Thank you very much and thanks for the invitation to speak here today. Here's my disclosure slide. I have done consulting for some of the companies that made the medications for hepatitis C, but this talk will not include any discussion of medications and has been adjudicated by the Education Committee to be without conflict of interest. There will be discussion of investigational diagnostic testing that's off-label in the United States at this point. So my objectives over the next 15 to 20 minutes are to do three things. One, I'd like to review the current screening guidelines and available tests for hepatitis C. I'd like to highlight some novel strategies targeting key populations at risk for high prevalence situations with hepatitis C, and I'd also like to discuss some novel and emerging screening tests as they pertain to the future of hep C elimination. Our current screening process begins with a need to identify who to screen. So right now, the current guidelines suggest we should be screening patients at risk for hepatitis C through known risk factors, as well as those fall within the baby boomer birth cohort. And after we identify who to screen, we offer a screening test, and the preferred screening test currently is an antibody test. This can be achieved either through venipuncture or through a rapid finger stick test. Once this test is performed, it's then recommended to do a confirmatory test, which is typically a hepatitis C RNA test. This test can be done either as reflex or through a second venipuncture. And to do a reflex testing requires some consideration to how you collect the specimen, how it's stored, temperature considerations, and transport to a central lab for analysis. If you don't do a reflex testing, it requires a second venipuncture, and these steps can lead to patients being lost along the care cascade, as we've just learned. The AASLD has endorsed this screening mechanism through HCV Guidelines website, which is easily accessible. It involves three to four steps in its current iteration. First is the screening test. Second is the confirmatory test with RNA testing. Quantitative RNA testing is still recommended before treatment, as some medications may be influenced by the current viral load. And genotype testing is still recommended in terms of how to treat these patients most effectively with our current regimen. Similarly, the CDC recommended algorithm for diagnosing current HCV infection involves several tests, including screening, confirmation, and linkage to care. But, you know, wouldn't fewer steps be great? And I think for me as a treater, you know, I'm typically coming in at the level of linkage to care. These patients are typically coming already diagnosed to me, so, you know, I enjoy getting a chance here to review the literature and look at what's coming for diagnostic testing. I've included here a table for the currently recommended screening tests. This is also available on our Guidelines website. There are seven tests currently. They're all antibody-based tests. And I will call your attention to the lack of RNA testing or other diagnostic tests on this recommended screening list at the moment. Six of these seven are based through venipuncture, and one of them is through a finger stick test. So when it comes to implementation of the current available screening guidelines, the decision to screen requires a conscious effort to identify patients either as having risk factors or as being within the birth cohort. And these strategies are designed to be complementary, not mutually exclusive. And we know that in the current environment in the U.S. at least, patients under age 40 who inject drugs or newborns born to mothers with hepatitis C infection are among the rising populations that would be missed if only birth cohort testing was implemented. I'm including here the list of risk factors. I know everybody in this room is well aware of what these risk factors are. I just call your attention to ask the question, who has time to ask all these risk factors? And most people don't, and there's plenty of data supporting that fact as well. And we know that through these two mechanisms of risk factor-based testing as well as birth cohort screening, we have reduced the burden of hepatitis C in the U.S. by about 50 percent over the last seven years, but still more than 2 million people remain infected. And new strategies on how to find these patients have had to be developed and strategized. So many patients right now remain with active infection for hepatitis C in the United States, at least over 2 million, and we still believe that many don't know they're infected and potentially don't have access to the care they need to find that diagnosis and to be treated. So why does risk factor-based testing fail? I think we all are aware of many of the pitfalls along with this, including lack of time to ask the risk factors as well as lack of willingness for patients to report them. But I think importantly, the risk factor-based testing requires the patients present to care to be screened. And so what we're doing here is we're missing a large population of patients who may not be within your normal cohort of patients seen in the office or seeking medical attention. So alternative strategies for screening have been and are currently being studied, and I think unless we embrace some of these new strategies, we will fall short of our goal of HCV elimination in 2030. So in the next section, I'm going to highlight six important novel strategies that are being used for screening as they have impact on identifying hepatitis C in these key populations. So first I'll talk about emergency departments. I'll look at dialysis units, prisons, homeless shelters or homeless population in general, hospitals as a place for screening as well as to find patients. And I'll also mention countries with increased prevalence. And all of these are key populations with potentially high burdens of hepatitis C that may be outside of our normal cohort of patients who are being screened. So over the last few years, we've seen emerging data on emergency department screening for hepatitis C. We've seen across emergency departments in the United States high prevalence of hepatitis C positive tests, over 10% in multiple locations around the country. Without testing has shown high participation rates. However, linkage to care really continues to remain an issue with this population. And I think from our own experience at my institution, a lot of these patients who test positive are there for something else. It's not their priority, and they're not very motivated to follow up after that or they have competing medical concerns. So only about one in three patients who are screened positive in the emergency departments eventually seek care for treatment. It is more common to see patients screened for hepatitis C in emergency departments today, particularly among those in the birth cohort, although many emergency departments have adopted a universal screening strategy. Dialysis units also represent another location for a potential micro-elimination situation. We know that dialysis is a key risk factor for HCV acquisition. And as many as 30% of patients on dialysis for more than 20 years may become infected with hepatitis C. It's a captive audience. These are patients who are seen for 12 hours a week in medical situations, and occult HCV, so those with antibody negative chronic hepatitis C may be present in this population. The current screening recommendation in dialysis patients is to do antibody testing every six months with reflex PCR testing as a screening test of choice. However, if a patient in a dialysis unit is identified as having hepatitis C, it's then recommended for everybody in that unit to be screened with a PCR test. There is a bit of a competing interest in this population, however, among kidney transplant programs who may see chronic HCV infection as a pathway to transplant sooner. And so there's a disincentive to treat some patients who are waiting for kidney transplant in dialysis units, although many of the major dialysis companies have really taken HCV elimination to heart and have endorsed screening in their populations. We know that prisons are a site of increased prevalence of hepatitis C, not just prisons but jails as well. As many as 40% of patients incarcerated in California state facilities have active hepatitis C infection. In Texas, over 17% had hepatitis C testing that was screened positive. Again, this is another captive audience for screening as well as for treatment. And in this population, in inmates who are incarcerated for more than three months, there really is an opportunity to treat and eliminate hepatitis C within this population. And these are also people who may go back into the community once their sentences are finished and be at risk of transmitting hepatitis C new infections to other people. So there's a number of studies now that have shown that this is a population that can be screened effectively as well as when coupled to a motivated treating specialist, whether it be a general practitioner or a remote telemedicine consultation with a hepatitis C provider, can really provide high cure rates among that population. One of the WHO goals with elimination is to reach prisoners. And right now, only about 35% of countries have plans to actively screen or treat these patients within the WHO arena. Homeless patients or people living in shelters are also at high prevalence and high risk of hepatitis C. These are, again, patients not typically involved in regular care who may seek for screening opportunities. This is a worldwide problem, although a lot of the data comes out of the U.S. and Europe. There's a lot of overlap in this population between homeless, incarceration, and people who inject drugs. In this cohort, different ways to reach these patients are needed. So whether that's mobile interventions, engaging at the shelters directly, and importantly in this population really is the key population to benefit from co-localization of testing and treatment. Hospitals are another site where a lot of screening efforts have occurred in the last few years. And this is partially motivated by investigators, but partially motivated by law. In many states in the United States have laws that mandate baby boomer screening, at least offering baby boomer screening to patients admitted to hospitals. In my home state of Pennsylvania, there's a Pennsylvania Hepatitis C Screening Act that mandates offering hepatitis C testing to all baby boomers involved either in primary care or admitted to the hospital. It's an opt-in system, not an opt-out, which has a number of pitfalls in of itself. But these interventions have been shown in some states to increase the number of screening tests in particular. Electronic health records are also something that has been studied extensively in the last few years. And EHR-based interventions definitely increase screening rates by 20 to 30%, but they run into similar pitfalls as the emergency department testing where not everyone is able to be linked to care. I highlight this reference here, number five from Vermont, where over 90% of the patients who are screened were able to be successfully linked to care with an integrated health system. So perhaps these EHR-based interventions are really best for larger systems with a big catchment who typically stay within the system themself and can seek opportunities for treatment. In general, hospitals are a site where screening can occur. I'll highlight one study here from China where investigators screened over 450,000 patients hospitalized at multiple hospitals across China over a one-year period of time and impressively found over 4,000 patients with hepatitis C infection. This came out to a rate of about 1 in 113 tested, so a little less than 1%. The highest cohort here were among people aged 60 to 64 and 90% of them were over age 40. And so the authors recommended here that all Chinese hospitalized patients over age 40 be offered hepatitis C testing. Dr. Thomas called into account national efforts and I agree here the national efforts are really important when it comes to screening. Some countries with high hepatitis C prevalence have endorsed national strategies with the goal of hepatitis C elimination. Egypt with its 100 million health program has screened over 35 million people in six months. Rwanda was another country that screened over 120,000 people at 30 locations in one week. And these are countries that have now identified many patients and treated patients with hepatitis C. The key with these national incentives really is the ability for affordable treatment. So when there's treatment available, testing is more motivated. So large scale national action, political buy-in, these are all really important when it comes to screening hepatitis C. Mobile screening has been integral in some of these countries, in particular Egypt. And access to treatment, again, can drive screening motivation. So I want to talk for a minute about simplifying screening. So I mentioned in the beginning that fewer steps really would be nice. So what is it that we really need to know when it comes to treating hepatitis C? Really it's just do they actually have active hepatitis C infection? I think as an academic hepatologist, I love knowing genotype and resistance and viral load. It's very interesting to me, but it's really not that important when it comes to eliminating hepatitis C globally. and I have to believe that as hepatologists we need to kind of get out of that silo and share that with everybody. So really I don't care that much if they have an antibody test that's positive, I really care if they have virus. And so right now the reason the antibody test is part of the algorithm is due to cost. It's a cheap test and it helps to identify patients inexpensively. However, if the cost of RNA testing or another test were less expensive, antibody testing would be unnecessary. So there's some socioeconomic data suggesting that in high prevalence areas where there may be over 70% prevalence, RNA testing alone may be effective and cost-effective. So what are some candidate tests that we can use to identify active hepatitis C infection? Really there are two out there right now. One of them is one we've been using for many years, which is hepatitis C RNA testing, and the other is hepatitis C core antigen. And so I think a lot of us in the room would do a double-take core antigen. Are we talking about hepatitis B here? No, this is hepatitis C core antigen, and it's something that we really don't think a lot about in the U.S. So I think most testers and treaters are are very comfortable with RNA testing. We've been using it for many years. Once you throw core antigen into the mix, it probably confuses a lot of people. It is less well-known and the test is not currently available in the U.S. in commercial settings. However, I'll just call your attention to the structure of the hepatitis C genome, and the core is right here. It's in the structural portion, and then nucleocapsid peptide 22 is testable within the blood. And two recent meta-analyses, in particular, have shown that core antigen testing has high sensitivity as well as very high specificity to detect active hepatitis C infection. It has the potential to replace RNA testing in high-prevalence areas and has excellent correlation with patients who are viremic with a viral load over 3,000 IUs per ml, which is typically most patients with chronic hepatitis C infection. However, for either RNA testing or core antigen testing to replace screening for antibodies, really it's going to require decreased cost. It'll require point-of-care capability, and it will require some ease of logistical constraints such as cold storage, transport media, and central testing. Dry blood spots have the potential to improve logistics when it comes to this diagnostic testing as no cold storage is needed, no venipuncture is needed. You could use a finger stick or a heel stick to obtain blood for dry blood spots, and you have the potential to use whole blood and not need a centrifuge to work out the plasma or serum for standard draws currently. Dry blood spots can detect core antigen as well as RNA. They do detect core antigen less effectively, and it requires a higher RNA level to do so. They are generally not as accurate for RNA testing in patients who have low-level viremia, but again, since most patients will have a viral load over 3,000, this may be a strategy that can be used for both core antigen or RNA testing using dry blood spots. They've been shown to be durable at various temperature extremes, and the accuracy may increase by using more than one spot, so a lot of times dry blood spot cards have multiple spots, three to six spots for instance, and you could punch out two of those and analyze them and get a pretty high yield. It also offers the potential for peer testing or home testing. You could stick yourself with a lancet, send it into a lab, and not worry about going somewhere to do it, and it may also be possible to do quantitative PCR testing from these spots as well. The big breakthrough though, I think, would be if we had point-of-care RNA testing available, and this is a multiple-step strategy here, but one, you could eliminate antibody testing, you could eliminate the need to send a blood test somewhere for essential testing, and it allows for simultaneous treatment initiation. So right now, this is not available in the United States, but there are two systems on the market outside the U.S. currently. There's the expert HCV viral load from Cepheid. This is a quantitative RNA test, which produces a result within one to two hours, and there's the gene drive HCV test, which is a qualitative PCR test with a lower limit of detection, about 2300 IU per ml. So in comparing these two point-of-care tests head-to-head, one can see that they both have similar turnaround times of one to two hours. They have the ability to detect pan-genotypic infection. The quantitative expert test is a lower cost per test, but a higher startup cost, and it requires special disposal conditions, whereas the qualitative test has a higher per cost test, but a lower startup cost, and I think both of these tests are currently marked for use within the European economic area, though neither is clear by the FDA at this time. The other thing to ask though is, is qualitative testing enough? And I think that historically that hasn't been for most treaters, but I think we're going to need to embrace the idea that qualitative testing is sufficient when it comes to diagnosing and treating hepatitis C if we really want to eliminate hepatitis C worldwide. So I'm going to end with this futuristic picture from Tanya Applegate and colleagues, which I really enjoyed her recent publication called Hepatitis C Diagnosis and the Holy Grail, and you know I think what we're looking at here is the potential in the future to walk in somewhere for a test, receive a point-of-care test in real time within a short period of time, decide is active infection present, and begin treatment that same day with a pan-genotypic regimen that's highly efficacious and very well tolerated. The patients will then receive a reminder several months later to return to the clinic for a test to confirm that they've been cured, and if they continue to have risk of recurrent infection, there could be the opportunity for at-home testing or self-testing through either dry blood spot, which they can mail in, or some other form like that, either for core antigen or even for RNA. And you know if we could really achieve this, this would be sort of the, you know, the optimal situation to eradicate hepatitis C around the world. And you know while we're not quite there yet and these tests are not quite ready for primetime, the future does hold promise for these tests. So I'll leave you with these following take-home points. Number one, current screening practices or risk factor-based and birth cohort screening are not adequately capturing all of those infected with hepatitis C around the world. Number two, targeted testing in higher prevalence populations, including those who are incarcerated, homeless, on dialysis, or seeking acute medical care in hospitals or emergency departments, can help to identify more hepatitis C infected patients. Number three, national political support can have big impact in higher hepatitis C prevalence countries. And number four, simplifying the screening paradigm, focusing on active hepatitis C infection with point-of-care RNA or core antigen testing holds promise. Thanks very much for your time. Thank you so much, Jonathan. We will open this session for questions and I'm gonna start by asking our two lecturers, if questions please focus on screening and diagnosis. The United States Preventative Task Force has proposed new screening guidelines for a one-time screen for everyone between the age of 18 and 79. Is this an improvement over risk-based and birth cohort screening or are, what is your opinion about that? It's an improvement, but I think the burden of hepatitis C primarily lies with outside the United States, so it's helpful here. If you're gonna use that outside of the U.S., it would be even more helpful. But again, it's how are you diagnosing this test? Is the antibody test enough and should we maybe wait till we have a better diagnostic test available to do that? Yeah, I think it's a great question. It also, I mean, some practical issues come up with it, like the ability to get reimbursed for the testing. That endorsement makes that more likely for the payers. And so, in many ways, I think it's a good step forward, but I also agree that when you think it globally, that that advisement probably will have not so much impact on a global level. A great step forward for the United States and definitely one that will capture more of the young people affected by the opioid epidemic and some of the more recent infections. David, on that note, I was grateful for your discussion about prevention. Could you comment on how we currently approach acute hepatitis C? And right now, if you follow our guidelines, we are waiting up to six months to treat people. There is some discussion about being more aggressive about it now. Whether you think that will have a significant impact or whether we should be much more aggressive about early intervention in those people? Now, that's a really good point. Unfortunately, as everyone knows, we don't have a hep C vaccine that's licensed and there's been less effort to develop one than would be advisable given the burden. But that said, the methods that we have to prevent infection are proven in terms of harm reduction, but difficult to sustain at the population level. A recent CDC report showed that something like more than 80% of new hep C infections in the United States were reported from someone living more than 10 miles from the nearest syringe exchange program, for example. So the idea that around the country in very rural areas, even in a high-income place, we'd be able to develop that capacity just raises new questions. And the idea of treating to prevent is also interesting. Obviously, the people who just got it are involved in the very practices that spread, and so the public health benefit of treating them is high. And probably, in my opinion, outweighs the risk of their being reinfected and that discounting the value of that treatment. John, I had a question for you around the Pennsylvania Screening Act and what your take is about whether a legislative strategy like that is effective, or in your case, in your state in particular, and your understanding of the other states. I think in Pennsylvania right now, there's really no data, to my knowledge, showing that it's actually been studied to know if it's effective yet. So anyone from PA in this room, if we want to get together with that when we get back, call me. I think from a practical standpoint, the way that hospitals implement it is variable, and in hospitals who are integrated networks where you can link to care easily and most of those patients are retained within that system, it certainly has the potential to be more effective than in one-off hospitals where patients may not follow up with their care there. It has been effective in New York, at least, in terms of increasing screening rates in particular. So I think that that kind of leads into David's task that we really need to shift hepatitis C out of our clinics and into the public health sector. Any idea how to successfully do that? I mean, medicine is so heterogeneous across the United States. How do we get the public health sector to actually own hep C? I think that's a great question. Thank you for asking it. First of all, I'd like to announce that John Ward has a coalition that he's pulling together to achieve global health elimination and that provides a forum for the kind of coordination and shift towards public health that I think is necessary. Could you imagine if we were all sitting around waiting for people with TB to walk into the primary care office to get treated? Like that would just never happen, right, Kami? So it's the same sort of thing and I think it's a complex answer. I'll start out with people have to care. I was really blown away from some conversations I had last night with the Egyptians. The Egyptian situation with hep C is like what we have with HIV. Everyone knows someone that died of it. Everyone is personally affected and there's absolutely no trouble getting public health buy-in and public buy-in in Egypt, which is why they've been, partly why they've been so ridiculously successful. And in contrast, there's very little awareness, relatively, in the United States and considering our income, we've not been able to make that shift. So I think it's those kinds of things that are necessary, making the case to the stakeholders and raising the dial on, raising the volume on the epidemic. All right. Thank you both very much.

hepatitis C

screening

diagnosis

high-risk populations

targeted screening

elimination