Thanks very much Nancy and Andrew and thanks to ASLD for keeping elimination so high on the forefront of what needs to occur with Hepatitis C. So I'm delighted to kick off this session to talk about the cascade of care for Hepatitis C and I have no disclosures. So you may or may not know that five particular microbes contribute most of the global mortality related to infectious diseases. Whether it's... Take it all the way to the right. All the way to the right, okay. I'm going to do something that's going to help everyone. I'm going to make space for that and then this is going to work. Okay. So whether it's tuberculosis, HIV infection here in the red, chronic Hepatitis B and C in the blue or malaria shown in the green, these five contribute most of the mortality due to infectious diseases. What's interesting is if you look over time, there's been change in global mortality from each of these and the curve from three of the five are dropping. So HIV most profoundly declining here in the red but also the declines in tuberculosis related to mortality and malaria. And so that raises the question of why. Why for three is mortality declining and for two others is it going up and perhaps even more importantly why is mortality from Hepatitis projected to exceed the combined mortality from the other three by 2040? And that has to do with today's topic, this topic of the cascade of care. It's not because there's any one thing, some tool that works for HIV for example and not for Hepatitis B and C. In fact, as you know, for Hepatitis B we have the only really effective vaccine among all these five infectious diseases and it's not because of there being a cure for the three and not for the others because for Hep C of course we have a cure that only takes 12 weeks and is extremely safe to achieve. So it must be something else and the one point I'm going to make, and I'm going to make it a bunch of different times in a bunch of different ways, is that it's because there's a public health response, there's a funded, vigorous, intentional, coordinated public health response to the three where the mortality is declining and incidentally it's declining because of that and it's temporally correlated with that global response. And for two, Hepatitis B and C, and I'll be talking about C mostly, it's going up. So that kind of gets to this business of are we delivering the tools that we have into the populations where it's needed? And that's broken down and conceptually considered with this classical cascade where we take, for example, the... Sorry, this is going to be a challenge. I'm going to shift that over a little. Okay. So with the... Let me screen what you're... Yeah, I can see it here. It's just... It's weird. It's going up on a hill, so it's hard to get it stable. So let's talk about Hepatitis C. 71 million people anticipated to be infected. The cascade has to do with proportion diagnosed, which is worldwide less than 20%, and then the low proportion who are treated and cured. And often we consider it in 2015 when it's sort of the baseline for the WHO Elimination Program and then with regard to the WHO Elimination Targets of 80% tested... Sorry, 90% knowing about their infection, 80% of them being treated and cured. So that's the light blue, if you will, and I'm going to be showing lots of cascades, so get familiar with these. It's always starting on the left with the number infected and then moving across. A couple of quick points with the overall global cascade. First of all, the efficacy of treatment is not the problem, right? You didn't need to come to this Elimination Seminar to figure that out. We know that we can cure Hepatitis C with 8 to 12 weeks of highly safe and well-tolerated medications. So those two curves are often the same. The proportion treated and the proportion cured is essentially the same from a public health perspective. Instead, the problem has shifted to the left. It's over here now. When you consider Hepatitis C at the population level, it has to do with testing, finding the positive, finding the infected individuals, confirming their infection, and then linking them to care. Now, I'm not going to say this too much, but it's also important when you're considering global elimination to add to the cascade something even further to the left, which is prevention. We have to do something about the 1.7 million new cases that were occurring in 2015 and reduce those, in fact, by 90%. So the cascade conceptually then also has to consider the preventive services and specifically the degree to which we're making the blood supply safe and the degree to which we're delivering harm reduction services such as needle and syringe exchange. Those are critical parts of the cascade. They're sometimes left off when we're focused on just testing and treatment. I'm going to now shift from the world to a few countries and illustrate what I consider to be the pivotal points using the cascade model, if you will. Let's talk about Pakistan, where one of the top five countries in the world with the top five burdens of hepatitis C, more than 8 million persons expected to be infected in Pakistan. The interesting situation there is that no more than a million are already aware of their infection, and roughly 500,000 treated and most of those cured. So this is a situation in 2015, and then once again the 2030 goal. Look at what this low-income country needs to do to achieve elimination. They need to go out and find another 7 million positive individuals. I've been to Pakistan. It's an enormously challenging goal to achieve. You have to test, of course, not just 7 million. It's estimated that you need to test 20 to 25 million to find an additional 1 million infected individuals. So that just underscores the problem. Now in Pakistan it's nice because they have access to inexpensive medications, but there the model suggests that the challenge will be actually it will be more expensive to test, to find another million, than it would be to actually provide treatment to those that would be newly discovered as being infected. So substantial challenges in this representative low-income, high-burdened part of the world. Now flip the paradigm to Iceland and notice that the axis has changed. Now we're in thousands, not in millions, and we're talking about 1,000 people in a relatively high-income part of the world being infected, and in a part of the world where they have a national elimination plan and where they actually had a registry and knew who was positive and who wasn't before the program unfolded. So not surprisingly, with very quick success, the country's been able to find the positives and then link them to care and deliver care, and nearly that country by 2018 is already on target for elimination. So two countries, both with national elimination plans, both with relatively affordable approaches to the drugs, but vastly different challenges, one with very high burden, relatively low income, and the other one the opposite. There's published experience from Georgia that someone in between also underscoring that in order to find an estimated 150 million, sorry, 150,000 individuals with chronic hepatitis C, that testing will really be challenging. So they went out to find them. They tested a million individuals, found roughly 50,000 with chronic hepatitis C, and then as you can see, everything works out well from there. The linkage and the cure rates were quite high once that original discovery of infection was achieved. Now the situation in the United States is also informative. A high income country, no national elimination plan yet, and access to these drugs since 2014, 2015. We have what's thought to be somewhere between 2.5 and 3 million individuals chronically infected still in 2018, about half diagnosed, and most of those diagnosed treated, and most of those cured. Now the situation can be understood with greater granularity, such as this modeling exercise that Jay Chotwal published recently. And here focus on the viremix, which is the hash part of these curves. So if you consider 1.4 here, and this is the middle curve in each one of these is 2018. And I'm contrasting the NHANES population, which is of course household representative households in the United States, to those not in households. And this is chiefly homeless and incarcerated populations. I'm showing these data just to make the point that even within countries, you can describe a cascade that varies according to the setting. In the United States, we've done better, of course, with people who are not incarcerated who are in households. Here shown by the relatively low proportion who are viremic of all those who are antibody positive here in 2018 compared to, for example, in corrections where most are still untreated. So the cascade is able to reveal to a population level where the challenges remain and give some insights into what still needs to be done to achieve elimination. In the United States, it's useful to return to this point of the very left side of the cascade, that is prevention. Just once more to underscore the importance of doing that, because of course we're not. We have an increasing incidence of Hep C in the United States. And instead of achieving a 90% reduction in incidence to eliminate Hepatitis C by 2030, we're still experiencing rising Hep C incidence. The treatment cascade's also been described within a particular population. So not a country, not different populations within a country, but here just asking the question within a segment of a subset and the so-called concept of micro-elimination. So here's HIV positive individuals in the Netherlands. Most persons with HIV, almost all in the Netherlands, are included in this registry. So it provided an opportunity to have a clear denominator to expand testing and provide universal access to testing and treatment, which resulted in the identification of 1,471 persons who are candidates for treatment. And of those 1,471, you can see that within a year, there was very high success in taking DAA treatment and expanding it out through this sort of one-time massive test and treat program and eliminating Hepatitis C within a distinct HIV-infected population within one country. Now the Netherlands example also underscores that, if you will, the right continuum, the cascade really should wrap around because after achieving an SVR, someone can of course be reinfected and that's the threat that they've had to their elimination is that they're already reporting that some of those who achieved SVR are being reinfected, once again bringing up the importance of prevention. So I tried to use these examples to make a couple of points that I think are important from the cascade that relate to global elimination. I did not mention many other important examples, including, for example, the astonishing success that's been reported from Egypt, where nearly 50 million people have been tested to achieve their elimination program and the situation in Australia and in other countries. I did not prioritize by the importance. I found published examples that I thought would be illustrative. It's important to know that then these examples teach us that there's been terrific success and that elimination can be achieved. The tools are there, but it requires a plan. It requires coordination. It requires funding and it requires a deliberate concerted effort and when that's been the case, elimination appears to be on track and when it hasn't, there's a lot still to be done. It's possible that new tools could help us and in this part I would underscore the potential for long-acting treatments for hepatitis C, which would make it possible to test and cure at the same visit and would eliminate some of the situations where we lose people from linkage. But once again, the most important point and my perhaps only, is that these efforts need to be funded and coordinated and shifted to the public health sector as opposed to just treating hepatitis C in your clinic. And I think the HIV example is the one I began with when I considered the population level and I'll return and finish with this. If you consider what's happened with HIV since that curve I showed you, in 2019 more than 20 million people will receive HIV treatment. So more than 20 people will receive 12 months of HIV treatment. More than 240 million person-months of HIV treatment will be given. And if you're quick at math, well, and first of all, you'll understand that that's the reason that that curve came down. That's why that happened. There's no question. They went out and tested and found those people and gave the ones who needed it the treatment. Now if you think about hepatitis C, that amount of treatment that will be given in just one year for HIV would cure everyone in the world if it was done just once because there's only 71 who need 8 to 12 weeks of treatment. So that's just to underscore what is possible because it's already been achieved and sustained each year for HIV. And what is absolutely necessary, if what occurred with HIV to bring down that mortality will prevent what's expected and predicted for hepatitis C and B. So that's my message. We need a public health coordinated response to drive the cascade around the world. Thanks very much for your attention.

infectious diseases

mortality rates

public health response

hepatitis C

elimination programs