for about 75% of infections. Genotype 2 and 3 make up the bulk of the remaining 25%. Genotypes 4, 5, and 6 are found in other parts of the world. The importance of genotype is that genotype is one of the strongest predictors to interferon-based therapy. We will talk more about this, but in general, genotype 1 responds less well to interferon-based therapies than do genotypes 2 and 3. It is also important to note that the genotype does not predict liver damage.
Slide 13: Moving on to talk about epidemiology.
Slide 14: Hepatitis C is a global health problem. As you can see, hepatitis C affects about 4 million Americans, but is even more common in other parts of the world, including Africa, Southeast Asia, Western and Eastern Europe. Overall, the WHO estimates there may be as many as 200 million people infected worldwide, and this is a major cause of morbidity and mortality.
Slide 15: Here in the United States, the CDC has investigated causes of acute hepatitis C. This gives us a hint as to what are risk factors for the acquisition of this viral infection. The most important risk factor is injection drug use. The exposure to contaminated blood today drives much of the infection. In the past, prior to July 1992, blood transfusion accounted for a significant proportion of infections, but today with screening—both by antibody and nucleic acid testing—blood transfusion is quite safe. You can see other exposures listed, including multiple sex partners and percutaneous needle exposures.
The issue of sexual transmission of hepatitis C remains a vexing and complicated issue. But it is fair to say that this virus, in general, is not efficiently transmitted by heterosexual intercourse.
Slide 16: Among injection drug users, hepatitis C is really quite common. In this study by Villano and colleagues, the cumulative instance of hepatitis C infection over a period of 96 months was nearly 30% among injection drug users. And you can see it is substantially higher than that of HIV. It is estimated that on a needle, hepatitis C is 10 times more contagious than HIV. This is what drives much of the hepatitis C in the United States.
Slide 17: Interestingly, in the United States, the estimated instance of acute hepatitis C has fallen over the past 20 or 30 years. Initially, the decline occurred following a decrease among transfusion recipients. This was due to the heightened awareness of the risk of blood transfusion following HIV/AIDS.
There was surrogate testing, and then, in the late 1980s and early 1990s, we developed antibody testing, which made the blood supply even safer. There has also been a decline among injection drug users that may be due to high prevalence rates or saturation of the population, but may also be due to safer injection practices as a result of HIV/AIDS. In any event, the number of new cases in the United States is estimated to be 30,000 to 60,000 a year.
Slide 18: The real issue in the US is prevalent hepatitis C. Armstrong and colleagues recently published, in the Annals of Internal Medicine, a survey of 15,000 persons 6 years of age or older in the United States, sampled between 1988 and 1994. This was a probability sample designed to match the US population with one important caveat: these were free-living Americans. So, persons in prisons or other institutions, or persons who were homeless, were not sampled. And these patient populations may have a high prevalence of disease.
What they found was that about 1.6% of all Americans, or about 4 million people, have hepatitis C infection. The peak prevalence is among individuals age 40 to 49. Here, about 4.3% have hepatitis C. Not surprisingly, like other diseases, the prevalence varies by ethnicity or racial group.
Slide 19: In this earlier survey, done by Alter and colleagues, hepatitis C was found to be more common among African Americans. Indeed, the highest prevalence rates are among African American men between the ages of 40 and 49. Here, we see as many as 1 in 10 are infected with hepatitis C. High rates are also seen among Hispanic Americans, and greater than Caucasian Americans. The reasons for this are not entirely clear, but we can see there is a racial distribution of hepatitis C, with the most common group being African Americans.
Slide 20: The other important point to note is, when you look at hepatitis C in select populations, there are a large number of patients with hepatitis C who are difficult to manage or perhaps underinsured. They include injection drug users. It is estimated that about 300,000 are in the United States. Homeless individuals—perhaps 22%—are infected with hepatitis C, US veterans—about 8%. HIV-infected patients represent an important population, in that hepatitis C is very common and it is estimated that about 30% of HIV-infected patients are coinfected with hepatitis C.
The other population is those who are incarcerated. Some estimates are as high as 15% to 40% of all prisoners in the US have hepatitis C, a potentially major problem that we have not yet begun to deal with.
Slide 21: Well let’s talk about hepatitis C disease progression to end-stage liver disease or liver cancer.
Slide 22: This is, of course, important because we do not want to treat everyone with hepatitis C. We want to treat those who are at risk for progression. Hepatitis C progression is a challenging area for research. What this diagram demonstrates is that, following acute hepatitis C, the majority of individuals who are infected will go on to have chronic hepatitis. In this scenario, the virus evades the immune system and is unable to clear the infection. Chronic hepatitis C can then lead to progressive illness. It is estimated that 20% of patients with chronic hepatitis C will progress to cirrhosis over a period of 20 years.
Now, it is also important to note that not everyone who acquires hepatitis C will clear the virus. So, the issue here is that a person who is antibody-positive, as we will discuss, needs to have further testing.
Slide 23: Well, let’s look at some factors that are associated with disease progression. And I will start with the caveat that we really do not understand why some people progress to cirrhosis and others have mild hepatitis C disease. We know that older age, longer duration of infection, and being male are all associated with more rapid progression. In addition, having other causes of liver disease, such as iron overload, fatty liver disease—which is increasingly common in the US—as well as alcohol use, all can accelerate progression. Having other viral infections, such as HIV and hepatitis B, are also important prognostic factors.
Interestingly, the hepatitis C viral load and genotype are not associated with progression, as we discussed earlier. So, the magnitude of viral load is not an important prognostic factor.
Slide 24: Poynard and colleagues conducted a study looking at more than 2000 individuals who underwent liver biopsy. They estimated the rate of progression over time based on the date of acquisition and the current biopsy. And in general, there are 3 major categories that are seen. Some human beings are slow progressors, and, over a period of 20, 30, 40 years, very few will progress to cirrhosis.
Other individuals are more rapid progressors, and in this scenario, they can progress to cirrhosis in a short period of time—even 10 years. These individuals might be older men who use alcohol concurrently and have other diseases, such as HIV. And then some are intermediate. The challenge for clinicians is to decide how an individual patient will progress. And here, the future can be very difficult to predict, but we’ll rely on things like liver biopsy.
Slide 25: Now, what happens after cirrhosis develops? Well, when cirrhosis develops, hepatitis C becomes an important medical disease. Here, you can think of cirrhosis as a life-threatening condition. About 6% of all cirrhotic patients will decompensate or have liver failure each year. An additional 4% will develop liver cancer. So, the death rate is estimated to be 4% a year in cirrhotic patients. Now, liver transplantation is really the only means to correct a failing liver today. So, this is an urgent issue which is clearly driving much of liver transplantation in the United States
Slide 26: Our goal with therapeutics is to prevent the development of cirrhosis and, if cirrhosis is present, to prevent decompensation and cancer. This study by Fattovich, although more than 10 years old, really demonstrates the severity of cirrhosis. What you can see is that after the first event of decompensation, death occurs very rapidly. About 50% of cirrhotics who have a decompensating event, such as ascites or a variceal bleed, will die over a 10-year period. And, it is estimated that over a 10-year period, about 30% of cirrhotics will decompensate and 10% will have cancer. So, this is a significant issue.
Slide 27: The other issue that has been noted in the US is the rising incidence of hepatocellular carcinoma. In this study by El-Serag and colleagues in the New England Journal of Medicine in 1999, he demonstrated that there was a substantial increase in liver cancer between a period of time from 1976 to 1980, and a later period from 1991 to 1995.
What is striking is the greatest incidence of liver cancer was seen in African American men. Now, you will recall that the epidemiology suggests that this is a group with a high prevalence of hepatitis C. So, hepatitis C is driving a 41% increase in liver cancer mortality. Indeed, it is one of the only cancers with rising incidence in the US
Slide 28: So, what is the burden of this disease? Well, Gary Davis and others have put together models looking at the estimated burden of disease in the US, France, and Australia. And these studies are all very consistent. What you see is that there is an estimated increased prevalence of cancer, cirrhosis, and morality between 60% and 150% to 233% between 2008 and 2020.
Slide 29: This is shown graphically in a study by John Wong and colleagues entitled “Predicted HCC-Related Mortality.” And what we can see is that Dr. Wong and colleagues estimated that the death rate of cancer and other liver events will peak in the United States in 2015, and this is simply based on the epidemiology I showed you earlier. Patients infected in the 70s will progress over time, leading to medically-important events. So, we are about 7 years away from the peak of the hepatitis C epidemic, unless we have more effective therapies to stop the progression of the disease.
Slide 30: Now, one comment about liver transplantation—it is the leading cause of transplantation in the US, but transplantation is a challenging issue. There is a shortage of organs. There is a nearly 100% recurrence of hepatitis C in the new liver. And we see that survival rates of the liver transplant and the patient are good, but certainly the recurrent infection is a major problem. So, transplantation remains a procedure of last resort in the HCV-infected patient.
Slide 31: Well, let’s look at evidence-based treatment options.
Slide 32: Clearly, to stop the progression of disease, we need effective therapies. I want to make some comments first about the diagnostic algorithm for hepatitis C. What is recommended is that patients who are deemed to be high-risk by their healthcare provider, those who use injection drugs, those who have been exposed to blood transfusion before 1992, and any human being with an abnormal ALT, should have an antibody test. Today’s third generation antibodies are really quite effective and are very sensitive and specific for the diagnosis of hepatitis C.
Now, if that is negative, it is unlikely the person has hepatitis C, except in the setting of acute hepatitis C, where it may be important to check with other testing. All persons who are antibody-positive need to have an HCV RNA or PCR test. This is important to confirm chronicity. As I mentioned earlier, some individuals clear viremia and, here, their PCR will be negative. Any person who is infected, that is, they have a positive antibody in a positive PCR, should be further evaluated for treatment.
Now, this may mean they discuss with the doctor the need for treatment. It may also mean that they undergo liver biopsy. But the important thing is that everyone with chronic hepatitis C needs a medical evaluation.
Slide 33: So, what are the goals of treatment? Well, the primary goal of treatment is to eradicate hepatitis C infection. There is growing evidence that hepatitis C can be cured. And this is the best way to delay fibrosis progression, prevent decompensation, and prevent liver cancer. So, let’s look at the response rates that we have seen over time.
Slide 34: Peginterferon is the mainstay of treatment. Although monotherapy of peginterferon α-2a and α-2b are available, combination therapy with peginterferon plus ribavirin is the treatment of choice. And we will show the data and discuss why this is the treatment choice in the United States and world.
Slide 35:The other point to make is that the viral response to hepatitis C treatment options has increased dramatically since 1990. In 1990, we had non-A, non-B hepatitis, and interferon-α given Monday, Wednesday, Friday, which led to eradication rates in about 6% of patients—pretty dismal. By treating longer, after 48 weeks, this increased to 16%, but the big breakthrough was the addition of ribavirin. As you compare interferon for 48 weeks at 16%, adding ribavirin more than doubled this to 41%. Peginterferon given once weekly, a longer exposure to interferon, and a more effective antiviral therapy, led to a 54% to 61% sustained virologic response. So, you can see a dramatic nearly 10-fold increase in efficacy just in a period of 12 years.
Slide 36: However, different patient populations respond differently. And, what you can see is that when you look at different patient groups treated with peginterferon-α once weekly, and ribavirin given twice-a-day by mouth, hepatitis C genotype 2- and 3-infected patients had the best response—75% to 90%. Hepatitis C genotype 1 had a slightly lower response rate at 45% to 52%. And some subgroups, such as African Americans and those with HIV coinfection, had even lower response rates—25% to 30%.
Another important point is that, because of the side effects, many human beings cannot take interferon, such as mental illness or drug abuse. And here we are unable to effectively treat hepatitis. So, novel therapies that spare interferon are really urgently needed.
Slide 37: Let’s turn to some of the data. In 2002, the NIH Consensus Panel met to review the current data and make recommendations based on it. Peginterferon-α plus ribavirin was more effective than standard therapy with ribavirin and peginterferon alone. They recommended that genotype 1 infection be treated with peginterferon once weekly and ribavirin at a weight-based dose of 1000 to 1200 milligrams a day for 48 weeks, genotype 2 and 3 infection—peginterferon-α once a week, plus ribavirin at a fixed dose of 800 milligrams for only 24 weeks. So, the treatment course is shorter and a bit easier for genotype 2 and 3 infection.
Slide 38: Now, to clarify what we see with treatment, I want to review the patterns of viral response. After starting peginterferon/ribavirin therapy, the goal was to see a rapid reduction in HCV RNA. And we would like to see it negative as early as possible—a rapid viral response, defined as the absence of virus in the blood after 4 weeks of treatment. And the early viral response is defined as having at least a 2 log10 drop in the virus by week 12, or achieving a negative viral load. A nonresponder is a person who fails to drop their viral load to undetectable or 2 logs by week 12. The hope is to continue therapy to allow eradication of the virus. And after treatment has stopped, in people who respond—called a sustained viral response, or SVR—we did not see detectable virus again.
Slide 39: So, with these patterns in mind, let’s take a look at data. The first I would like to review is by Fried and colleagues, published in the New England Journal of Medicine in 2002. This study established that peginterferon α-2a plus ribavirin was more effective than peginterferon alone and interferon α-2b given thrice weekly plus ribavirin—genotype 1, 46% overall; genotype 2 and 3, 76%; clearly a more effective therapy.
Slide 40: In the next study by Manns and colleagues, published in the Lancet in 2001, a very similar pattern with peginterferon α-2b at 1.5 micrograms per kilogram, given along with ribavirin. However, in this study the ribavirin was given 800 milligrams a day. Here, the genotype response rate was 42% and the genotype 2 and 3 response rate was 82%. Clearly, for genotype 1 infection, it was more effective than peginterferon at a lower dose and standard interferon plus ribavirin.
Slide 41: I want to come back to this point about the Manns study and the use of ribavirin 800 milligrams a day. That is clearly not what the NIH panel later recommended. The reason for this is demonstrated in the study by Hadziyannis and colleagues, published in the Annals of Internal Medicine in 2004. This is a randomized controlled trial looking at 24 weeks versus 48 weeks of therapy. It also looked at ribavirin dose for genotype 1, either 800 or 1200. And the striking fact about this study was that the best response was peginterferon-α plus ribavirin at weight-based dose of 1000 or 1200 milligrams a day at 52%—clearly better than 800 milligrams by about 11%, and clearly better than 24 weeks. This study is really what has solidified the NIH recommendations and it is how we manage patients today.
Slide 42: Indeed, ribavirin concentrations appear to be important. In this retrospective analysis by Jen and colleagues you can see the ribavirin concentration at week 4 was associated with a higher response at week 24. So, the more ribavirin in the blood, the better the results in terms of our response. This has led to a mindset in treatment, which is, deliver as much ribavirin as possible, but it is often limited by toxicity—particularly anemia—and we will come back to that.
Slide 43: So, does sustained viral response indicate a cure? A recent study by Swain and colleagues followed 997 treatment-naïve patients who were treated with interferon and/or interferon plus ribavirin for more than 5 years. 99.2% had no evidence of virus. So, we think for many patients this represents a cure.
Slide 44: Now, perhaps the most convincing evidence is that cirrhotic patients treated with interferon who have a response appear to have better clinical outcomes. In this study by Bruno and colleagues, published in Hepatology in 2007, there were 124 cirrhotic patients who responded to therapy. When compared to those who did not respond to therapy, or who were not treated, there was clearly a lower risk of liver cancer and liver-related death, suggesting that, particularly for cirrhotic patients, interferon-based therapy, when effective, can lead to a life-saving medical benefit.
Slide 45: I want to talk about one important point for the management of hepatitis C from the 2002 NIH consensus conference statement—this is the term EVR which is defined as a minimum of 2-log decrease in viral load during the first 12 weeks of treatment, or attaining a negative viral load. EVR is an important point to determine when treatment is not working.
One of the important points that we have identified over the past 5 years is that the time to achieve a negative viral load or undetectability is an important predictor of response. To put this in a simple way, the faster someone responds to treatment, the better the odds of having sustained response.
Slide 46: In this study by Ferenci and colleagues, achieving a negative viral load in the serum by week 4 was associated with a 91% chance of success. But people who took a longer time to get a negative viral load at 12 weeks, or even 24 weeks, had a lower probability of response.
If someone got their viral load negative by 12 weeks, the response rate fell from 60% to 70%; if it took 24 weeks, the response rate for a 48-week treatment course was 43% to 48%, and the primary difference here was viral relapse. That is, at the end of therapy, at 48 weeks, the virus came back into the serum, suggesting the virus was not eradicated. There has been a number of ways this has impacted care. The first is the question of whether the rapid responder, that is, the negative by week 4 or RVR, really needs the same duration of therapy as the slow responder. Perhaps these are 2 different people and you can treat the rapid responder shorter.
The other issue is that the slow responder may need longer therapy. Perhaps 48 weeks may not fit all patients. If some go shorter, some should go longer. And let’s take a look at a couple of studies.
Slide 47: Mangia and colleagues, from the New England Journal of Medicine in 2005, studied a short course of peginterferon α-2b plus ribavirin for genotype 2- and 3-infected patients. They treated some rapid responders for only 12 weeks and others for 24 weeks and saw very comparable SVR rates—85% in the 12-week course and 91% in the standard 24-week course, suggesting very similar response rates.
However, there was a slightly higher response among the standard course—91% versus 85%. And one of the issues with a small study like the one by Mangia and colleagues is that this may be an error as a result of small sample size populations.
Slide 48: Shiffman and colleagues recently presented a larger trial known as ACCELERATE. And in this study, peginterferon α-2a plus ribavirin was studied for either 16 weeks or 24 weeks. And in a nut shell, what this very large study, including more than 14 patients, showed was that response rates are quite good for genotype 2 and 3, but were better with 24 weeks of therapy. Among those with a rapid viral response, the response rate was 90% with 24 weeks and 82% with 16 weeks.
So, this has really put to rest the idea of short course therapy for genotype 2- and 3-infected patients. And I think, right now, most treating clinicians will be very reluctant to treat with shorter therapy.
Slide 49: That point is summarized on the idea that short duration of therapy for RVR is not routinely recommended. I would say that for some patients, strictly those having side effects, one might consider stopping therapy early if they had a rapid viral response. So, we can see that short therapy is not recommended. What about longer therapy? I think this is an important point in clinical practice today.
Slide 50: There are a number of studies and I will review one here. This is the TeraViC-4 study published by Sanchez-Tapias in Gastroenterology. Now, this was a randomized controlled trial done in Spain. What they did is they took people who had a slow response. Slow response is defined as a detectable viral load at week 4. There were 327 people that met that definition. They were randomized to either 48 weeks of therapy or 72 weeks of therapy.
What is shown in the figure is that the end-of-treatment response rates were similar—52% for 72 weeks and 48 weeks with 61%. But the SVR rate shown in the darker color indicates 46% for longer therapy and 32% for shorter therapy. So, in this study, longer therapy reduced the risk of viral relapse and led to higher response rates.
Slide 51: Now, in my opinion, longer therapy may be considered for slow responders. And the way I would summarize this is that, if a person takes a long time to respond—12 or 24 weeks—the risk of relapse may be as high as 50%. So, for genotype 2- and 3-infected patients, they should achieve an undetectable viral load by week 4. If that is not achieved, 40 weeks of therapy may be needed. For genotype 1, they should have a negative undetectable viral load by week 12. And if that is not achieved, they should be treated for 72 weeks. The important point is that you only treat longer in people who respond to therapy. So, if the viral load does not get negative on treatment, treatment should be stopped at 24 weeks.
Slide 52: Well, let’s look at adverse effects.
Slide 53: One of the important points of therapy that has really driven much of the current therapeutic environment has been side effects. Now, treatment-related adverse effects are really very numerous. They could be summarized as neuropsychiatric symptoms, which include depression, irritability, insomnia, fatigue, decreased libido in many individuals, as well as cytopenias—anemia, neutropenia, and thrombocytopenia. Now, the major side effect that we see effecting patients is anemia, and I will talk more about that. There are also many other side effects that can be reported. I have listed a couple of the important ones, including retinopathy and flares of sarcoidosis—particularly among African Americans who have a higher prevalence of this disease. There may also be more rare effects that, fortunately, we do not see very often, but may be important. For more patients, fatigue, mood effects, and cytopenias represent the lion share of what we deal with.
Slide 54: Let’s look a bit more at the behavioral symptoms. Depressive symptoms are quite common—about 60%. Irritability can be a common feature—at least half. Some individuals had decreased concentration or memory problems. And there is also this fatigue or loss of energy, now, that may be the hallmark of treatment. There are clearly problems with sleep, problems with apathy. I would also like to note that these can be treated effectively with antidepressant therapy, like SSRIs. And a number of studies are beginning to emerge suggesting that antidepressant treatment may be effective.
Slide 55: Let’s talk more about the anemia. Ribavirin causes hemolytic anemia, this is where red blood cells are destroyed. And then, interferon can inhibit the bone marrow. The net result of this is that most people lose about 3 grams of hemoglobin. Now, if 3 grams of hemoglobin are lost in about 4 weeks, that is a significant drop. Some lose even more hemoglobin. You can see in this figure that about 10% of men lose at least 5 grams of hemoglobin. So, a man might go from hemoglobin of 15 down to 10. Anemia, of course, is associated with fatigue, shortness of breath, and clearly a decreased quality of life. In addition, some patients have to reduce ribavirin.
Slide 56: Over the past 5 years or so, there have been a number of studies looking at the use of epoetin-α, or “epo”, to manage peginterferon/ribavirin-induced anemia. And what this study showed was that the majority of patients who were treated with epo in a randomized placebo controlled trial had an increase in their hemoglobin of at least 1 gram and most got greater than 2 grams back—about 57%.
Slide 57: What was the effect of increased hemoglobin during epo therapy? Well, that is shown in this study by Afdhal and colleagues, where individuals who got at least 2 grams of hemoglobin back had an increase in their energy and activity scores, and overall, a substantial improvement of quality of life. So, there is a role for epo in the management of hepatitis C, although we need to use this carefully in light of current safety recommendations regarding the use of epo. And I would recommend that epo be used to increase the hemoglobin to 12 but not beyond that point.
Slide 58: Now, moving to another cytopenia, that is, neutropenia or white blood cells. White blood cells do decrease during therapy and these data were taken from the FDA submission for peginterferon α-2a. And what it shows is that a number of patients had a decrease in the absolute neutrophil count below 1000, and a few go below 500. This clearly is something that needs to be monitored, but from a clinical perspective, this issue of neutropenia is not as major a problem as we have with anemia.
Some clinicians will use filgrastim to increase the white blood cell count, but in my opinion, close monitoring of patients by checking the ANC, and judicious reductions of peginterferon dose can manage the majority of patients who develop neutropenia during therapy. So, the use of G-CSF or filgrastim can be relatively limited.
Well, we have talked about the current efficacy rates—about 50% for genotype 1, about 80% for genotype 2 and 3. We have also talked about some of the toxicity. And it is clear that for many patients peginterferon and ribavirin is effective, but it is also clear that it is a major challenge to treat a significant number of people. And as I highlighted earlier, there are nearly 4 million Americans with chronic hepatitis C.
Slide 59: So, let’s talk briefly about emerging HCV therapies.
Slide 60: There are a number of therapeutic strategies being investigated. Perhaps the most promising are viral enzyme inhibitors, a class of therapies now known as STAT-Cs. These are specifically targeted antiviral therapies for hepatitis C. They include medications that target hepatitis C polymerase and the hepatitis C protease. These are distinct targets, but promise to do the same thing for hepatitis C that was done for HIV.
I will talk briefly about a protease inhibitor that has now reached Phase II clinical trials. Genome sequence-based therapies, such as RNA interference and antisense oligonucleotides, do hold promise, but I would suggest these are a long way off and I will not focus on them. There are also other strategies, such as novel interferons, and I will talk briefly about albumin interferon which is now in Phase III trials. It is suggested that interferon will be part of the treatment regimen because of its antiviral effect.
Slide 61: Let’s first look at the protease inhibitor known as telaprevir. In a study called PROVE-1, telaprevir given orally 3 times a day was combined with peginterferon-α plus ribavirin, and compared to standard treatment.
What is shown graphically is the number of individuals who responded at week 4 with an undetectable viral load. Now remember that that is a rapid virologic response, which we discussed earlier. 79% of those on telaprevir plus peginterferon/ribavirin were undetectable, compared to only 11%. At week 12, it was 70% and 39%, so clearly triple therapy with telaprevir is more effective. But, as is noted, there are more side effects with telaprevir and also virologic breakthrough.
The point I want to make here is that this therapy is potentially promising; however, there are clearly issues to be determined, which include viral resistance as well as side effects. So, I am excited about the development of hepatitis C protease inhibitors, but certainly recognize that we have a ways to go before the completion of Phase III clinical trials and FDA approval.
Slide 62: The other medication I said I would mention is albumin interferon. Now, albumin interferon is a molecule that can be given every other week or perhaps even once a month, and has a very long half-life. So, one of the advantages is that it can decrease the number of infections. This was a Phase II trial of more than 400 patients presented by Zeuzem and colleagues. And it shows the response rates—these are sustained viral response rates out to 12 weeks after therapy. Now, you can see the albumin interferon, given at every 2 weeks or every 4 weeks, was very similar to peginterferon α-2a plus ribavirin. So, we see 54% sustained virologic response for peginterferon α-2a ribavirin, and between 53% and 59% for albumin interferon. As I mentioned, this is now in Phase III clinical trials, and we will see how this fits into future strategies.
Slide 63: Let’s move on just to talk about the economic burden of hepatitis C and let’s look to see whether treatment actually makes sense from a pharmacoeconomic perspective.
Slide 64: First, let’s look at the direct cost in millions of dollars. Well, I mentioned earlier that Dr. Wong showed us that the morbidity and mortality will peak by 2015. Not surprisingly, the cost of medical care will also peak by 2015 in the US. So, you can see over the past 20 years a rising medical expense due to hepatitis C. Now, these are not expenses due to medical therapy, but the cost of caring for liver failure and liver transplant.
Slide 65: So, is treatment cost effective? There are a number of studies suggesting that yes, it is cost effective. I selected one from the Veteran’s Affairs health system that looked at the cost effectiveness of peginterferon-α plus ribavirin. They took the typical patient, if you will—a 45-year-old with genotype 1 infection. They found that peginterferon α-2a and α-2b were very similar in terms of their cost effectiveness versus no therapy. There was a net cost decrease and a gain in quality-of-life years of about 2.35, and the incremental net monetary benefit was more than $125,000. So, clearly, this therapy is cost-effective and strategies are needed to deliver therapy to more individuals.
Slide 66: To summarize what we have discussed—hepatitis C is common, affecting nearly 4 million Americans, and the disease burden is increasing, estimated to peak in the next 5 to 10 years. Peginterferon-α and ribavirin is the standard-of-care and the data strongly support the use of more ribavirin in genotype 1, hence the current recommendations.
The week 12 EVR “rule” is important, but we now recognize that viral loads should be tested at week 4 and week 12 of therapy, and that for some people, particularly the slow responders, longer therapy, in my opinion, is indicated to increase the probability of sustained virologic response.
Aggressive side effect management is definitely needed to keep people on treatment, and we have learned a lot over the years. We have learned to use SSRIs as antidepressants. We have learned to use epoetin-α judiciously to manage anemia. New treatments are under development, but I point out that these are in phase II and III clinical trials and much work needs to be done before they actually reach the clinic to help patients.
Current therapies are cost-effective and greater application treatment is needed to see the health benefits. In other words, too few Americans are treated for hepatitis C and we need to treat more if we are going to really solve this problem of hepatitis C.
Slide 67: Thank you. This concludes my presentation. I will now turn the program back over to Dr. Smith for a discussion of the case study mentioned at the beginning of this activity.
Slide 68: Thank you, Dr. Sulkowski. Let’s now return to our patient, Mr. Jones. What makes him a difficult patient to treat? Invariably, there factors that can predict a patient’s response to therapy. Some factors are modifiable, others are not. Factors that are not modifiable are his age, ethnicity, histology, genotype, and viral load. Treatment factors that could be modified include his weight and adherence to the medication regimen.
Slide 69: What are Mr. Jones’ treatment options? He could be treated with a combination of peginterferon α-2a or α-2b and standard or weight-based ribavirin.
He could also be treated with combination therapy using consensus interferon and ribavirin. Lastly, he could await novel therapies.
Slide 70: Once treatment is initiated, Mr. Jones should be monitored for both viral response and toxic effects. Therapeutically, we would tailor his treatment according to his viral kinetics. Therapy could be shortened or lengthened based on his HCV RNA at weeks 4, 12, 24, and 48. Toxic parameters requiring monitoring include cytopenias—like platelet count, neutropenia, and hemolytic anemia, which are the most common. Lastly, we will need to closely monitor Mr. Jones for his adherence to the regimen and his sobriety. Remember, our goal is to help Mr. Jones achieve a successful outcome.
Thank you for your time, this concludes my presentation.
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