All right, thanks so much, Dr. Vines. We have Dr. Susanna Naggie with us here today from Duke. To talk about Hepatitis C in 2019. And are we on a path to cure? Dr. Naggie got her M.D. from Johns Hopkins and then went on to Duke, where she completed internal medicine residency, her chief residency, and her ivy fellowship. And she currently serves the director of infectious disease at Duke's Clinical Research Institute. And also, she is the associate dean for Clinical Research at Duke's school of medicine. She has hundreds of publications and invited presentations on the topic. So should be very interesting discussion. Thanks for being with us today Dr. Naggie. Thank you very much. I think I will use a slightly different mic, so hopefully everyone can hear me OK. So first of all, thank you very much to the ID division for inviting me to come speak at Grand Rounds. I'm very excited to be here. I've had a great morning talking to the ID fellows and some of the faculty. You guys have a great infectious disease group as partners here at UVA. So again, I'm talking about Hepatitis C. Some people may think that there's something to talk about anymore, right? Because we've cured it, it's over. What am I going to do with the rest of my career? But there's actually plenty to talk about as relates to HCV. And over the next 40 minutes or so, I'd just like to talk to you all about some of the concepts of elimination, you know, eliminating HCV from the face of the earth it only infects humans. And therefore, it is actually an infectious disease that we should be able to eliminate. The question is, can we? Do we actually have the tools that we need to do that? Otherwise, my career is officially over. So-- I do have some disclosures, I will say that the ones that are directly related to this are research related grants without being [INAUDIBLE] for DAA's. There is a disclosure I don't have on here, so I know for many people in this room, Duke is a four letter word. So I just want to make sure you all know that I'm actually not a Duke fan, I know this is being taped, I'm not a Duke basketball fan. I'm a Duke medicine fan. But I went to Maryland undergrad and so I'm a twerp. For better or for worse, they're not even in the ACC anymore, so I quit watching basketball, to be honest with you. All right, so a couple of objectives. One is EPI and elimination goals. Testing treatment and really what does it mean to treat and cure a patient of this viral infection, how does that play out in terms of their health outcomes. And I'm going to circle back to elimination again to really talk about what are our tools for elimination and where are we and what are the challenges that we see ahead? So I'm going to start this off with a case. I will say that, at my home institution we do tend to start off with the case. Because this all should be in the end, especially for internal medicine grand rounds, relevant to the patients we take care of. And this is actually a patient that I saw in clinic a couple of weeks ago. And he was referred to me from hematology. Which you may find odd. 81 years old, he's had Hep C for a long time. He was diagnosed in 2000, when his wife was diagnosed. As an asymptomatic patient but he's probably had it for a lot longer. He probably got it, which was actually a little odd, heterosexual transmission from his wife. Which is uncommon but I could not find any other reason for this man to have Hepatitis C. And she had a blood transfusion, after an accident, back in the early 1990s, before we tested blood for Hepatitis C. He's been followed by his PCP now, for right-- this is 2019. So 19 years with labs every year and ultrasound every year. But does not carry a diagnosis of severe liver fibrosis or cirrhosis. He carries a diagnosis of hypertension, which is well controlled in CKD 3, which has actually been quite stable for some time. We have no Hep C genotype, we don't know his HIV status, we don't know his Hepatitis B status. And what's happened and how he ended up at my clinic is for the past five years-- if you look back at his labs, his platelet count has declined over that part of time. And now, his white blood cell count has dropped. And so, he got referred to hematology for concerns for malignancy, given his age which is a fair concern. And he had a bone marrow biopsy. And I like to say there's no better way to diagnose cirrhosis than a bone marrow biopsy. So this is, you know, this is a big deal. And as you can imagine and having this conversation with this patient who then did get referred to me because his bone marrow biopsy did not show any concerning changes for malignancy but probably for some systemic chronic disease. His questions were can this issue from my bone marrow, actually be from my Hepatitis C? How does that work? And the answer is not actually from your Hepatitis C, it's from the liver disease from your Hepatitis C. How does this happen, I actually feel fine. And I don't know, how many folks in this room are actually actively treating HCV? OK. Thinking about treating HCV? Any of the internists who haven't jumped in yet but are thinking about it? I'm talking to you. This whole talk is for you. So this is the conversation I'm having with a lot of my patients right now. We've treated all the patients with severe disease, we've treated the patients who are symptomatic, treated the patients who have abnormal liver tests and that sort of thing. The many patients I'm seeing in my clinic now, are people who feel fine. And say, why would I go through a treatment? And they also remember the interferon days. So in their mind, like, that's going to make me feel horrible. If I feel fine what's the big deal. And then, the other questions he had for me is can I even afford treatment? I hear insurance won't even pay for these medicines, they're so expensive. So we had a lot to talk about. And it actually was a good-- at the end of the day was a good conversation. So let's talk about HCV epidemiology and elimination goals. So just to talk about the epidemiology for HCV, probably the best numbers that we have were presented by the WHO in a global hepatitis report in 2017. So this reflects data globally up through 2015. And overall, there's about a 1% prevalence of HCV globally, active infection. This is not positive antibody but maybe they don't actually have active infection. These are people living with this infection. And not surprisingly, there's a range and the prevalence. And in the United States we say our range is probably somewhere around 1 to 1.2% with over 3 million people living in the US with chronic Hepatitis C. So this is a slide. And I'm going to use this really interesting pointer that you guys have here, so this is a slide that actually, if you go to the global page report. It actually ends, as I mentioned in 2015, which shows in blue the HCV, HPV, or liver related numbers for mortality, globally. And what you can see here is just into 2015, Hepatitis was about to surpass tuberculosis and HIV for the leading cause of death, OK. And this is primarily driven, as I mentioned by HCV and HPV. So they promise that a really nice a [INAUDIBLE] paper in 20-- Just recently, actually a couple months ago, that took these numbers and actually pulling from form and format it all in Lancet just recently projected mortality for 250 different chronic diseases in humans. And projected these numbers up to 2040. And you can see, that we are way behind if we are going to change this curve as it relates to the number of people they project to die from hepatitis. Whereas, in tuberculosis, HIV infection and malaria, we seem to at least kind of have it under some control. I'm not saying it's important but this is a pretty big difference in terms of mortality that's being projected. This is about chronic infection, right? But the numbers here about incident infection, I'm going to keep coming back to this, it's really hard to eliminate an infection if you keep getting new ones. And the numbers here that were presented by the WHO showed that we had 1.75 million new infections in 2015. Those were more infections than we had leaving the planet, either by cure or by death. So this is a major, major challenge for us as we think about elimination. And I don't know how many of you know this but did you know we have an acute Hepatitis C problem in the United States right now? I don't know for Virginia-- No, North Carolina started seeing this happen a couple of years ago. But the primary kind of, Sentinel states Kentucky, West Virginia-- started seeing this a long time ago. Actually, one of our ID colleagues told me in 2011 to 2012, she knew there was an opioid epidemic when she started seeing more infectious endocarditis patients being admitted to the hospital. And she wasn't in Baltimore, right? Where you know you might see those constantly. But she was in, you know, she was in Kentucky. And she was like, there's something going on here. And that was the sentinel event to see that we have a major problem. So you can see that Acute HCV, new HCV infections have increased by 300%. Along with this, is infective endocarditis. We now have an epidemic of new Hepatitis B cases. A fully vaccine preventable infection in these people that are getting infected. This is a major issue for us. And I imagine many of you have seen some of these statistics but they're really concerning. This is primarily an epidemic in our younger people. And so for those of us who have kids, it's a terrifying statistic to see. Which is that if you look at the numbers here, you can actually see the increases everywhere but it's really in our folks that are less than 40 years old, right. These are kids who are transitioning from their parents medicine cabinets of opioids to heroin injection. And it's really scary. These are the numbers from the CDC that really brings home the point that this is although there is also an increase in dark blue and urban areas, which is primarily where we've been used to seeing injection drug use. This is in suburban or non urban areas. We're talking about in many cases, rural areas. And these numbers are people less than the age of 30, in four states. Kentucky, Tennessee, Virginia, and West Virginia this is terrifying. We have a major problem. This is pretty equal between men and women, I would argue. And what does this translate to for women? It translates to more children getting infected. You know, historically we've always talked about testing pregnant women. Which some of you may know, the recent AASLD guidelines recommended universal screening for Hepatitis C in women specifically who are pregnant. But what this line shows you is women in the this heavy dash line with HCV infection that are pregnant. So this is a significant, as you can see, the numbers here. In this state are actually higher across the countries 89% increase. And that means you have an increase in children, whoa, who are being tested. The rates of vertical transmission, something that we generally thought was quite low for hepatitis C, now numbers are coming in across these states of somewhere around 10% vertical transmission of Hepatitis C. This is a major, major problem. The WHO recognizes this is a problem globally, this is not just a problem in the US. As you can imagine, the burden of the disease is actually not heavily in the US, it's globally in many other countries. And so, the WHO set forth four goals and their global Hepatitis plan for countries to aim for, as it relates to the concept, that if you can hit these goals, all modeling says, you can eliminate this from your country. And technically, it means you could eliminate from your state, you could eliminate it from your Hospital Center, you can eliminate it from your clinic. And we use the term micro elimination to say, likely this is not going to happen on just one scale. Has to happen in everyone's clinic. We've looked at micro limitation of our people living with HIV and are Duke in Durham v.a. Clinics. But what they focus on is an 80% reduction in incidence by 2030, 65% decrease in mortality by 2030. It's 90% diagnosis coverage. So of the people that have the infection, they want 90% to have been tested and diagnosed. And then, treatment coverage of those tested and diagnosed we want 80% treated and this is by 2030. So I'm going to give you some recent statistics. So the CDC just released these numbers. This is a progress report for the United States. And what you can see here is incidence. So if we're going to meet our projections, to achieve the 80% reduction in incidence. This was the projection that was put forth by the HHS. This, is where we are. So if I were a medical student, I would fail. Right? This is not good. We are not going to meet this statistic, at least. At least one of these targets. Where we are doing well is liver related death. So mortality, the US is on track. You can see that the projections were that we wanted to get down to 4.1 by 2020, and in fact we're already at 4.13. And I think what this actually reflects is something that we never really imagined which is how quickly you can turn this liver disease around when you cure people that have Hepatitis C. I don't think we ever imagined that within a couple of years, you would actually see the health benefits of a cure. And I think that's what this is, right? It isn't like of a sudden, all these people start drinking. It's that we-- we're not treating all their fatty liver disease, this is their HCV being treated for those people who are getting access to treatment. So we'll the US make it? That's the big question here. And what you can see here is that, for instance reduction based on our trajectory we will not make it by 2030. We will make mortality reduction by 2022. We will make diagnosis coverage by 2025. And we will make treatment coverage by 2026. So this next picture shows you that there are some countries in green who are on track. There's a long list, I'll just cut these off to show you we have some better potential and then you should United States down here, which is primarily driven by this incidence issue. This acute infection that we do not have control of in this country at this point in time. What I can also tell you however, is that one of the countries which is up here is Australia. And I just led a session at our big idea week meeting on elimination. And we had one of the groups who are leading the elimination efforts in Australia to come talk to us. And it was very concerning. People look at Australia as a leader in this and what they said on that stage was we did really well for the first couple of years. When we secured drug and we got to the people that were in care. But we've plateaued, we flat lined. Because there are so many people we aren't getting to. And they're worried that two years from now, they're not going to be in the green they're going to be in the red. Because they're going to fall off the curb. And if they're going to fall off the curve, I think many of these groups will to fall off the curve. And so we really have to think about how we keep people on the curve and get people on the curve to be able to truly achieve elimination. How do we do this? Testing, right? You can't get treated if you don't know you have it. Then, making sure that everyone who knows they have it get treated. The treatments, which I'll talk about, are amazing. And I don't know how many of you have heard about the direct acting antivirals for hepatitis C, I'm sure many of you have because one of the first drugs was priced at $1,000 a pill. Which is absurd, right? So many people heard about these. I don't think people can fully understand how amazing these treatments are. I mean, for me at least, as someone who does virology and HIV and Hepatitis B and C, I mean, I think in my lifetime this will be one of the greatest medical discoveries for human health. Period, right? HCV is no longer the leading cause of transplant in this country because of these medications. The problem is we're not seeing the full potential because most people aren't getting access to them. Harm reduction, I mean to go back to this over and over again, right? We have an injection drug use epidemic. And you can't stop it by telling people not to do it. I mean, you obviously don't want to encourage them to do it. But you need-- I mean, we all know this, right? Scott, Indiana-- How many of you guys heard about the outbreak of Acute HIV and Hep C in Scott, Indiana? OK, so you know that the state of Indiana's Department of Health at the time is our current secretary for DHHS, right? He's the Surgeon General. How did he get that state under leadership that did not support the concept of needle exchange and harm reduction out of that outbreak? For a period of time, he did harm reduction strategies. That's how Scott County, Indiana broke out of that outbreak. So it mean, you know, this sadly it becomes political but it's really mostly about health and common sense, right? And if you're going to do it, provide a safe way to do it. While engaging people in addiction services and addiction counseling and that sort of thing. And then, the question is what about a vaccine? So this is a big question, most people who do this sort of work, and I'm not really one of them-- I'm a clinical investigator. But they say there's no way you can limit infection from the face of the earth without a vaccine. Without true prevention, right? So the question is, is that true? Can we treat ourselves out of an epidemic like this with just DAE's or do we need a vaccine to help us do it? So I'm going to talk about testing and treatment now. So previously, prior to 2012, the way that we tested people for Hepatitis C is what we call risk based testing, right? So a patient comes into your office and you say, do you use drugs? Have you had high risk sex? Have you been exposed to anyone's Hepatitis C? And what do you think most patients say, no. Right? So based on risk based testing, we knew we were missing 75% of the people that were living with the infection, right? So what the CDC and others did was look at something that's very common epidemiology research which is birth cohorts. Are there certain behaviors that kind of run within different age groups that might help us identify a group of people that we can identify by something that has no stigma. We're not going to ask if you use drugs, we're not going to ask you if you had sex with, we're just going to say, when were you born? All right? That's going to help, right? So baby boomers screening, right? Anyone-- 1945 to 65-- I'm not going to ask for a show of hands of how many people in this room meet that criteria who've been tested for Hep C. But I'll bet you it's lower than it should be. Right? I have actually had people come to me and say, I actually went to my doctor and told them aren't I supposed to be tested for Hep C? And they're like-- oh, no, you don't have any risk. Right? So this is a problem, we have our own biases as providers. And we don't test people even when it's recommended. So what we know now that baby boomers screening has been recommended since 2012, so over seven years, right? Is we're still missing 50% of the people. So baby boomer got us up to, you know, up to-- from 25% to 50%. But we're still missing 50,000 people living with this infection, right? That's a major problem. I don't know how many of you saw this, but the USPSTF just put out the period for the draft recommendation and kind of-- the community period for people to make comments on a universal Hepatitis C testing. It's about time, I have to say. I can tell you that AASLD guidelines will put this out very shortly, I think, as well. Given this rollout, right? So they say it should be done, I think we should get behind it and say this needs to be done. And I think this will make it a little bit easier, right? So now it's just like HIV testing. A patient comes into your clinic, I don't care why you're seeing them. If you're rounding on cardiology consults or ID consults, you should just say, make sure they get an HIV and Hep C test, that's standard of care. Right? And then, hopefully, we can make this better. And this includes again, pregnant women. So that hopefully will help us improve the testing part of this, right? To identify more people. What about treatments? So again, treatment is quite fantastic. And it's quite easy to do. And that's one of the things for the internists in the room, especially, is to say, like, this can be done. This doesn't have to be done by some specialists. In fact, it can't all be done by some specialists. Although, we just had a conversation this morning, that I also get that you have many other things on your plate to do. So HCV is very interesting. This is a very rapidly replicating virus. It actually is much faster than HIV, I think is the most rapidly replicating virus in the human. It also does not have proofreading capability. So it makes mistakes and it doesn't fix them. Which for a virus, actually works out really well. If you're trying to develop mutations that get you around the pressure of a drug, right? So resistance for HCV with a single drug happens in about two weeks. So we had to use combinations of drugs just like in HIV, which is quite natural for I think those of us who do HIV treatment. The other major limitation is actually get you the vaccine issue. As you can see here-- So the smaller the diagram of the figure, the less diverse the virus, right? So for HCV-- how many of you guys knew that there are now seven genotypes for HCV? So one through six clinically is what we talk about believe it or not, this is actually old. There's actually now genotype 7, 8, and 9. And the reason we know that is, is the roll out of DAA's happened across the globe. The companies that were running these studies had to do sequencing and genotyping to understand why patients failed. And in doing that, they've now discovered two additional genotypes of this virus. So this is a very diverse virus. Which makes it very difficult, to some extent, to consider treatment. But now, we have pan pan-genotypic regimens. We have regimens that we can give, that would treat any of these. Which has a huge impact. Especially, when you're talking about rolling out therapies into low and middle income countries with the concept of getting a genotype to help make a decision is just not going to happen. So now, you can just give that drug and you can be comfortable that the patient takes it then to work. I think this is challenging though, when you you're talking about a vaccine, right? So the concept of developing a vaccine it makes it much more difficult when you have this much variation. So some people actually-- my patients sometimes ask me, I don't understand, if we can cure Hep C, why can't we cure HIV? So the reason is when we talk about viruses that chronically infect humans, we think about HIV, Hep B, herpes virus's, right? Once you have them, you always have them, right? Herpes comes and goes, CMV comes and goes, right? Especially in transplant patients and that's because they all have a latency phase, right? In the nucleus, they either integrate or in the case of Hep B, CCCDNA that's always there, right? Hepatitis C doesn't, there's a big, gaping hole right here in the nucleus, right? Totally [INAUDIBLE] this is why we can cure this virus. This is why we can eradicate it from the human host. I don't want to belabor this too much, given the audience. Just suffice it to say that the drug targets that we have for Hepatitis C are not dissimilar than what we have for any other viruses. We think about the drugs that we use for herpes, these are targeted towards enzymes that the virus has to carry with it to replicate, right? It's the same for Hepatitis C. So we have protease inhibitors, keep pushing the wrong button-- we have protease inhibitors, which focus on the protease, which is an enzyme obviously required for the translation process for the virus. We have nukes, for the polymerase, which is the replication of the virus. And then, we actually have drugs that target a protein that is critical replication although, it doesn't appear to be enzymatic activity. So we have three primary targets, proteases, NS-5As, polymerases, we combine them together in various ways to get highly active drugs, OK. The NS means non-structural-- so structural proteins which are here for the virus, from the virus, the viral cat, et cetera. These are non-structural meaning, they don't use the form the virus, that they're used to help the virus replicate. So this timeline summarizes where-- I think, where the field is come so, so quickly. I just want to highlight a couple of things. So one, the first DEA's were approved in 2011. Now, I don't know if anyone use these but they were worse than using interferon, to be honest with you. Because you were using them in addition to interferon, but they had their own really horrible side effect profile. But pretty quickly, by 2013, we in fact had the first kind of true DEA therapies that did not have to be used with interferon. And in fact, that many of us started using in combination of label. You can see how rapidly from 2013 to 2017, in four years, we suddenly had all oral therapy. Pan-genotypic, one drug or three drugs in one day can cover all genotypes. We had curative therapies for patients who had, had a liver transplant, a kidney transplant, patients who had deep competence roses, these are people that we had nothing to offer before but a transplant for what you know many patients can't get. We had therapies for people that were on dialysis. Again, previously patients did not have options if they were on dialysis. And we have approvals in children now, right? HIV of course patients approved very quickly as well. This is, I mean, to me it's unbelievable. Right? But the big issue is with all of that is how many people are actually getting it and how much is the potential impact for this actually happening? So the AASLD which is the American Association for the Study of Liver Disease, so the big hepatology society and IDSA say we're just a big idea society, came together to create these guidelines. And the only thing I'm going to say here is it says, every patient living with Hepatitis C, should be cured of their Hepatitis C. Unless, they have a terminal illness and they're going to die within a year and it's not from their liver. OK? I have had patients on the transplant list that we have made a decision to treat and they come off the transplant list. And they never need a transplant, right. We also have people that are on the transplant list, who are going to wait a really long time for an organ. How many of you know, that we are now giving HCV positive organs to HIV negative donors? I mean, non-recipients. You guys are you're doing it here at UVA, it's fantastic right? This is unbelievable. I don't even think that anyone can really imagine that, that would happen. Although, in reality, someone says, we've been giving people CMV positive organs forever, what are you guys getting all excited about? It's a good point, all right, touche. But this is the thing, right-- this is no longer about liver disease. it's not about staging a patient's liver disease and saying we should have a conversation about whether or not we should treat your Hepatitis C. This is a conversation of give me a reason why I shouldn't be treating your Hepatitis C. And I actually, literally, in my VA clinic this week had a patient who came in he's had Hep C for a long time, he's actually a really healthy 65-year-old. This man, his father is still alive and is 103, also a veteran. Actually living in our long term care facility. 103? I was like, I've told you, you could live for 20 years, actually, I think you could live for 40 years, now that I think about it, right? And he didn't want treatment because he had someone who tried to convince him to take therapy with interferon, he knew it was horrible. And he was like, Doc, I was right then. And I think I might be right now. Like, why would I do this? And what I told him was, this is not just about curing your Hepatitis C to prevent you from getting liver disease, patients who live with chronic Hep C die more than people who don't. All cause mortality, right? Take the liver disease out of it, they still die more. So I tried to tell him, this is about your health. And if you live 30 or 40 more years like your dad, your liver could actually become a problem. But overall Hepatitis C will increase your risk of dying. So I think those are these are really important-- I didn't want to pressure him, right? And you know, I think he came in expecting a fight. And I said, I'm just going to give you the information, you can come back and we can decide whether you want to do this. But I convinced him. All right, so initial treatment. I'm not going to go into [INAUDIBLE], but I am going to refer you. This is actually a paper that we just published in JAMA that is basically written for the internist, OK. It is written for the generalists who is interested in getting into Hepatitis C and it summarizes what you have to do, what tests you have to do, and what are the therapies. And when I can tell you is, at this point in time, we have four fantastic FDA approved regimens for Hepatitis C for initial treatment. And we have fewer for re-treatment but I didn't get to talk about that here, OK? I am going to use this slide to summarize a couple of things. So you can see that not all of these are pan-genotypic, right? So if you're practicing in a rural setting, where you can't get a genotype. Or you're practicing in a setting where you have patients at a very high risk and using IV drugs, maybe you go with it pans your typical argument because you don't know whether or not you're going to be able to feel good about the coverage. And so part of the decision making and how you choose a regimen is going to be based on their genotype, right? Or if you have access to a genotype. If you get a genotype you might choose any of these and if you have a two or three, you only have two options. But that's the first decision point in making a decision about treatment. The other that I want to highlight is our treatments now are eight to 12 weeks, that's it. These are finite therapies and there is no recommended regimen on the guidelines that's more than 12 weeks of therapy. Which is pretty impressive, right? A couple of things to highlight, in HIV we're used to the concept that if you can start someone an HIV drug and antiviral therapy to check for resistance first. I'm just going to say that, this is not really played out in Hepatitis C. Although, many of us who came from an HIV background were certain that it would. And we would scoff at the hepatologist sitting next to us, I'm just kidding. When they talked about resistance isn't going to matter, they were right, OK. Resistance matters a little bit but not a lot. And only one regimen requires baseline resistance testing before you start therapy, OK. It's a great regimen but you do want to check if there are a particular genotype and subtype for resistance. Other things to highlight, so how do you make a decision on which treatment? You want to know what their genotype is, right? You want to-- potentially, if you use the regimen of [INAUDIBLE] you want to know if they have resistance, if they're a 1A. The next question is, do they have severe kidney disease? So two of these regimens are not approved in patients with GFR less than 30. And two of them are approved in people regardless of if they're even on hemodialysis. So that's another decision point in deciding this. Two of these are approved in people with [INAUDIBLE] and two of them are not. And you can actually see, that the two that are approved and patients on dialysis, are the two not approved in decomp and vise versa. And that's because of the drugs that are in there, right? Protease inhibitors cannot be used in patients with severe liver disease. And these two regimens combine protease inhibitors and NS5A's. Meanwhile, these two regimens are protease inhibitors [INAUDIBLE]. So they're fine for the liver, the problem is these are NS5A and NS5B combinations but that is NS5B drug is not approved in people with GFR for less than 30. So the beauty of this is you have lots of great options. So then, someone might ask, well what do you do in a patient who is decompensated and has [INAUDIBLE] disease? I can answer that question, afterwards. But they have an option too, it's just off label, that's all. All right, and then, the other point of this is again, that I mentioned, transplant. We have two of these regimens that are proven patients that are kidney and liver transplants, right? So this is just really impressive but it's actually relatively straightforward if your internist kind of getting into this, you're not worrying about transplant and that sort of thing. And so there really are great options. The reality is we like to think as providers we have a choice but at the end of the day it's going to be the insurer is going to tell you what to use anyway. All right, so I did put this in and I think I have enough time for this but-- the reason I put this in is just to say, you know, when these drugs were approved we had all oral therapies that were very safe and well tolerated. And the only approved regimen we had was interferon based regimens that were a year along. So if you went to a patient and said I want to randomize you to a study. You're either going to get interferon for a year or this new pill for eight weeks. Would any of you be willing to randomize in that study? Right, I mean, and to be fair, most investigators didn't feel that they had equipoise in asking their patients [INAUDIBLE]. I said, the part of the problem we ran into is that many of these studies were single arm studies that were compared to this birth control. We have a couple of studies that actually are now randomized compared to each other. Usually, within the same companies drugs. But this was a PCORI-funded trial that actually compared our three main drugs at the time. Which was, the [INAUDIBLE] regimen, so ledipasvir/sofosbuvir and then what I call the PrOD regimen, because it's got so many names, it will take all the rest of my time to say it. But at the end of the day, this regimen actually fell out and the study ultimately compared in a randomized fashion ledipasvir/sofosbuvir, which are again, one regimen is good for patients with kidney disease, one is good for patients with liver disease. At the end of the day, the take home point with all of these numbers is there was no difference. So I think actually nice that we do have a randomized controlled pragmatic trial that says, it doesn't matter which one of these four drugs you give, they're all the same. They're all equally safe as long as, you choose the right population. And they are equally effective, you will cure 98% of these people, OK. Gaps have closed for people living with HIV, as well. Just for the sake of time, I may go through a couple of slides quickly. But I do, for this audience, want to highlight the benefit of SVR. So SVR, sustained virologic response, is a biologic surrogate from what I call clinical cure. When a patient takes their treatment, 8 or 12 weeks, they've done the drug. 12 weeks later, we bring them back to clinic can we check their Hep C viral load again. And if it is still undetectable, then they are cured. The virus is gone. There's no latency and it isn't coming back, right. And that's a really amazing thing for these patients, I can tell you that. Many of them carry a lot of guilt for having Hepatitis C. And it is a really big emotional deal for them when they are cured and they feel that they have some reason to not feel so bad about potential behaviors they had at some point in time in their life. So SVR is cured, just think of it that way. So the thing I would say is in the interferon days we had many, many studies that looked at patients who got interferon based therapies and they followed for a long time to say if you got cured of your Hep C versus if you didn't. Did you have less liver cancer? Did you have less decompensation? Did you die less? And the answer was absolutely yes. We're just beginning to get to the point now, where we have this data for DAA's, right? Because the DAA's have really only been around clinically for about five years. And the bottom line is the answer is yes. So I'm going to walk through this slide. So this is a slide that shows years after starting therapy and probability of being free from HCC. So a straight line is better, right? So what this shows you in a nutshell is if you have cirrhosis and in HCV, people who get a liver cancer are mainly the ones who have cirrhosis. This is different in Hep B. Hep B you can get HCC regardless of cirrhosis. So what this shows you is that if you have cirrhosis and you do not achieve a cure, then your risk of developing an HCC is quite high after two years. So about 15% would develop a liver cancer within the first two years after therapy, right. If you don't have cirrhosis-- So generally they're not at risk, right? And you get cured, well, good news. You don't get liver cancer. OK, great. These two groups took exactly the same, our patients with cirrhosis coming in the door with a lot of risk, who get cured. And it basically, it stops the train dead on the tracks, right? You can see this huge gap between cured and not cured in terms of the number of patients who get HCC. But they look exactly the same as the people who don't have cirrhosis. Who don't get cured. That's because these people continue to progress, they keep getting liver damage, and they develop liver cancer. So if that's an argument for treating people who don't have cirrhosis, I'm not really sure what is. Did you guys know that we still have states that deny access to daily therapies for people who don't have cirrhosis? Yes, we do. I'm going to skip through this, just for the sake of time. But suffice it to say, I can show you slides about mortality, all caused, liver-- doesn't matter, these drugs save people's lives. And they prevent diabetes. This is a little bit of it-- So this is a slide actually, where I talked about-- so you actually see that Kaplan-Meier curve that really starts to divide for people that have cirrhosis, right? So we know if you have cirrhosis you're at higher risk. If you're cured, you have less risk of HCC but you saw that if you're cured and you don't have cirrhosis going in you get no HCC, right? So there's a big difference there. Part of my research program in addition doing clinical trials is-- this is actually one of the RO1's that we have-- is trying to say, can we further risk stratify? We know you have cirrhosis. We know you're high risk but we can we further risk stratify you to know if you have cirrhosis and you're cured. Can we say that we know that you're going to get cancer and you're not. So we are working with a fantastic core metabolomics lab at Duke who does-- we have what's called targeted broad profiling. We have a very strong interest in lipids as a determinant of risk in HCC and in patients with HCV. And you can see here, that we've developed a metabolomic model that with 87% accuracy, can differentiate two years prior to the event, whether someone's going to get a cancer or their liver is doing anything to compensate. We're validating this now. But this is some of the work that we're doing at Duke to try to say, can we now take these patients-- a huge number these patients have severe liver damage. Right now, everyone with severe liver damage gets an ultrasound every six months or an MRI or a CT. They see us every six months and we spend a lot of money on these patients care essentially, for the rest of their life. Yet, the liver can regenerate itself, right? And is there a way to actually risk stratify to say maybe you need more follow up and maybe you need less. And that's one of the things that we're working on. All right, so am I talking fast enough for you guys? Sorry. I try not to drink as much coffee but that was hard to do. So the last few slides I got to talk about, again, let's circle back to elimination and say-- so, you know, we have these tools, right? We have testing, we have treatment-- but we know that already from the US perspective, we're falling off the curve when it comes to incidents. So what are the challenges and how can we address them? And I think, when I say we I mean, we, like us. When we have patients who are coming in and we ask them the questions about their IDU. For those of us who work with these patient populations are there ways that we can engage them in certain care that can help them reduce their risk, right? So barriers-- Some of the barriers to treatment in access are perceived, some of them are real. We talk about cost, I'm going to talk about that really briefly. Engagement and care, I think, my patient that came in and said, I don't really think I want treatment but I'm just showing up in your clinic now. And I haven't seen a liver person in 10 years, just to have this conversation one more time before I leave and never come back. Engagement is hard. Especially, when we're getting to the patients who don't have symptoms. And therefore, it's harder to convince them to take treatment. Prioritization by patients and providers, I think my patient's story tells you that neither he nor his provider prioritized his Hepatitis C treatment. Oh sorry, I think I can go back. Concern for re-infection, reaching the highest risk patient population. So we do know the patient who is the highest risk. Who's driving the epidemic, people using IV drugs, right? Is there a reservoir in our society where we know that there are very high rates. You saw that in the US maybe were 1 to 1.2%. If you go into the incarcerated population, the rates of HCV can be as high as 50% or 60%, right. Are there groups that we can target to decrease the burden of the infection in our community? So I mean, who doesn't love a good VA story, right? The VA gets such bad press. It's hard to even get them good press. But I've been practicing in the VA for a very long time and I will say for all the not's that the VA takes, they have excelled in the treatment of Hepatitis C. And that is because Congress-- they've agreed on nothing for the past five to 10 years. They have agreed on veterans. Veterans should be treated. Veterans should have access. The VA remove restrictions to DAA access years ago. And the VA is likely to be the first health care system in the US to eliminate Hepatitis C, which I think is fantastic. Right? How did they do it? They did it because they could negotiate drug costs with the drug companies. And because they in fact, had the resources to do it. So it can be done. And I do want to dispel the myth about [INAUDIBLE] costs, right. So when these drugs first came out there is no doubt, it was offensive that anybody would price the drug at $1,000 a pill. So that wholesale cost per cure, was $92,000. And that is crazy, right. It's also crazy that we have health insurance like Medicare that can't negotiate drug costs. But that's a different story. Today, the cost of drugs of those four that I showed you, did you guys know two of them are generic in the United States now? OK. And one of them was priced wholesale cost at $26,000 for an eight week course. So cost, yes, that's expensive. This is about cure, OK. The models for the longest time have always said, that it is not just cost effective to treat Hep C, it's cost savings. Now, we have even cheaper drugs to do it, right. So it's all the more cost savings. And I don't know how many of you have heard this story but there are also novel models. So Louisiana was the first state to do this subscription based Netflix model. How many people here have Netflix, right? You pay one set rate, you get all the screening you want. Imagine paying a company one set rate, you get all the drug you want. Australia was the first country to do it. Louisiana was the first state to do it. Why did they do it? They knew that they had two patient populations carrying the heaviest burden of the disease, patients on Medicaid and patients in prison. And they said, we want to cure all of our patients, on Medicaid and in prison. And so they paid a company for, you know, per year set costs and they're as a state making a huge commitment to doing this. Washington state just signed on, right. We just wrote a piece in the North Carolina Medical Journal to try to convince North Carolina to do the same thing. So the other thing I'll tell you is that-- so there's a group called the National Bar [INAUDIBLE] to this round table, they actually give report cards to every state regarding access to drug, right? And I think you guys should be proud that Virginia is a B plus state. North Carolina is actually a B state. We were a D state, I'm pretty sure you guys were too not that long ago. But Medicaid and many states have actually raised their thresholds for getting access based on fibrosis levels. So in terms of this, they look at it by is there a threshold? Is there a-- do you say that you can't get access unless you have a certain fibrosis stage? Do you say that people have to be off drugs or alcohol to get treatment? Right, these are some of the things that they look at and overall, Virginia is doing well. Although clearly, you can get an A, most people in this room like getting A's. So that's what we achieve for it right? All right so I'm going to I'm going to move through these slides actually really quickly. This was highlighting again, with re-infection with high infection rates. Acute incidents, new infections in our IDU's-- The point that I'm going to bring home with this slide right here is treatment as prevention. So many of you have probably heard about this in HIV. So how many people in this room have heard about treatment as prevention for HIV? How many of you have heard about you equals you? Right. Undetected means you can't transmit, right? Undetected means untransmittable, which is which is a weird word. And I'm not even sure that's a real word but-- you equals you. If that's true for one virus, it's got to be true for every virus, right? And so the concept for Hep C was the same. If we treat HCV, the way you transmit the virus by having virus in your blood and you can't transmit it if you don't have it in your blood, then probably, it's the same for HCV. And there are models that clearly show, there's this concept right-- a patient gets acutely infected. Should you let them naturally clear, right? The human host can clear the Hep C virus at about 20%. So should we give him an opportunity to clear? The problem is, while you're waiting those six months or a year to let them clear, they're also infecting other people. And this model simply says it is cost savings, cost savings, to treat people when they're acutely infected, OK. Which the current guidelines do not recommend. I just want to say that. But I think that's going to change too. So we now have multiple real-- This is not a model. These are real people. This is in the Netherlands, when you have a very small country you can actually show really well how quickly treatment as prevention, in real life. So they opened up and expanded access to HCV therapies right at the end of 2014. And what I'm showing you in these curves is not people who got treated, new infections. They could show that as they treated patients and cleared about 75% of this patient population, new infections dropped by over 50%. This has now been shown in Iceland, as well. And so this is key, right. Get to these high risk patients, get them treated, so they can't transmit. I was just going to wax on the different treatments but I think that's not necessary. So I'm going to focus on the prison population to bring this point home, right. So the idea of triggers prevention is clear, the other ideas if you treat the reservoirs of the infection, people that are transmitting, it isn't just good for those people, it's good for the entire community, right? So what this shows is models suggesting that if you treat people in prison, infections averted by in-prison HCV management. You don't just prevent infection in people in prison, which is in red. You mostly prevent infection to people in the community. Because when people come out of prison and go into the community, they are at risk of transmitting, right? So this is a clear benefit. While in prison, treat them. Our treatments are no longer a year, it's eight to 12 weeks. Some people get the argument, well you know, the problem is if you treat them and they leave and you know, well, yes-- but they're not going to leave in eight to 12 weeks. We know that especially in a prison, right? Maybe in a jail, not in a prison. This is a really great population. And we have one of the ID faculty here, who actually is doing this and working with the prison system in Virginia to do that. Which I think is fantastic because we've tried. And today, we have failed in North Carolina. So all right, I think I'm going to go to my-- so, got a vaccine? The answer is no. I just wanted to highlight this because this was just presented at our big ID meeting last week in D.C. The first HCV vaccine that's been presented on the podium in my time and infectious diseases-- and the sad news is that it failed. So this was-- what this slide shows is that, there are different types of vaccines that can be developed in terms of presenting the peptides or the antigens to the human host. Most of them fall off once you get through kind of animal models and into humans. This was a viral vector. They actually had a hit, kind of a prime, and then a booster. As part of their vaccine to present the Hep C antigens to the host and it did not work. It did not prevent infection in very high risk IV drug populations in Baltimore and other cities. Interestingly, what it did do, though, was and so-- the placebo group is in the black line, and the gray line is the vaccine group. And this is Hep C viral loads. But so, in those who got infected, which they couldn't prevent. The viral load was greatly blunted. So there was some immunity, right, they could control replication. They just couldn't clear the infection. Given, they obviously didn't have enough T-cell prime to do that, so. I mean, some people worry that with this, maybe, like, is it dead? Is anyone going to be willing to fund Hep C vaccine work moving forward. Even though, we're very worried that without a vaccine, elimination won't be possible. All right, so, in summary, Hep C elimination is possible but we are falling behind. And that's a big concern. The WHO has identified four key focus areas-- diagnosis, treatment, incidents, decrease in mortality. The current opioid epidemic is a major challenge for us in the US. To have any control in any chance of elimination. Universal testing is coming. If you're not already doing it, you probably should start. Then you can be like, I'm way ahead of the curve, right. And a high conversion to treatment is needed. Everyone with Hep C should be offered therapy. And I'm happy to have that debate. And then, harm reduction and prevention is going to be critical. There's no way we're going to treat ourselves out of this if we don't prevent the infection to begin with. And a vaccine at this point is not on the horizon. Back to my case, this patient has a high risk of die from his liver disease, he's 81. He has hypertension CKD, he is unbelievably well otherwise. You could say, he is 81, why would you do this, right? But we put 81-year-olds on dialysis, I'm just saying. So I think this is a patient who, if I don't treat him, the chances are he will die from his cirrhosis, even in the next 10 years. And so I actually started him on treatment just this week. And with that I will say thank you. Those of you who, as research faculty know, it takes a village. To raise up a clinical investigator and I have many people to thank so I've just listed them here. They include my mentors, the leadership at my institution, my collaborators, and the research team that helps me do all this. So thank you guys for your time. Thank you for the invite. We may have time for questions, if you'll just wait for a microphone. So all can hear your question. OK, number one, thank you for the talk. I thought it was really great. And my question is are you at all looking at the possibility of fibrosis regression with the achievement of SVR? Can you speak your thoughts on-- Oh, absolutely. So one is, fibrosis regression is known. So we know that the liver regenerates. I will say, we don't know where the point of no return is. If you take a patient who is a decomp and you treat their Hepatitis C, you know, do they re-compensate. And will they ever get another cirrhosis category? I think that's the one that we don't know as well, although, we have seen these patients who are decomp's who come off the transplant list. Their [INAUDIBLE] go up, their INR's go down, and their MELD scores improve. So regeneration clearly happens. We have multiple studies that have done paired liver biopsy. Cirrhosis pre-treatment, over time and regression, actually happens. The issue is, I'll give you two examples, Hepatitis B. Take a patient with Hepatitis B cirrhosis. Put them on a nucleotide analog therapy with just standard of care. Five years later, 50% do not have cirrhosis. It's amazing. It just melts away. Hepatitis C, the farthest out we have is three years. But you take a Hepatitis C infected patient with cirrhosis, cure them of their Hepatitis C, three years later, 15% no longer have cirrhosis. So what I tell my patients who have cirrhosis is this, it does regenerate. But if you look at the Kaplan-Meier occur for after cure, how long does it take before the rates have hepatitis-- [INAUDIBLE] carcinoma drops in plateaus, it's about 10 years. So what I tell my patients is it's like smoking and lung cancer. The day you quit smoking, your risk of lung cancer remains high for 15 years. I tell my patients with cirrhosis. I'm not going to repeat your liver biopsy or follow you in that way. But what I think, is that it takes about 10 years for your liver fibrosis to regenerate to the point that you no longer have the risk of liver cancer. Does that make sense? So yes, and I will say this, a lot of people are doing this. But DAA's is following non-invasive markers. Most people don't have a tolerance for biopsy anymore, which is a shame because as an ID doctor actually was credentialed for a liver biopsy, which my chief loved. Because I could actually do something that brought a building code in but that's over now. But people are doing noninvasive, primarily elastography. To say, can we use repeat elastography at some point to say, now you're OK. And you're not at risk of developing liver cancer anymore. I would just say, we don't have any data for that yet. We need long term follow up to know that. But people are absolutely doing this. Yes, that's a great question. I enjoyed your talk. One quick question, you indicated that just going by history you would only capture 25% of patients who-- Correct. So there's a huge number. And I'm wondering whether we have really ruled out the possibility that people can get Hep C from mosquito bites? That's a fascinating question. I mean, never say never, I guess. But I think ultimately, universal testing will address that, right. I mean, I don't know that we know of any viral-- I mean, while viral infections are transmitted. But I don't know about Hepatitis C, right? I mean, we think about arboviruses and that sort of thing. It's a fascinating question. But you are right, that no matter what-- there are many people who ask for risk and you have no idea what it is. And I'll admit I don't ask about mosquito bites. And how much they get per year, but I will say, we don't know all the ways. Right? And for many years, people didn't view Hepatitis C as a sexually transmitted infection, which we now know it clearly is. Right? And so, I think that's why universal testing will address this. But I can't, unless someone else in the ID community can comment on it. But I don't think we have any knowledge or evidence at this point that it's transmitted by bite. You know, bugs. Yes. A common question. [INAUDIBLE] That's right. The question is will be [INAUDIBLE] been involved in using Hep C [INAUDIBLE]. Yes. How do you feel about early treatment [INAUDIBLE]? Let me just to clarify, what you mean is, in a patient who's getting a transplant, and that positive organ in a negative donor-- [INAUDIBLE] Yes, Perry [INAUDIBLE]. So I think there's two camps right? There's the preemptive, which is kind of what we used in transplant, right? Preemptive, treat them. You-- with kidneys, especially, it's almost 100%. Right? The data so far of transplant in these patients is it's 100%. They're going to get infected. There's no doubt about it, right? It's high. I mean, the data that we have so far it's near 100%. So in those cases, I think you would say, that there are studies that are ongoing to kind of look at the two models. Do you do preemptive and treat them right off the bat, from pretty much close to day one. Maybe it's week one weekend or something-- but versus waiting until they have clear infection. I wouldn't call it chronic but like, clear infection, right? And maybe get through the period where they have their graft is still kind of kicking in. And there's all these other things-- I'm definitely in the preemptive camp, I can tell you that. I actually, literally, had a conversation last night with one of my colleagues at Duke. Who had a patient who was actually a [INAUDIBLE]. But Duke does it a little bit later. And one interesting thing that he talked to me about was the viral loads some of these patients is exceptional. The viral load in the patient he talked to me about was 94 million. And what I will say to this, and then also, happen to be at a PPI. Which I was like, oh my god. So that's the issue here is, we don't-- none of the studies in the registration program had patients with viral loads of 94 million. And an HCV in particular, we have clear evidence from the beginning of time of HCV, that baseline viral load predicts treatment response. Right? So to me the concept that you would let a virus get to 94 million before you treat it, when you could treat it knowing it's going to come back anyway, preemptively, I think at the end of the day that science is going to say it's better to treat preemptively. [INAUDIBLE] I know. So, yes-- right. To that, that was the issue they had to crush it, put it in the tubes, all that stuff. But I think some of them have been able to kind of make it work. What I will say is this, in the transplant programs that I've heard of that, that are doing this and doing some of the studies is they, before they do the transplant they all have commitments from their institution. That if the insurer does not cover it-- and actually, my understanding and Duke's on over 80 of these now, but my understanding is that over 90% the time the insurer actually covers it. That's number one. And then, they've had to go to the institution uncommonly, but the institution has committed to doing it because you can make a case for how it saves money for the institution to get these people and organ. [INAUDIBLE] Yes. It just depends on how hard-- Yes. So I mean, again, and this is maybe a state based thing. Because we talk about the acute. And I've had and-- I've gotten acute treatment for patients without-- because I can't prove their chronic cause or not. And the insurers do it. But I do think you have to have your ducks in a row. And if you don't get it approved by the insurer then you have to do it quickly. I mean, the reality is six months is the definition of chronic. So if they're actually holding you to six months, then the cat's way out of the bag by then, right. So it sounds like they're doing-- they're not really doing chronic, they're doing four weeks, who made that? Insurance companies. So I mean, the other thing I would say is, you can talk to those insurance companies. You can have conversations with the leadership of those insurance companies and say, like we are saving you money, right? At the end of the day, we're going to save you money by doing this. We're going to get your patient a transplant way sooner, right. And that can-- I mean, there are many people who've been doing the Hep C thing for a while who've had conversations with the insurers and convince them of doing this. So I know that sounds crazy but I would actually consider it if you actually, in your state, have particular insurers who are still doing this four week thing which they've totally made up. Because by definition, that is not chronic infection. Yes. And it's highly unlikely. There's no way these people are going to naturally clear, right? They're severely immunocompromised. So-- it works. This may be a naive question but, thinking about viral load, you kind of mentioned it. You know, with other viruses we-- like CMV after transplant and stuff, we think about viral load matters. And it can add to risk probability for developing laminitis or something like that. And I was under the impression that with HCV viral load maybe is a little more arbitrary and doesn't matter necessarily. Is that true or do you think there is a threshold where like resist treatment and resistance will be increased or? Development of worsening-- It's a great question. So I would say it doesn't matter when you're talking about disease. So there's no study that's been able to show that the viral load predicts fibrosis stage, risk of cirrhosis or disease. And that's kind of we talk about too, right? CMV's is a disease. [INAUDIBLE] diseases it's reactivation that kind of thing. Whereas, in Hep C, all the way back to the interferon days, level of virus did predict response to therapy. Just think of it, ledipasvir/sofosbuvir, it's approved for 12 weeks. But if you have a patient who's [INAUDIBLE], never treated, and their viral loads less than six million, you can do eight. That's a perfect example, right? So I don't think it's so much necessarily about resistance. But because we don't have any evidence for that. But presumably, if it takes longer for the virus to come down, why would it increase the risk of relapse? Presumably it is because you are therefore selecting out for some resistant variant that is there. And that can then be the variant that relapses, right? We just have evidence of that but it may well be. So that's why I get really nervous about 94 million. And in this patient's case who did relapse. And so, my colleague was going to be going to the hospital asking them for a regimen. And they were asking me, what regimen should I be asking for? Because the patient just failed [INAUDIBLE]. And what I said was, you know, what I'm worried about is it was 94 million and the patient was on the PPI. Which is generally, not recommended for that regimen. And you add a few things in, other drug interactions. All of a sudden, you've got this mix of different predictors that probably play a role. But I told him, we need to study that. That was the first I'd actually heard of someone saying, these viral loads you're really impressive. And I think many people say, but I heard it doesn't matter. It doesn't matter for disease. It does matter for response to therapy. I had a quick question about your predictive models, I thought they were very interesting. And so, you do baseline plus amino acids or baseline-- Predictive models, good I can talk about those. And so what I was curious about is that I mean, you've got your area under the curve-- Yes. 6.87 did you ever look at a combination approaches if those analytes-- Yes. You're studying and-- Yes. Improve the curves or not? Yes, so thank you. I mean, I just didn't spend much time on it. So those models are-- so the first thing we put to the models we're actually known, kind of, clinical predictors, right? So liver enzymes, age, race, liver fibrosis-- that sort of thing. And then, we added in for each one the different metabolite profiles. So we did amino acid separate, added onto all the clinical variables. We did each, you know, bile acids and then lipids. And then, the final model-- and I'm happy to walk that with you here-- is actually all combined. And when we get all combined, believe it or not, we kind of, get one metabolite from all the different ones. It's actually primarily amino acids, bile acids, and lipids. And that's what gets us up to .87. So I think that's what you were asking, whether it was a combination. And yes, it was. [INAUDIBLE] There is. Yes, come on up. Veiling-- but no. I mean, there's-- there are a couple that keep coming up, yes. Naggie, thank you so much for being here. Yes, absolutely thank you.