Thank you very much for inviting me for this session. As you can tell by my name and soon my accent, I am from Texas. My talk today, for the first few minutes, will focus on just bringing up and discussing some key themes about cost-effectiveness, cost-effectiveness analysis, because that's the focus of what I will be talking about. But most of the presentation will be sharing information, sharing data on effectiveness, cost-effectiveness of screening, and little information that we have on linkage to care, but focusing on the two common diseases, liver diseases, that we've been listening about or hearing about all today, hepatitis C, virus infection, and non-alcoholic liver disease or non-alcoholic steatohepatitis. So just to get everyone up on to the same page, cost-effectiveness analysis, these are methods that allow us, with a way, to examine both costs and health outcomes of different interventions. The central key component of cost-effectiveness analysis is the trade-off, the trade-off that is involved in choosing between alternative strategies, while simultaneously looking at the cost of these strategies and potential health benefits of these strategies, looking at all of them together, with the main overarching goal of finding the intervention that offers the best value in terms of the benefits that you want to achieve. So the intervention that will get you the most health possible, given the resources that we have available. So I'm going to show you a few examples of what that might look like for the topic that we are discussing today, some relevant examples. This comparative nature of a cost-effectiveness analysis, it could be screening versus no screening. It could be screening everyone versus screening only the high-risk patients, or it could be screening using alternative strategies, imaging or blood-based markers. So if you heard about all of these today, I'm going to be now going into the data that we have available for some of these things in the next few slides. But before I do that, what a cost-effectiveness analysis does, it compares. For a given intervention, how much more will it cost to gain an additional unit of health outcome, compared to the alternative intervention? So there is a change in cost, delta cost, which is divided by a change in benefit, delta benefit, and that gives you the incremental cost-effectiveness ratio, or ICER. So now we know the terms, what they mean. What the incremental cost-effectiveness ratio tells you is compared to one intervention, how much more will it cost to gain an additional unit of health benefit, be it life year gain, be it quality-adjusted life year gain. So now let's go over this hypothetical scenario before we look at real data. So here I'm showing you three different strategies plotted in this graph, where the cost is along the y-axis, and effectiveness is along the x-axis. So this red dot is do nothing. The green dot is screen high-risk individuals for a given condition. And the orange dot is screen everyone. So doing nothing is the cheapest strategy here, it's the lowest on the y-axis. It's also the least effective strategy. Compared to doing nothing, screening high-risk patients, or screening all patients, it's more effective, but it also costs more. So whenever you see these lines, these dots, the next reflex is to try to draw a line between these dots. And if you draw a line, that is the incremental cost-effectiveness ratio. So looking at this segment of the line, that means how much more will it cost to screen everyone compared to screening just high-risk individuals, and how much more benefit will it gain if you do that. So that's the ICER. And in general, ICER values of less than 50 to 100K, they're per quality-adjusted life years. And they're thought to be acceptable. They're thought to be acceptable, but the key point here is that you are still paying more than the alternative strategy. It's just that the additional cost is thought to be worth the additional benefit. But what about this strategy here, right there? So this strategy here, it is more effective, but also it's the cheapest. So here, this is actually cost-saving. We're not spending more to achieve more health. It is actually cost-saving. And this strategy is a term for that. It's called the dominant strategy. Now that we know the basics 101 for cost-effectiveness analysis, let me show you how the same scenario, this hypothetical scenario, was actually evaluated in a study that Ray Kim mentioned earlier. I'll spend a little bit more time talking about this study. So this is the study, cost-effectiveness of universal screening, that actually is forming the basis for the recommendation that we heard about, about one-time universal screening in the US. It turns out that it's published in the best journal in the world. I'm the editor for the journal, in case you did not know that. So here, this is, we went over this data, explained it really nicely. There are 2.7 million individuals with hep C in the country. Most of them are in this birth cohort. That led to the CDC recommendation of screening the birth cohort individuals. That recommendation came out in 2011. Things have changed since 2011. HCV incidence is rising in younger individuals. We also have far more effective treatments. And one thing that we didn't talk about, WHO has set the goal of eliminating hepatitis C from the world. And the target is to do that by 2030. So given all these changes, the really, what the question here is that, should we move away or scale up from birth cohort screening and actually do a universal screening in the US? And that is what this study looked at. There are three comparisons for this study. They looked at no hepatitis C screening, birth cohort screening, and then universal screening. The main outcome was quality-adjusted life years. It's a composite outcome looking at how long you live, but also how well you live. There were a few key assumptions in this analysis. One was the testing was based on the test that we have available in clinical practice right now. It's an antibody test followed by a nucleic acid testing for confirmation. One was treated with DEA if the patients were positive in this analysis. And the key assumption in this analysis was it was a perfect linkage. Everyone who tested positive was linked with care and got DEA treatment. I want you to hold on to this thought because I will come back to it. This is a graph similar to what Ray showed, but looking at it from a different perspective. Here I'm showing you the relationship between the monthly cost of DEA, which is along the x-axis, with the incremental cost-effectiveness ratio, looking at the two strategies, the two recommended strategies, the birth cohort screening and what's being considered right now, which is the universal screening. The base case in this analysis assumed that the monthly cost of DEA right now is about 8,000, somewhere between 8,000 and 9,000 US dollars. So at that level, if you draw the line from this point to the y-axis, this is where it hits the incremental cost-effectiveness ratio of a little over $10,000 per quality adjusted life year. So a total of $11,000 per quality adjusted life year. And if you remember, less than 50K is thought to be cost-effective. So based on this analysis, universal screening in the US would be cost-effective compared to the recommended birth cohort screening. What if we have access to cheaper DEAs? This is where the line would fall. And here, if you now draw the line from that point, that arrow, to the y-axis, there's actually... The value is zero. So below the monthly cost of $2,500, universal screening dominates. Remember the concept dominates. What it means is that it is less expensive and more effective than birth cohort screening. So this is the result from this analysis, again, with the caveat that the assumption was 100% linkage to care and treatment. Hold on to that. So this is the US scenario. Most of the patients with hepatitis C virus infection in the world actually live outside of the US. So here are the countries with the highest burden of HCV infection worldwide, China being the one that has the highest number of HCV-infected individuals. The second one is Pakistan. It's a small country, but has the highest prevalence of HCV infection in the world, with estimated between 9 to 11 million individuals living with hep C right now. So we looked at the cost and effectiveness of screening for hepatitis C virus infection in Pakistan. I'm going to share the data with you in the next few slides. Pakistan has an advantage. Like many other developing countries, the cost of treatment is pretty small. DAs are available for as low as less than $60 for the whole course. The main cost burden in these countries, they actually come from testing. Testing for viremia, testing for even screening, antibody testing. And there are several testing options that are available, and the range, cost range is quite variable, with the cost as high as $137 for an RNA test, to as low as $5 for the new innovative point-of-care testing, which is being implemented in several countries. When we looked at, in the simulation model, estimated the annual cost of hep C treatment in this country, in Pakistan, and I'm going to show you data from now, 2018, to 2030, because that's the target year for WHO for elimination strategy. So in the status quo, what's happening right now in this country, where there is sporadic testing with the currently available testing modalities, it is going to cost a large amount, $684 million in the current year. Under the status quo, if things stay the way they are, the cost will fall a little, a little, not by much, by 2030, most of that is because patients will die of hep C. What happens now, if you have to scale up testing and treatment to the whole country, at the mass population level, using the same test that we have available right now? The cost is going to be substantial in the first few years. It's going to go up to $1.26 billion, compared to the number that I showed you before. However, it will fall to a substantially lower value by 2030, and the two lines will cross in 2026, eight or nine years after implementing mass level screening, where the annual cost of hep C management will fall below the cost in status quo in 2026. But what if we are more innovative, and we're using the newer and cheaper, more feasible testing strategies? With different scenarios, the curve shifts. It shifts downwards to the extent that some of the new methods with point of care testing, followed by HCV core antigen confirmation, or new tests like gene expert confirmation, the lines are very similar. There's a slightly higher cost up front, but then it crosses the current status quo cost in two or three years after implementation. So again, showing that mass screening in a country, in an underdeveloped or developing country, is also cost saving, if it's not at that level. Just to summarize what we've gone over so far, based on the literature that we have, and there are many other analysis coming out from many other countries, this suggests that universal screening for hep C may be cost effective, and perhaps even cost saving, compared to what's happening right now in different countries. But most of these models, including the two that I've just showed you, they do not account for very important costs that are associated with strengthening the infrastructure for mass screening. They assume that the mass screening is going to be perfect, it will be 100% implementation, and we know the reality is not such. They do not account for those costs, just because those costs are not available. They also do not account for gaps in implementation, and gaps in linkage to care, again, assuming perfect implementation, perfect linkage, which is somewhat of a reach. And I say that because many studies show that there are actually big shortfalls from testing to linkage to treatment in different patient populations. It's not just that, those gaps are hard to fix. It's hard to really bridge those gaps, and even with dedicated interventions. And here is a study that I'm sharing with you, it is a large multi-center randomized control trial in the UK, that just came out recently. The practices in an area were randomized to an intervention and control group. The intervention group had 50 practices, and for those, invitation letters were sent out to patients who were thought to be high risk for viral hepatitis, those were immigrant individuals. With that, there was intervention that was targeted at the provider level, with incentives provided to the providers, and a dedicated person who sat in those practices to help the providers reach out to patients for hepatitis C screening. The control group was eight practices that had opportunistic screening. The intervention went on for 18 months, and the target was to look at people who took up the screening, as well as how many people were treated. With this intervention in place, the control group had dismal screening. Out of all the individuals who were eligible for screening, 1.7% actually took screening in that 18 month time frame. It was better in the intervention group, with 20% of individuals who were eligible, underwent screening. However, only 20% of the individuals agreed to be tested, even with this intervention that was in place. 80% did not. So this study is one of the few examples that are out there showing you how big of a task this is to really have successful outreach outside of our clinics into the population to bring the patients in where they actually did reside. So I am highlighting the same point that was discussed by Ray Kim, that what we really need to do... We really need to shift our efforts, focus our efforts on finding ways to ensure that there is successful implementation of screening and linkage, so that these HCV-infected individuals who are sitting out there in their communities not knowing that they have the infection can actually be brought in and linked to treatment, because without that, none of these interventions are going to be effective or cost-effective. So how about this condition? We heard quite a bit about it just recently. I have to say the data on the cost-effectiveness of finding these patients and linking them to care are very mixed. I'm just going to show you two extreme examples, and then we can discuss this more during the discussion section. This is, again, a fresh-off-the-press, hot-off-the-press paper in Journal of Hepatology. It is looking at cost-effectiveness analysis using a micro-simulation model, but relying on actual patient data from six screening programs from different parts of the world. So they're using patient information and using that information to populate this decision model, and they're focusing on two different strategies. The main goal of these strategies is to find patients who are risked for advanced fibrosis. Again, we heard that in NAFLD, advanced fibrosis is the key characteristic that we want to identify. So the two alternatives are every patient undergoes a TE, transient elastography, followed by a biopsy if needed, or we rely on what we rely on right now as standard of care, ALD-based testing. There is a key assumption in this analysis as well. The key assumption here is that patients who were diagnosed earlier will experience reduction in fibrosis progression year after year after year. So that is an important assumption in this analysis. So with this, the authors found that one needs to test 33 individuals in general clinical population to identify one individual with advanced fibrosis. The number needed to screen is much lower if the risk of the population is higher. So eight obese patients, seven diabetic patients, and 13 who are using alcohol use need to be screened with these modalities, with TE, to identify a patient who is at risk for advanced fibrosis. And compared to ALD-based screening, using transient elastography was cost-effective in this analysis for most of the countries that they looked at. But going back to the assumption, that the assumption here is if you identify these patients earlier, it will change the natural history of the disease, that it will be a reduction in fibrosis progression, which is great, but I think it is too optimistic right now and a little too premature. We really need to look for and find more data to have more confidence in this assumption. This is the other side of the story, another cost-effectiveness analysis, now focusing on patients with type 2 diabetes. Looking at no screening versus ultrasound and followed by biopsy-based screening. And here, they assume that everybody is going to get treated with piaclitazone. In terms of the effectiveness, they found similar results. The patients are less likely to progress to advanced disease and less likely to have labor-related outcomes. But when they looked at the side effects of the treatment, it really lowered down the quality-adjusted life year. And what they actually found, that no screening was the preferred strategy. It was the dominant strategy, so very different results from these cost-effectiveness analyses. So whereas for hepatitis C, we have better treatments, we have highly effective treatments, and when we just look at those treatments from that point of view, universal screening for hep C appears cost-effective, maybe even cost-saving. But there are really mixed data on cost-effectiveness of screening for NASH. And I think it's really too early to look at whether these strategies will be cost-effective for NASH, because we really need more estimates about incidence. We have actually very good estimates about prevalence. But incidence, as well as progression of disease, we need better treatments, safer treatments, more effective treatments, and other issues are going to be relevant. Access to care, screening programs, how do we best reach out to the patient, and just the massive size of the population that we have to deal with, especially where I live, in Texas. This is me carrying my lunch tray out. If I'm not in the mood for steak, this is the alternative, super-sized burger. And here is the dessert. That really is a doughnut, a Texas doughnut, with the actual doughnut from Europe as a comparison. Thank you very much. Five excellent talks from very accomplished speakers. I'd like to invite our speakers up for a brief panel discussion and Q&A. So thanks very much, everyone. Those were amazing talks. Question to those of you who have put together screening fairs. So I get pressed by various stakeholders, county hospital, the American Liver Foundation, to put together screening fairs, but I really worry about linkage to care and how much responsibility we then bear for making sure those patients get taken care of. Have any of you done screening fairs, and if so, how have you implemented them? We've done actually screening fairs in the different communities for hepatitis B. For example, screening in Korean churches in Northern Virginia, where I live and I work, or having fairs in Vietnamese sort of festivals that come in. What you have to have is basically not only the screening tool, but also linkage individual available at the same time, so that not only you're doing the initial test, Not a fear, per se, but we have a project where we are using population-based tools to identify patients which have more significant disease, cirrhosis, and trying to then link them to care. The main goal of this intervention is to link them to care. Even with this population, which has more significant disease, who have complete access to a healthcare system, it has been a very difficult challenge to link them and bring them and keep them in care. It's a glass-half-full, half-empty situation, so yes, we were able to bring in 40 to 50% of that population, but we were not able to bring in the rest. So it's better than doing nothing, but it is significant challenges, and that implementation effort, time-consuming, lots of effort, so I do not know if it's cost-effective or not right now, but I can say that it took a lot of effort. how little people know about that as well from a UK perspective I think from blood-borne virus That's a very big point. If you go to a health fair and set up a booth for patients. And we do meet monthly with the health department and we have linkage to care. We treat their patients. My main limitation there is the state has screening budget, but no confirmatory budget. So the issue is the finding the active hep C. Then the other issue is providing insurance for them to be treated. So is there a move in the ASLD or in our group to do this hepatitis C core antigen or anything so we can confirm these cases and treat them as soon as possible? Because the other way is to, in a high-risk group like peeweeds, which I do this in the needle exchange program, we have about 500 patients that are screened and we assume that about 150 of them are positive. Then you stop there. Then what do you do? So is there a move to do something about this confirmatory test at the same time? Linkage to care is useful, but if there's no payment, it's still zero. So I think these issues we have to address on how to not only link to care, but a lot of these peeweeds, homeless, don't have insurance. Then how are we going to link care without insurance and without treatment? So that's the reality I'm facing now. I just met with the health department Tuesday before I came here. We're going to meet them and we're trying to do an incidence and prevalence of all these peeweeds, 500 of them, in a needle exchange program in our Walla Walla County. So that's where the reality is. How do we approach this? That's a very good question. Any comments on that? I'll do tongue-in-cheek and say, vote wisely next November. Yeah, I mean, I think the key here, if we can do something about this hepatitis core and get this expedited as a society to expedite this quickly, because otherwise, as you could see, the curve, the cost will be so high. But if we expedite the testing through the FDA, say we have a national emergency opiate epidemic, we need a new test that's cost-effective, and from there we can at least solve half of the pie. The other pie would be the insurance that we can get expedite Medicaid coverage on Hep C. If that's done, then we can solve this quickly. I was going to follow my stupid comment by saying that USPSTF recommendation is at least supposedly make it easier for the Hep C screening test to be paid for. The problem is Hep C screening has been mandated 10, 15 years ago, but a lot of this mandate has no teeth. That's our problem. No teeth, no money. we need to be vocal about these, because what you're saying exactly what's needed. And I feel that some of this is done better in other countries than we're doing here. I presented data for Pakistan, lots of work needs to get done for Pakistan, but Egypt is a great example. They have, Egypt, they have an excellent program where they did mass screening and linkage, and very successful, so learning from them and figuring out what can we actually bring in here is important, but somebody will have to take the ownership and leadership in that. That's why the ASLD has to voice out a uniform. So ASLD is not gonna be able to do this. This requires a national policy. The reason that Egypt was actually successful was because the president of the country put actually a national policy together to screen and pay for it, link and pay for it. There are actually programs that are successful in Portugal, they are successful in Iceland. The United States problem is that we do not have a national policy of how to deal with hepatitis C that deals with all of those issues as you brought up. If screening is fine, you can even link them to care, but if you cannot actually afford a medication, then it's all for nothing. That only can be done through a national policy for viral hepatitis, which we haven't had here. Thank you. Yes, I hope you'll forgive me for asking a tangential question, but I have specific need to address this with Zobar. Bob Perillo from Baylor in Dallas. Not infrequently, we'll see Asians who come to us with fatty liver being the presumed diagnosis by all that we know without many metabolic features that would push them towards having a more easier assessment as having fatty liver. Their BMIs are often within the normal range. And from my preliminary reading on this, this is not terribly uncommon in East Asian patients. Now, here's the question. Should we be a little bit more relaxed about them? Do we have any natural history data? And how many of those people will ultimately develop NASH? So, thanks, Bob, for the question. I think it's a very important question. First of all, when you look at the Asian population, and if you actually take the appropriate BMI for Asians, you'll see that actually most of them will have that same metabolic risk factors. In fact, even if their BMI may not meet the criteria, even the correct criteria, when actually you do abdominal MRIs, they actually have a lot of visceral fat. In the United States, we actually looked at the prevalence of lean NAFLD within the United States. It was about 7% in general population. When you look at lean NAFLD and you compare it to lean controls without fatty liver disease, they are more insulin resistant. They have more diabetes. But if you compare them to actually to the obese or overweight, then they're less metabolically abnormal. So in my view, that most lean quote-unquote NAFLD that exists predominantly in some areas of Asia, for example, in the rural area of Asia, that they probably have still some degree of insulin resistance, and this is really what we have to focus on. In terms of natural history, they may actually be a little bit less progressive in the Asians, and Vincent Wong actually showed this. We actually have a presentation here, an oral presentation in the next, I think it's also on Sunday, that looks at lean NAFLD long-term outcome in the United States. That's not a benign disease, at least in this country. There's increased mortality. So if they come and they have fatty liver disease, then I treat them the same way. Last point I wanna make is that there is an effort from a lot of us to really even get rid of this terminology of NAFLD, because that's a disease that there is so much overlap with other diseases. For example, moderate alcohol consumption with metabolic syndrome, having hepatitis B with metabolic syndrome. If you actually take those, the metabolic diseases that we purely call fatty liver disease, and expand this, it affects all other liver diseases that needs to be also taken care of. So there is actually an effort. Jacob George from Australia is actually leading this, and in fact, there's gonna be a paper in gastroenterology that a lot of us actually contributed to, to actually come up with this sort of notion. Is this the right terminology, not to call it fatty liver disease? Or should it be metabolic liver diseases that really affect a lot of different diseases? But lean NAFLD is a special population. Just one last point. In the rural area, if you look at India, for example, in the urban area, they all look like what we see in the United States. They're basically urban area or obese diabetic. When you go to rural area, they're more lean NAFLD. And maybe there is actually a diet issue, an environmental issue. Maybe there is more microbiome, this biosis sort of playing a role there than actually overt insulin resistance. Any genetic association? So there is probably some genetic. When the PNLP3 is actually quite known, and there are others, but whether you actually have that in the Asian population, in fact, PNLP3 has actually been also associated with high fatty liver disease in the Asian population. But I think there may be more that we haven't actually discovered yet. Our last question. they may have still impaired health function and they can improve their health function probably if they are aware that there is a problem. I think ACLD can do something, but I think it has to go to the more general practitioners because most of those tests, the primary care physicians are the ones who are ordering that. But I think it was either Ray or Fessia, someone actually showed the data that the number of patients that will have tests and have really significant chronic. Thank you very much

cost-effectiveness analysis

screening

liver diseases

hepatitis C

non-alcoholic liver disease

universal screening

national policies