Hello, everyone. Thanks for the opportunity to communicate and educate today. We have two other wonderful presenters. We're going to go over the basics. This lecture is meant for the treatment novice and for those who want a review on the basics of treatment, but we're going to cover epidemiology, natural history, and pretreatment as well. With that, Lisa Catale from the University of California, San Francisco, will be our first presenter on the epidemiology and staging. Okay. Thank you. It's my pleasure to present epidemiology and screening for hepatitis C. I have one disclosure that is not relevant. The objectives of this part of the webinar are to review the prevalence and burden of hepatitis C around the globe and in the U.S. I'll also be touching on how the epidemiology of hep C has changed in the U.S. and how screening strategies have also changed. And we'll be going through the current HCV screening algorithm together. So why do we screen for hepatitis C? Chronic hepatitis C is a silent disease and can lead to liver damage over the course of several years without any symptoms. And because it is asymptomatic, we really need to identify those who are infected so we can treat them with highly effective HCV medications to prevent these liver related complications and from new infections from occurring. So the World Health Organization estimated that in 2015, 71 million people worldwide were living with hepatitis C and almost 400,000 people died of complications of liver disease or liver cancer. And the world mortality rates of chronic hepatitis C and B have increased over the past 30 years, as you can see by this blue line here. And compared to the mortality rates of these other infectious diseases, HIV, TB, and malaria, you can see that the death rates continued to climb and surpassed them in 2016, taking the lives of over 1.2 million people. And of particular concern that in the United States, from 2003 to 2013, the number of HCV-associated deaths exceeded that of the top 60 other notifiable infectious disease conditions combined. So why the discrepancy in mortality rates? Well, the answer lies in the greater national public health responses that have effectively lowered the mortality rates for these other infectious diseases. And this is clearly what is needed for chronic hepatitis, also given its trajectory. So in 2016, the World Health Organization proposed to eliminate hepatitis C by the year 2030, with a 90% reduction in incidence and a 65% reduction in mortality. And this was largely driven by advances in direct-acting antivirals, which had revolutionized the landscape of hepatitis C, making treatment much more simple and much more effective. So how have the United States been doing with screening strategies? Well, unfortunately, we have not been among the countries on track to eliminate hepatitis C by 2030, because we've been missing important population targets. The first population we've missed are people who inject drugs. 30% of all HCV infections in North America are among people with recent injection drug use. And although novel screening strategies have been implemented to overcome barriers, such as in emergency rooms, hospitals, homeless shelters, et cetera, linkage to care has continued to be an issue in this population. The other key population are people who are incarcerated, because 30% of people with hepatitis C spend at least part of the year in a correctional facility. Prisons are a major opportunity for us to screen people and link them to care and treatment. So what is the estimated prevalence of hepatitis C in the United States? Well, we know that it is the most common blood-borne pathogen, and approximately 2.7 million people in the US are chronically infected, but 50% of these people may not know they're infected. And although we've done a very good job of curing a lot of our patients, in the shadow of the opioid crisis, new infections, unfortunately, more than tripled over this five-year period here. And this study, published by the CDC in 2017, found that the number of acute cases between 2010 and 2017 quadrupled, and when they broke it down into age group, the people ages 20 to 29 were primarily affected. So this slide really nicely shows how the epidemiology has changed in the United States. So if you look at the top of the slide, this data from California and New York, note that there was a predominance of reported HCV cases in people born between 1945 and 1965, or the baby boomer cohort. Even eight years later, as we were able to treat, cure, and link those patients to care, there was this second wave of new infections in the younger population, driven by the opioid epidemic, and a reduction of the baby boomer cohort. So how have the screening guidelines evolved in the United States? In 1998, the CDC first recommended risk-based screening, and listed here are all the risk behaviors or exposures for HCV transmission, which can be found on the HCV guidelines website. So injection drug use poses the greatest risk, and sexual contact is usually a less efficient mode of transmission, except for HIV men who have unprotected sex with men. Anyone who has received blood or blood products prior to 1992 should be screened, because this was prior to the time that routine screening of blood was implemented. And you can go through the list here as I speak. Mother-to-child transmission is possible. Global estimates have been about a 5.8% rate of perinatal transmission, but recent studies in the U.S. have predicted higher perinatal transmission rates than this in higher-risk populations, especially in HIV-co-infected pregnant women. So for our female patients who have had children, we always recommend a one-time screening of their children. So I'd like to call attention to the fact that many of us don't have time to go over all of these risk factors with our patients in clinic, and patients are also not always willing to report them. Risk-based screening also assumes that people with these risk factors will present to clinic in order to be screened. So we later learned that risk-based screening actually failed to identify over 50% of infections. So in 2012, the NHANES population sample here showed a high prevalence of hepatitis C in the baby boomer cohort, as I mentioned earlier. And this led to the recommendations from the CDC and the U.S. Preventative Service Task Force to expand screening to beyond just risk-based screening to all adults in this cohort without prior ascertainment of risk factors. And as the epidemiology changed, as I highlighted earlier in the last decade, the CDC and U.S. Preventative Service Task Force both drafted recommendations for universal screening in all adults. In November of last year, AASLD recommended an opt-out one-time screening of all adults 18 years or older and risk-based screening in children and adolescents. Then more recently, just this month, both societies, national societies, followed suit, and we have now universal screening guidelines of all adults. Both societies do recommend screening in pregnant women, and the CDC specifically supports screening in correctional facilities. These are the full guidelines that can be found on the AASLD IDSA website. Note that periodic repeat HCV testing should be offered to all people with behaviors or exposures associated with an increased risk of HCV exposure, and they specifically recommend annual testing for all people who inject drugs and for HIV-positive men who have unprotected sex with men. And now for a more practical part of this talk, how do we screen for hepatitis C? So we screen with an antibody test and an HCV RNA test. There are many venipuncture tests available. We recommend reflex testing so that you can test the antibody, and if positive, it will automatically reflex to an HCV RNA test. A positive or detectable HCV RNA test will indicate active infection. There are rapid finger stick tests available in settings, and this is very good for mobile health settings or syringe exchange settings, but you still need to do phlebotomy in order to determine if the person has active infection. All of these antibody tests are highly sensitive and specific. A reactive test indicates current or resolved infection, and once infected, will always be reactive. Note that HCV RNA test will always be positive before the antibody test in a newly infected person, and I'll be getting to that in just a moment. So let's go through the testing algorithm. So first step is to check the antibody test. If you have a negative antibody test in a person, in a patient with a normal ALT with no recent exposure risk, you can stop there and assume that you don't need to check the HCV RNA test and they don't have current active infection. If the ALT is elevated, however, or you have a high index of suspicion, for example, a recent potential exposure, an immunosuppressed patient, or a person on hemodialysis, you would go on to check the HCV RNA test, and if the HCV RNA test is negative, this would indicate no current infection, and you would communicate that they have not been infected and they have not previously been infected. If, however, there is a high exposure or behavior, again, the HCV RNA should be done, and if both are negative, you would retest both the antibody and the HCV RNA in six months. Now let's look at the scenario of a negative antibody and either an elevated ALT or immunosuppressed patient or a patient on hemodialysis or a recent potential exposure. You go on to get the HCV RNA test, and the HCV RNA test is positive. This would be compatible with current active infection, and what you would communicate to your patients is that they either have acute HCV or occult HCV. Let me describe for just a moment what acute HCV looks like. In acute HCV, the HCV RNA becomes detected within six weeks of exposure, sometimes within two to three weeks of exposure. This is followed by a rise in ALT, and usually the antibody does not become detected until about 10 weeks after exposure. I will caution you for your hemodialysis patients if you happen to screen a patient who's on hemodialysis, you should consult with a nephrologist prior to moving forward with treatment because this patient may be eligible for a kidney transplant, and if eligible, if they're willing to sign up for an HCV positive kidney, it could get them sooner to transplant, and it wouldn't be in their best interest to move forward with treatment right away. Our messages to the patient with acute HCV is that some patients with acute hepatitis C will clear on their own, about 15 to 40 percent of the time, but HCV guidelines does recommend initiating treatment without waiting for spontaneous clearance with this test and treat strategy to really reduce community transmission, and of course, you will counsel your patient to reduce behaviors for HCV transmission. Let's look at another scenario of an HCV positive test and an HCV RNA test that is negative. This is compatible with not being currently infected but exposed in the past, and this could either be previous spontaneous clearance or the patient has been previously treated and cured. You would want to make sure that you communicate that the patient does not have immunity to hep C, and they can always be reinfected. In other scenarios, this could be a false positive antibody test, so you might want to consider alternative antibody testing, or if you suspect a recent exposure or evidence of liver disease in your patient, you might consider repeat HCV RNA, and finally, if you have an HCV antibody test that is positive, it reflexes to a positive HCV RNA test. This is compatible with current HCV infection. The messages to your patient would be you are a candidate for highly effective treatment. You should evaluate your patient for the presence of advanced fibrosis, as Dr. Perlman will be getting to just in a moment. You want to counsel on alcohol intake and educate on the prevention of hepatitis C transmission, and I really want to encourage all of you to treat your patients as there are many strategies that you can use to overcome potential barriers, such as participating in tele-mentoring programs, such as Project ECHO, collaborating with HCV treaters through telehealth, and utilizing care navigators and an interdisciplinary team. In conclusion, HCV is a global health problem, and a greater public health response is needed to reach those elimination goals by 2030. Given the changing epidemiology of hepatitis C, HCV screening guidelines have now transformed to universal screening of all adults. However, novel test and treat strategies are still needed for those high-risk populations to identify infections and increase the capacity to treat and eliminate hepatitis C. I'll just pass it on now to Dr. Perlman. Great. Thank you, Lisa. Appreciate it. It was excellent. My task for the second of the three lecture portions will be to talk about the natural history and staging and what we can do prior to initiation of these direct-acting antivirals, so what you need to do to get prepared to get your patients cured. Right here are my disclosures, and this is the outline of what I'm going to cover, including not only the pretreatment eval, but at the end of my segment, we're going to talk about the benefits and the advantages of sustained virologic response, which is the same as a virologic cure. So as Lisa had said, we have 2.7 million in the United States, but 71 million in the world of, in the United States, of approximately 50% of whom are aware of the infection. Generally, it's about 25% are aware, probably because of not as frequent testing and availability of those tests. About half of those infected are in baby boomers, and although the rate of infection is getting higher in the younger population, I still want to emphasize that in the United States, 1.6% are in baby boomers relative to about half a percent, 0.5% in those born after 1969. So although the younger have increased, certainly because of the opioid epidemic, we're still seeing our largest percentage in those born between 1945 and 1965 labeled baby boomers. And despite about half being aware, in this case, 59% of those aware, only 29% of the total patients have been treated, despite significant advances in therapy. So we have a long way to go, particularly difficult in the incarcerated population, which as you saw from one of Lisa's points, that many of these folks go through the prison and jail systems. But despite that, only under 5% of these patients have been treated with direct antivirals. So the worldwide genotype map, these are strange genotypes, 1 through 6, although some would say as many as 8, but at least universally agreed upon, 1 through 6 strains. Genotype 1 is the most common worldwide and represents about 44% of all the isolates, and in most areas of the world, genotype 1 predominates, followed by genotype 3, which in the world is about 25%, and then that's followed by genotype 4, which is predominantly in the Middle East, but of course with global travel, we're seeing it everywhere, but that's about 15%. So it goes 1, 3, and 4 in terms of prevalence in these strains. In the United States, it's a different story. It's actually genotype 1 predominates, especially type A, subtype A. Not important these days so much to know these subtypes, but just know the vast majority of our patients, about 75%, are genotype 1, followed by 2 in the U.S., and then followed by 3. Genotype 1A is more common in the Americas. Good way to remember A for Americas, whereas type B is more common in Europe. So here is somewhat very close to a slide you had seen earlier looking at the natural history. As Lisa had mentioned, approximately 15% to 40% or 45% are lucky enough to clear this spontaneously with no help through the healthcare system, and then this extremely rare entity on the right, acute liver failure from hepatitis C. Much, much more common in viral hep B and hep A for acute liver failures, but rarely described for C. But the vast majority, as you can see, 55% to 85%, once infected, will not be able to clear this spontaneously. And the natural history is such that over approximately, good rule of thumb, 20 years, 20% will develop cirrhosis, although with various cofactors that we're going to discuss momentarily, up to about a third of these patients could develop cirrhosis, depending on the population, in up to 20 to 30 years. So it's not something that will develop extremely rapidly, but obviously the problem is cirrhosis with its attendant complications of end-stage liver disease, decompensation, which would include things like new onset ascites, encephalopathy, bleeding varices, and so forth, all the complications that we associate with the terrible complications of liver disease. Likewise, hepatocellular carcinoma, perhaps the most feared of all the complications, could evolve in approximately 1 to 5% of those who are cirrhotic. Not noted on this slide are patients that are one step away from cirrhosis, or what we call F3 fibrosis, stage 3, and they should likewise be screened for hepatocellular carcinoma because they can likewise progress to have liver cancer. The annual mortality at the bottom of the slide shows approximately 2 to 4% of those chronically infected with cirrhosis will die yearly. So here are the host factors associated with progression. Those with certain factors, whether it's host or behavioral factors or even viral factors, will cause progression faster. So if a patient has many of these cofactors, they may see a much quicker rate to cirrhosis rather than someone has perhaps an absence or only one of these factors. The age at infection is most important in terms of, once they're infected, it seems interesting that under 40, they tend to get it progressed rather at a slower course rather than over 40 when they get the infection. That's most important. They are going to progress quicker. So it's not a linear progression. It actually goes up exponentially, particularly women who are postmenopausal, whereas the estrogen is a protective effect against fibrogenesis. We're not clear on all those mechanisms, but we do see a much faster progression rate postmenopausally. The duration of infection is important. Someone who's had it for three decades versus one is more apt to be cirrhotic, of course. Hispanic ethnicity and other genetic factors play a role. Some of this has been elucidated and some has not. Some of these are genetic factors like interleukin-28, now called lambda interferon-4, but some of these factors are, again, in the genome and are more apt to cause more advanced liver disease, although this also is more affected by who could clear the infection. So even genetic factors has a difference among those that could actually clear it or cannot clear it. Certainly in the middle category, we know that alcohol in as little as 30 grams a day could, in some data sets, have shown tripling of the rate of fibrosis progression. Obesity, with or without insulin resistance, whether it's impaired fasting glucose or diabetes, can also speed up progression of the disease. Again, progression meaning the fibrosis scale, and we're gonna cover that in a moment with staging. Genotype three is, if we had to pick which virus was the worst in terms of the speed of fibrosis progression to cirrhosis, genotype three would be it, and that's in part because of the, we believe, the viral-mediated fat that we see in the liver biopsies of these patients. It's not so much the metabolic syndrome. They could be skinny without impaired fasting glucose and not have metabolic syndrome, but there's more fat deposition in these genotype three-related liver biopsies relative to the other genotypes, and that probably serves as a nidus for more inflammatory activity and, thus, progressive fibrosis after that. HIV co-infection, hepatitis B co-infection, all these co-infections, some parts of the world's schistosomiasis may actually progress faster than with just hepatitis C monoinfection. And here's the data looking at genotype three. Again, faster progression. This was first seen in the VA populations, in the US, the veterans, but showing faster progression relative to the other genotypes, not only faster fibrosis progression, but more hepatocellular carcinogenesis, primary liver cancer, more often in a genotype three-infected patient than the others. Not to say the others are not high, but relative to the other genotypes, genotype three is more. We're gonna actually do an entire webinar on this, and I encourage you to join us. I think it's the month after next, but looking at the extrahepatic manifestations of hepatitis C, which to date really has been somewhat underappreciated by many providers, and this is one of the big reasons for the extrahepatic causes mortality. It's not just the liver. It's a systemic disease, and you can see this more strongly associated diseases, including cryoglobulinemia, related vasculitis, porphyria, cutanea, tarta, tarta and lymphoproliferative disorders and non-Hodgkin's lymphoma being the most common. These are well-described membranoproliferative glomerulonephritis very specific. Not all of the membranoproliferative glomerulonephritis or hep C related, but many of them are. Now, if we look at the possible associations, I've bolded some of the stronger evidence relative to the ones not in bold, which are weaker on the right side. We do know that insulin resistance, even though it's a co-factor for progression, that the core molecule of hepatitis C will actually worsen insulin signaling. So these patients actually have more insulin resistance, say, relative to hepatitis B patients. So there is something to that. And conversely, when we care them with these direct acting agents, we can actually improve some of this insulin resistance. And this has been shown in many papers. The chronic renal insufficiency, we do know probably because of antigen and antibody complexes, it tends to be worse. Certainly those with pre-existing chronic renal disease, and if they were to get hepatitis C infection, they're more apt to progress about five times faster than those who don't have hepatitis C. So those with baseline chronic renal disease progress faster without. And likewise, people with end-stage renal disease, we know that those who are HCV infected with chronic renal have a worse outcome or shorter lifespan. This is prior to transplant, of course. Many have arthralgias, myalgias, and musculoskeletal nonspecific symptoms. And looking at neurocognition, we do see executive function, visual memory, and so forth impaired in many of these patients that can be improved post-treatment, post-cure. So it's not just, again, the liver. We're looking at many other organs, and perhaps not mentioned on this would be some coronary disease worsening of such, not because it causes atherosclerotic plaques, but because it's pro-inflammatory, and it makes the plaques unstable, and therefore higher rates of cardiovascular events and death related to the hepatitis C. So here is a schematic of the staging. This is the classic staging scale called Medivir, originally described in France, but probably the most commonly used, although not the only staging system used in the world. Stage zero, no fibrosis. These triangles are representing the portal triads, which, as you know, has the hepatic artery, portal vein, and the bile duct, the microscopic bile duct in one portal triad. And you can see stage one, the blue webbing, if you will, the crooked lines represents a scar. So portal fibrosis is nothing more than scar, the same as fibrosis in the portal triads. And as you get towards the bottom left of the slide, stage two, what we call fibrosis level two, F2 is the same as stage two, you start to see some of these scars or septa extend out from the portal triads. You can see those at the vertices of the triangle, which represents, again, the portal triad. And it's when you get many of these portal, excuse me, when you get many of these septa that extend out from the portal tracts, and you can actually walk between portal tracts without touching the hepatic parenchyma in between, where you can go from one triangle to the other, and you have many of these, what we call bridges, or many septa, this is the same as stage three. Stage three, which is one step before cirrhosis. And once we get to stage four, at the right side of the slide, you can see the nodule formation, regenerating hepatocytes, but basically, this is the same as cirrhosis when you say F4 or stage four. So when we stage, when we say staging, we're really simply trying to get a level of where they are, where these patients are, and their liver damage. So the liver biopsy had been the gold standard, an imperfect one nonetheless, but still the standard by which many of the other modalities are compared. Many fewer liver biopsies being done nowadays because of technology. Transgenal astrography, also called FibroScan, that's the one in the middle there, and that's the technical term is vibration-controlled transgenal astrography, as opposed to something like MR-astrography. FibroScan is a FDA-approved device, and it's not available everywhere. It's a fairly expensive machine, over $150,000 US dollars, although obviously discounts prevail, but it really is not common. You can find it in most big cities. Some places where they have an interest in hepatology research, you can get it, but it's basically a stiffness measurement of the liver, and if someone has stiffer liver, meaning more fibrosis towards the F3, F4 direction, you're gonna see a higher measurement of pressure that's reported by the FibroScan. The reader and the operator will give you a interpretation of where the patient is based on that stiffness and based on that shear wave that they're pushing through the liver to determine its softness or stiffness. And the shear markers on the right are probably most commonly used. You may have heard about the proprietary FibroSure that I put in red, and that basically takes markers like alpha-2-macroglobulin and haptoglobin and puts it into a proprietary formula that they won't reveal what that formula is, that's why you pay the royalty, but they will interpret for you. Some of the big commercial labs will do this in the US like LabCorp Quest, and they will give you back the interpretation. Likewise, you can use the APRI, A-P-R-I, which is listed up there, or Fib4, and I'll show you these, which you can use basic parameters you have in your clinics to assess for the staging without spending any money. Nonetheless, everyone has advantages and disadvantages. As we get to some of these markers, like the Fib4, its accuracy may diminish. It has better predictive value at the ends of the spectrum, meaning if it predicts very, very low fibrosis, it's usually pretty accurate, and likewise, if it predicts very advanced fibrosis, it's generally accurate, but there's always exceptions. So we plug in the patient's age, AST and ALT, and that half power is the same as a square root times the platelets and thousands, and again, showing you the excellent negative predictive value if it's under negative of 1.45, but if you're over 3.25, you feel pretty confident that this may very well be a cirrhotic patient. Even easier, the APRI score, using in the numerator ALT over AST, all over platelets and thousands. Anything over two is suggestive of cirrhosis, and I thought there was a link in here that maybe didn't appear on this slide. I apologize, but these are widely available, where you can actually just plug it into an app. You don't have to do it on paper like I do, and you can easily plug the data in, and MedCalc and some other apps that are free for use worldwide. Okay, so cirrhosis assessment. The bottom line is you don't need a liver biopsy, but you do need to figure out if these patients are likely cirrhotic. So we can use several things. You can say the FIV4 is over three and a quarter, like we discussed, or the APRI over two. Another suspicion, high suspicious item, is if the platelets are under 150,000, and you have no other specific reason for it in the context of hepatitis C and liver disease, that's very suggestive of portal hypertension, and that's how I catch a lot of previously diagnosed liver patients in the hospital or wherever else when the thrombocytopenia is moderate to marked. We begin to think about possibly portal hypertension. If you get a FibroScan number over 12 1⁄2, you don't have to remember that, because, again, it will be on a report. Fibro, sure, well, likewise, you don't have to remember what's the cutoff, like 0.75, for example, for F3, F4 disease, but they will print that out on your report, and you will see it. Clearly, though, if you see liver nodularity on a CT or ultrasound or mesenteric varices with splenomegaly, atresus ascites, things that are what we call obvious ascites, or, excuse me, obvious cirrhosis, or end-stage liver disease, these are the clues to portal hypertension, and, clearly, you don't need to do staging since this is advanced and obviously advanced, but if it is cirrhotic, if your patient is cirrhotic, your next step before treatment is to determine if they're compensated or decompensated, and it's actually pretty simple. Those who are decompensated have suffered one of those events that we have discussed before, specifically the bleeding varices or encephalopathy, ascites, hepatorenal, et cetera, and even if the patient's had had an ascites event in the past and now have no ascites, that is still considered decompensation. So why is that important? We could also use this CPT score, looking at, it should be the opposite, a score of over seven, and we combine these factors, and not gonna have time to go over this, but if it's seven or more, that's a child's B or C, and those patients are in that decompensated realm. They can be treated and they can be cured, but that's sort of outside of the purview of the simplified treatment which we are going through now. Remember that if you have F3 or F4 disease, they still need to be screened for hepatocellular carcinoma because both of those stages are those that can be risky for hepatocellular carcinoma, and we use ultrasound typically. That's the one that's recommended by the American Association for the Study of Liver Diseases, and without alpha-fetoprotein, although that's controversial, and some sites are doing it, but plus or minus, we'll say. But the most important thing is imaging. Those who have cirrhosis at baseline should undergo upper endoscopy to rule out esophageal varices because these things could bleed, and that's the number one cause of death in cirrhotic patients in the West. Simplified treatment, so who is not eligible for the simple treatment? So these are the ones that you might wanna consider referring those who have decompensated cirrhosis currently or in the past, one who has failed therapy and still have detectable RNA or viral load, and stage liver, excuse me, renal disease, stage four or five where the GFR is under 30 mils per minute, those who had transplantation co-infection with HIV, and those that are surface antigen positive because the risk of treating them is the hepatitis B flare unless you suppress the B in some cases. So it becomes a little tricky when you're treating the C with a co-infection with B. You have to be aware, and there's a boxed warning on all of the agents that are currently FDA approved that that could be a possibility. So please do screen for hepatitis B. Pregnant, we would not consider in the simplified algorithm in those who have had liver cancer. So simplified, what do you do? Rule out the decompensated cirrhotics. First stage them, of course, but if they are cirrhotic, rule out decompensation. Look at their medications, drug-drug interactions, and the next speaker, Dr. Ravenden, will go over some of these important interactions. Make sure your patients are on board. They know the importance of adherence. Get these basic labs, and there aren't that many. You're gonna get a genotype, a viral load. You wanna rule out the co-infections with HIV and hepatitis B surface antigen. Make sure they're not pregnant prior to therapy, and just basic hepatic labs that you would typically get, including coagulation factors like INR, along with GFR, which is based on serum creatinine and age. So basic stuff, basic things that are in your clinic available, but most importantly, make sure they don't have these co-infections. Get their viral load and genotype. The genotype may come less in resource-limited settings, not as important since many of these molecules that we treat are pangenotypic, meaning they cover all of the genotypes and isn't necessarily to have that. Very quickly now, in my last minute or two, I'm gonna cover the importance of sustained virologic response. Reduced all-cause mortality, that's what's most important. That's what I bolded because of these extrahepatic manifestations. Yes, the liver-related deaths go down because you're decreasing the decompensation rates, all those awful complications we discussed, but not only that, liver cancer, but outside the liver from coronary disease, from kidney disease, from neoplastic disease, we are decreasing those by virtue of achieving the sustained virologic response, which is defined by undetectable viral RNA three months or 12 weeks after therapy is done or any point beyond that. So if they come in at week 14 post-therapy, that's adequate, obviously. We used to do six months post-therapy, but now we consider 12 weeks to be standard as sustained virologic response or undetectable virus. It's not at the end of therapy, it's three months post-therapy. And one final slide on the largest prospective study to date showing nearly 10,000 patients, about a third of whom had cirrhosis, followed up for almost three years with a great cure rate of 94%, but a multivariate analysis exposure to the direct acting agent was associated with a decrease in all-cause mortality by 52%. So a really significant and nice reduction when we look at overall improvement in lifespan. So you're not only curing them of a chronic illness when you cure them, you are giving them back years on their life that would have been curtailed otherwise from not only liver disease, but extra hepatic manifestations as well. So in conclusion, genotype one is the most common US and worldwide isolate. In 15 to 45% can clear it, but the rest of them are chronic, which is the majority. Approximately 20 to 30% will develop cirrhosis, but host behavioral and viral factors will speed progression. Non-invasive staging like FibroScan and serum markers are commonly used. When would you use a liver biopsy? It's pretty unusual. If two non-invasive tests don't agree, that might be a reason to go to the next level. If cirrhosis is present, make sure it's not decomp. If it's compensated, rule out varices with an EGD upper endoscopy and imaging for HCC. If you don't see those, feel free to go ahead and treat because compensated cirrhosis is fairly straightforward as long as you pre-screen them for these issues. And that is about it. I appreciate it. I'm gonna move on and introduce from Johns Hopkins Hospital, Dr. Ravindran, and he is a great educator and I pass the torch to him for the final section. Oh, thank you, Brian. Hello, everyone. After listening to this elegant presentation by Lisa and Dr. Brian Perlman, I think my focus is going to be today on treatment of chronic hepatitis C, naive patients, both non-cirrhotics and well-compensated cirrhotics. This is my disclosure. The overview of my talk is going to revolve around structure of viral genome, classes of drugs, treatment, on treatment monitoring, some of the data, both safety and efficacy data of the current drugs we are using and post-treatment evaluation. This is the hep C viral genome. As you all see here, it is a single-stranded HCV RNA. It encodes 10 proteins, three structural proteins and seven non-structural proteins. Structural proteins play a major role in the entry of the virus into the cytoplasm. But I want you to all focus on three enzymes in non-structural protein, which is protease enzyme, NS3, NS4A, NS5B. It is an RNA polymerase enzyme, which plays in a major role of replication. And NS5A enzyme also plays a role in assembly replication. So I was talking about the NS5A. NS5A plays a major role in the replication as well as in assembly, but also it forms like a scaffold upon which these proteins cling on to that. The protease enzyme is responsible for the cleavage of the proteins. So to begin with, the proteins are to be cleaved, then it has to be assembled. So all these three enzymes play major role in the replication of the virus. Now, this slide gives you the whole picture of the evolution of treatment, what happened in the past three decades. If you actually now stratify them based upon interferon-based therapy, which happened until 2011, as you see this, it was a step ladder pattern of your SV or beginning from 16% on monotherapy with interferon going up to 44% with percolate interferon and ribavirin. Unfortunately, this host-mediated treatment had many barriers such as a lot of side effects so that hampered the treatment. In 2011, first breakthrough happened. This was almost 20 years since we started the treatment with advent of telaprovir and bozoprovir, which is the first generation of protease inhibitor. But unfortunately, those first generation also had major side effects such as an anemia. Now, in 2013, the major breakthrough or game changer happened. That was this, the phosphovir, which is NS5B nucleotide inhibitor that was approved. In 2014, NS5A inhibitors were approved. So currently with a combination of this protease inhibitor and NS5A inhibitors, or NS5B inhibitor and NS5A inhibitor, currently we are getting SV or more than 95%. Now, if you classify these drugs, there are three classes of drugs, protease inhibitor, NS5A inhibitor, and NS5B nucleotide inhibitor. Now, these protease inhibitors are second generation, consists of glacaprovir, grizaprovir, and voxeloprovir. NS5A inhibitors are pebrantosvir, ledipasvir, and valpatasvir, and elbasvir. NS5B nucleotide inhibitor is sophosphovir. The hormone is the combination of sof and ledipasvir. It's actually a one pill a day for 12 weeks along with food or without food. Epcluse consists of combination or co-formulated with sof and val. It's one pill a day. Maverick is co-formulated glacaprovir and pebrantosvir, three pills a day along with the food. And elbasvir, the zepatier is a combination of grizaprovir and elbasvir. Now, currently, whom do you recommend for treatment? As Lisa has pointed out, we recommend for everyone chronic hep C infection as well as an acute infection, irrespective of fibrosis stage. Whom would you not recommend? Currently, we don't recommend anyone with a short life expectancy. For example, if I see a patient walks into my office with multifocal hepatocellular carcinoma with decompensated serotics, whom you can't transplant or you can't give any chemotherapy or any systemic therapy with a short life expectancy, we do not recommend the treatment. Now, certain selected group of patients as Dr. Perlman pointed out, decompensated serotics or co-infected patients, we recommend they should be managed by an experienced provider. This is the current treatment guidelines put out by ASLD. For more discussion, the detailed discussion, I would recommend you to log into hcvguidelines.org and go over them. But in a briefly, if you see the combination of SOF and VAL or EPCLUSA or Glucapravir, Fibrinosphere or Maverick as pointed out in the yellow color, they are pangenotypic. In other words, there are three pangenotypic treatment currently available. The combination of SOF, VAL and Voxelapravir, it's called Osevi. Currently, I don't want to discuss that. That is actually given for patients, for those patients who failed previous direct active viral agents. Let me focus on SOF, VAL and Glucapravir Fibrinosphere. Currently, the first line of treatment recommended by ASLD IDSA is EPCLUSA and Maverick. EPCLUSA is one pill a day for all pangenotypic, both non-sterotics and well-compensated serotics, 12 weeks duration. Maverick, which is a combination of Glucapravir and Fibrinosphere, three tablets a day with the food for all genotypes for eight weeks, both non-sterotics and well-compensated serotics. Of course, you could use other alternates such as Harvoni and Zapatier, but Harvoni for genotype two and three are not indicated for one, four, five and six. For genotype one, if the patient has got viral load less than 6 million, eight weeks is indicated. For rest of them, it's 12 weeks duration. Whereas Elbasvir and Grazapravir, 12 weeks for genotype one and four, except genotype 1A patient who has got resistant associated substitution in genotype 1A patients for whom they need 16 weeks of treatment with Zapatier and Ribavirin. Now, all these drugs, we get SVR rate above 95% currently. Now, once you make the decision which treatment you want to give to your patient, the most important thing is to review the drug-drug interaction with your patients and go over with them. I would recommend to download the University of Liverpool site on your app or on your computer because that gives you a detailed version of all the drugs that has interaction with that. But let me just go over with you some of them such as statins use. Be cautious about using statins. Reason behind that is when you use concomitantly, the dose of the statin, it increases the level and they can get into side effects. To give you an example, I had a patient whom the patient was taking Atrovastatin 80 milligram. Unfortunately, patient did not get the message across and he was taking a combination of protease inhibitor and NS5A inhibitor. Ninth week, he developed rhabdomyolysis and AKI, but fortunately, he recovered completely. In fact, he also had SVR. The another important medication is the Amiodarone. In post-market data, Amiodarone has been shown to cause complete heart block and in fact, some fatality. So please be cognizant of that. Now there are certain drugs such as carbamazepine and efavirenzuse are contraindicated because they're all enzyme inducers that causes sub-therapeutic level and you can use the efficacy of these drugs. Now use of opioid substitution therapy such as methadone or MAT is not a contraindication. You can concomitantly use them. For the rest of the drug-drug-drug interaction, I would recommend you to download or to go into the University of Liverpool site. Now let us discuss about the efficacy and safety data of these two drugs, Ebcluson and Maverit. This slide focuses on the ASTROL phase three program. ASTROL stands for a single tablet treatment for all regimen. It is a phase three program. There are five ASTROL studies, ASTROL 1, 2, 3, 4, and 5. ASTROL 5 mostly focused on patients with co-infected with HIV. ASTROL 4 focused on patients with decompensated serotics. For today's discussion, we'll focus on ASTROL 1, 2, and 3. In ASTROL 1, we enroll patients, genotype 1, 2, 4, to 5, 4, 5, and 6. We did not enroll patients genotype 3. Now this is actually placebo-controlled, randomized 5 to 1 in favor of soft and well. In ASTROL 2, we enrolled genotype 2 patients, soft and well, the comparator being sofosbuvir and ribavirin. That was approved treatment for genotype 2 for 12 weeks. Whereas in ASTROL 3, genotype 3 patients, the comparator being soft and ribavirin for 24 weeks. Now in these studies, we enrolled treatment 9, treatment experienced, both non-serotics and compensated serotics were enrolled. The primary endpoints were SVR12 and discontinuation due to adverse events. Moving on to the efficacy data, as you see here in ASTROL 1, the overall putting, clumping all genotype patients, we achieved 99% SVR. In ASTROL 2, we achieved 99% SVR when compared to the comparator being soft and ribavirin, 94%. In ASTROL 3, we achieved a 95% SVR with soft and well compared to sofosbuvir and ribavirin, 80%. It's also important to note that there was no viral breakthrough on these patients on treatment. Now, one of these question that always arises, can we use any acid reducing agent with EPCLUSA or soft and well? Answer is yes. How do you do that? As this slide points out, you could give EPCLUSA along with H2 receptor antagonist at the same time or 12 hours apart, either pre or post. We recommend to use Femotidine not more than 40 milligram twice a day dosing. And you could use antacids four hours earlier or four hours after use of the EPCLUSA or you could use PPI, which is omeprazole 20 milligram four hours after the patient taking EPCLUSA with food. Why this is very essential? Because the solubility of velpatazole is quite good in acid environment. The acid is reduced, you lose that solubility and you might lose the efficacy. Now, moving on to the data on Glicopravir and Piperentesvir, which is Maverick. There are a couple of slides I want to share with you. This slide has put out all the studies we did. Genotype one to six, eight weeks data, treatment nine and previously treatment experience with regulated interferon, ribavirin, adults without cirrhosis. To make it short, if you look into the ITT analysis, the overall SVR was achieved 98%. In modified intention to treat analysis, 99% achieved SVR. It is interesting to note that only two patients had viral breakthrough on treatment. Moving on to this slide, this slide focuses on efficacy of combination of GP or Maverick for eight weeks. All genotype from genotype one to six, treatment nine adults with a compensated cirrhosis. As you see the overall SVR was achieved in 98% of all genotypes, genotype three being 95%. In modified intention to treat analysis, 99.7% achieved SVR. Only one patient did not achieve SVR being in genotype three. And again, there was no viral breakthrough on treatment. Now let's focus on the safety data. When you talk about safety, there are two safety data you want to know. Number one, what are all the patients adverse event? Number two, is there any lab adverse event? Now, if you look into these studies clumped together, the adverse event reported by the patients on Maverick around 10 to 12% of them reported either headache or fatigue. Now, if you look into the lab abnormalities, the total bilirubin only five patients, less than 1% of them reported grade three abnormalities, which by definition bilirubin twice the upper limit of normal. But all these patients on continued treatment normalized the bilirubin. None of these patients have to withdraw or we have to stop the treatment either because of patient reported adverse event or lab abnormalities. 0.1% discontinued due to the drug related adverse event. Now coming to the safety data on SOF and VAL, more than 10% of patients reported headache, fatigue and nausea. And maybe one to 2% of patient reported either CPK abnormalities or increase in lipase, but none of them had any clinical significance nor we have to stop the treatment or withdraw the treatment. Now, moving on to the treatment monitoring, how do you monitor this patient? Now on treatment, what we have observed, as the virus level drops down, it seems like the insulin sensitivity increases. So some of these patients on oral hypoglycemic agent do get some hypoglycemic episodes. So be cognizant of that when they are on treatment. And also they are on anticoagulants such as warfarin or any other anticoagulant agent you want to monitor that INR. As clinically pointed out in all this trial, there are no lab monitoring is required because there was no red signals noted. Only reason we do fourth week labs, at least in US, because some of the insurance do require the HCV RNA data at the fourth week. Now, currently in this current situation, current climate we have, and also there is enough data to show that you don't have to see this patient in your office, you could do either phone visit or telephone health visit. Now, post-treatment we recommend to do HCV RNA and liver enzymes. As Lisa had already pointed out, it is very important to let the patient to know that they will have antibody positive rest of their life, but the RNA would be negative. And it is also important to know the liver enzymes after you finish the treatment, after you achieve the SVR. Reason behind that is, almost 30% of the patients currently we see have abnormal liver enzymes, not necessarily due to the hep C, but due to the other underlying condition, such as non-alcoholic fatty liver disease. And also it is important to counsel this patient for risk reduction, or at least to link them for the counseling for risk reduction for pre-wed as well as MSM. And as Dr. Perlman had already pointed out, even after clearing the virus, we recommend them to monitor for hepatocellular carcinoma in spite of achieving SVR. And let me conclude by saying, currently hep C is curable in 98 to 100% of the patients. On-treatment virologic failure is very rare. These side effects are so manageable and easy to treat them. I recommend concomitant medication review. Please seek the experience to provide a consult selected cases such as decompensated serotics. Serotics should be monitored for hepatocellular surveillance. Thank you for listening. Great. Thank you, Ravi. I appreciate that excellent summary. And does anyone see a particular question that we should ask? Maybe I'll ask this to Dr. Ravichand, and that is the use of preemptive DAAs in a seropositive hepatitis C individual before renal transplantation, though ATV RNA is not detectable. So this is someone who does not have chronic hepatitis C, just has an antibody. Any reason to give them preemptive DAA before transplant? Well, currently, you know, there is no data that would actually, you know, support that. So I would not recommend that. Yeah, I agree. And yeah, without that, then I would argue that's not an RNA. You know, if the RNA is not detectable, these are very sensitive assays. They don't have chronic hepatitis C. Obviously, if it were to appear post-transplant, I'd be very surprised. Then you can easily treat them nowadays with great direct-acting agents with FDA indications too, very easily. So they can be treated. As you know, we're putting in positive ATV positive organs and mismatched recipients under certain guidelines and they're being treated and cured successfully. So again, we're trying to focus on a very basic, you know, treatment algorithm and some very basics because this is the 101 course. For those interested in more detail, we're doing a 505 more advanced course later in the year, probably towards the fall. Maybe Brian, that might, maybe the questioner might have meant post-transplant, you know, with someone with HCV antibody, positive, not negative, what would you do, you know? In that case- But I think if the RNA is negative, then there's nothing to treat. PMT will not treat, right? Yeah, yeah, exactly. Okay, I think I answered most that I'm seeing coming through. I may have missed, what group of patients will require surveillance after treatment? Only really the F3, F4 patients for hepatocellular carcinoma screening, maybe variceal screening if they had it pre-treatment. And are the patients who recover spontaneously at risk for fibrosis? Well, if anything, they should be reverting their fibrosis. Paired liver biopsy studies have shown that they actually go backwards and they improve, assuming there's nothing that's pushing them the other direction, like a very fatty liver or someone who's drinking heavily. Assuming those factors that are pushing them towards more advanced fibrosis are eliminated, you should see regression of fibrosis at just about all levels, including cirrhosis. That's early enough. Yeah, Brian, if I can interject, I think that's a very important point because as I mentioned, some of these patients have underlying non-alcoholic fatty liver. So you have to monitor them, even if they cured the hep C. If you don't take care of the non-alcoholic fatty liver, they can develop cirrhosis. I do have a few patients similarly. Good, that's excellent. One of them is saying, do you do EGD screening in patients who have achieved SVR, SVR patients, I'm assuming that's what it means. So go ahead, Ravi. Yeah, I can take that. I think if you have a patient who achieved, currently both the ASLD and the ESL, we recommend to follow these patients, especially if they have cirrhotic with platelet count. If you start, the platelet count is dropping less than 150. And if they have fibroscan measuring about 20 kilopascal, answer is yes. Then you screen them with EGD for varices, you know. Right. Now what he's referring to, one of the other questions came through, the BUVINO-6 criteria, which are basically using the fibroscan results and the platelets to obviate or eliminate the need to do hepatocellular, excuse me, for EGD surveillance or variceal surveillance. If the patients have under 20 on their liver stiffness, greater than 150,000 is BUVINO-6, it's called. And you can eliminate the need for doing EGD if you use those criteria. And you'll only miss about one or 2% with significant varices. So it has good negative predictive value. But this is, I think, in reference to those post. But I think answering some of that similarly. There is an increased incidence of rapid hepatocellular carcinoma progression in type 3 decompensated patients. So we're getting to a pretty advanced type of patient treated with a DAA. What is your say on that? So, you know, there have been so many looks at this because initially it was felt that the DAAs were actually increasing the incidence of hepatocellular carcinoma. But I think some of those studies were flawed, those earlier studies. And now pretty much the accepted issue with that, the accepted conclusion is that it does not increase the hepatocellular carcinoma. If anything, it decreases the incidence. There's a little controversy about, does it increase concurrent, like two or more lesions or so forth? I can't answer to that. Ravi, you want to add anything on that or Lisa? No, no, I'm totally agree with that. You know, I think, I mean, current consensus is that we know DAA does not cause increasing in hepatocellular carcinoma. Right, I think that's the bottom line. I think these are sick patients to begin with and you're going to see them develop HCC. And I wouldn't blame it on the DAAs. If anything, the evidence is that it reduces hepatocellular carcinoma by about 71% when you compare it to patients who had not been cured with direct acting agents. There was a question that came about on COVID-19, are you continuing the treatment? My answer is I'm actively treating my patients even now, especially with the side effect being so minimal. And you know, we can do phone visits and I'm actually treating currently actively. Yeah, I agree. We're keeping ours virtually when we can. We try to keep our cirrhotics virtually, especially, and you know, they're doing well. We send them to get some blood work because I do like to get blood work, but that's not always required in a non-hep B, non-HIV infected patient. So you could do it without blood work. Yeah, I am as well. And that was the question, yeah. Yes, I am as well in San Francisco area. We're still treating. Good. And I think- Can I just direct the attention to a couple of websites? There's a few questions about drug interaction. Somebody was asking about HIV co-infected patients. How do we give meds together with antiretrovirals? That website that I indicated, there's a website called liverpoolhepdruginteractions.org is an excellent resource for you. And any more questions about more complicated treatments can be, you can also refer to the HCV guidelines website. It's pretty user-friendly, right? Good, yeah. Excellent, excellent. Thank you, Lisa. I do want to address one more question and that is, are there any risk factors associated with acute decompensation when you're treating the compensated cirrhotic patient? And the answer is yes and no. We know we want to avoid protease inhibitor-based regimens if the patient is very close to decompensated, meaning if their child score is very close to seven, I probably would not put people like that on protease inhibitors. The more advanced ones certainly had a history of decompensation. We would never, that are compensated now. We would not use protease inhibitors. But nothing's perfect with predictability. The low albumin in some studies have shown to be predictive. The more advanced ones that even though they don't qualify technically for child to be, they might be more apt to progress. Portal hypertension at baseline, meaning varices that are not bleeding and so forth. So it gets a little sticky, but I hope in general that answered your question. So I think we're going to need to leave it at that. Thank you guys for really spending your time with us. I know it's a difficult time and we appreciate it. We want to give you a distraction from another RNA virus and we hope this was helpful and there'll be plenty of others. This will be posted for those of your colleagues that were interested that couldn't attend. We'll be on the liver, I believe the liver learning site or WSLD and there'll be a webcast that's available. Thank you. Thank you, Brian.

hepatitis C

treatment

epidemiology

screening strategies

direct-acting antiviral medications

cure rates

Epclusa

Maviret

complications

transmission