Hello and welcome to the Hepatitis C SIG session for the annual program. Today, we're going to talk about the optimal hepatitis C treatment approaches to achieve elimination. We've got a fantastic panel today. I'm Dr. Mark Szolkowski, a professor of medicine at Johns Hopkins, where I direct the viral hepatitis clinic. I'm joined today by my co-moderator, Dr. Jennifer Price, associate professor of medicine at the University of California, San Francisco, where she directs the UCSF viral hepatitis center. I'll turn it over to Jenny to introduce our first panelist. Thanks, Mark. Our first speaker will be Dr. Sunil Solomon, who is an associate professor of medicine and epidemiology at the Johns Hopkins University School of Medicine. Dr. Solomon will speak to us about simplified hepatitis C testing and treatment. Great. Following Sunil will be Dr. Stacey Truskin. Stacey is assistant professor of medicine at the University of Pennsylvania, Perlman School of Medicine. It has a very important role as the chief medical officer for Philadelphia Fight, which is a community health center-based organization. She will talk to us about hepatitis C cure for persons who inject drugs. Our last speaker, I'll turn it back to Jenny. Our last speaker will be Dr. David Wiles, who's professor of medicine at the University of Colorado School of Medicine and chief of the Division of Infectious Diseases at Denver Health. Dr. Wiles will talk to us about achieving cure after DIA non-response. Please stick around after Dr. Wiles' talk because we will have a 25-minute panel discussion with all of our speakers as well as Dr. Salkowski and myself. Well, great. Thank you. Let's have a great session. Good morning, good afternoon, good evening, depending on where in the world you currently are. On the outset, I want to thank the organizers for inviting me to share my thoughts on simplification of HCV testing and treatment. These are my disclosures. Over the next 20 minutes, I'm going to talk to you about why we should think about simplification of therapy. What is the evidence of simplification? How do we apply that to practice and any special considerations for simplification of HCV testing and treatment? I'm going to start by talking about why you simplify treatment and testing. As many of you are aware, hepatitis C virus treatment has evolved pretty dramatically over the past two decades. If you think about what has happened in terms of SBR-12 or cure rates, we've gone from less than 20 percent to almost 100 percent cure in almost everybody who's being treated with a new generation of directly acting antivirals over the past two decades. What has also happened simultaneously is the treatment duration has dropped from almost a year to 12 weeks or even eight weeks of therapy these days. But I think most important is we have evolved from multiple injections every week that was extremely toxic, to pretty much regimens which are one tablet once a day associated with almost no side effects. But what has remained the same is the monitoring guidelines really haven't evolved with these advances in treatment. But these advances in treatment really prompted the WHO to establish very ambitious HCV elimination targets. To achieve elimination, we really had to transition HCV care from specialists to primary care and non-traditional providers because it really requires us to diagnose 90 percent of people and treat almost 80 percent of the 50 million people who are chronically infected with hepatitis C virus globally. The way we could do this is really by simplification, by removing barriers and improving access. Different ways of doing this are to minimize steps required to initiate DAA therapy or minimize the need for complex diagnostics and eliminate the need for in-person visits or prescription refills. If you think about the way we have evolved over time, we've also gone to this point where we want things to come to us with minimal barriers. If most of you are doing online shopping, now know that everything is secure online, and you just do one click and everything happens. It's similar, we need to think about how do we may take HCV treatment and management to that level, where it really can be simplified by minimizing the number of steps required to start treatment, minimizing the number of tests or visits required by our own treatment and minimizing the number of follow-up visits once you've completed treatment. I'm going to next talk about what evidence do we currently have for the simplification. I want to focus only on the different trials available. There are several government programs, but for ease of clarity and for definition of protocols, I'm going to stick to the different trials that have been published on simplified regimens. I think one thing I want to point out is there are two single arm trials and two randomized control trials. There's only one trial, which is the Minmon trial, which I had the honor of leading, which included participants from both high-income countries and low-income countries. This is particularly important for the elimination agenda because almost 80 percent of people living with hepatitis C live in low and middle-income country settings. The next thing I want to focus on is the populations where such simplified therapies or simplified strategies could be utilized. The one thing I want to point out to begin with is, all these trials excluded participants who were previously treatment experienced. Simplified therapy is not for previously treatment experienced patients. There were only two of these trials, which was the SMART-C and the Minmon that included participants with all genotypes, GT1-6 and GT1-7 in the Minmon trial. Two of these trials included compensated serotics and two of these trials included people with HIV, hepatitis C virus co-infection. What I also want to point out is participants with substance use. They were included in two different trials, which was the SMART-C and the Minmon. SMART-C excluded participants with active substance use, whereas Minmon allowed inclusion of participants with active substance use, but differed to the investigator to decide on whether they thought the participant was eligible or not eligible for the trial. The next thing I want to focus on are the different tests and the different regimens that these different trials did prior to initiation of hepatitis C DAA therapy. The most important thing I want to point out here is the only trial that did not use pretreatment genotyping was the Minmon trial. The other thing I also want to point out is different trials used different criteria to grade cirrhosis ranging from liver biopsy, to transient elastography, or to the APRI. But in the Minmon, we only used the FIB-4 to distinguish between serotics and non-serotics. If someone was serotic, we used the CTP classification to distinguish between class B, class C, which is a decompensated serotics versus the compensated serotics. The only two trials that used pan-genotypic regimens were the SMART-C and the Minmon, which used either GP or soft-well. The trial from India also used soft-well, and medication dispensation happened in different frequencies in the different trials. But of importance is both SMART-C and Minmon dispense the entire treatment course at study initiation. In the case of SMART-C, it was eight weeks of three tablets a day of GP, and in the case of Minmon, we dispensed 84 tablets of soft-well at study initiation. In terms of on-treatment monitoring, I think what is important to note is all these trials required no on-treatment clinical monitoring, and three of these trials required no on-treatment clinical labs at all. It really has come to that point where we really have no requirement for on-treatment clinical monitoring or on-treatment labs, because these drugs really are safe that we're currently using to manage the hepatitis C virus infection. All trials did use different ranges of remote contact, ranging from either every week or in the Minmon, we use it at week 4 to assess the urines, and in week 22 to remind them to come back in for their SVR assessment. As you can see from the last row, the SVR assessment was pretty incredibly high in all these different populations. In Minmon, we saw 95 percent but across all these different settings, whether it was high-income or low-income setting. In Smart-C, we saw 92 percent, and the simplified was 95 percent in the standard. But this was in the intent-to-treat analysis. When we looked at the aspirated analysis, the simplified arm actually had a much higher SVR of 96 percent. So we really did see extremely high SVR, even with the simplified on-treatment clinical and laboratory monitoring protocols. So now that I've told you what the different trials are and what the evidence is, let's look at how you actually apply this to our clinical practice. So I want to start with making it clear on who qualifies for simplified monitoring. So the most important thing is participants or patients do have to have active HCV infection defined as HCV RNA that is detectable. As I mentioned, all trials excluded participants who had prior treatment experience, so this can only be implemented in participants who are HCV treatment-naive. You can include patients of all genotypes and only compensated serotics and exclude decompensated serotics. Patients with HIV-HCV co-infection can be included in these trials, especially if the HIV RNA is under the limit of quantification. But I think most important is who does not qualify. So anybody who has HCV treatment experience would require a lot more intensive laboratory monitoring prior to treatment initiation. Patients who are pregnant or with evidence of chronic hepatitis B virus infection. When I speak about hepatitis B, I want to be clear that we're only talking about hepatitis B surface antigen positive. So patients with isolated hepatitis B core or anti-HBS positive, they can be included in these simplified monitoring protocols but patients who have HBS-AG positivity, they cannot be included in these simplified monitoring strategies. Patients with decompensated serotics or known or suspected hepatocellular carcinoma and patients with prior liver transplantation are not eligible candidates for these simplified monitoring protocols. So I want to start with screening and diagnosis. So I think we currently do a lot of risk factor in birth cohort screening but I think we should be transitioning more towards universal screening or opt-out screening. One of the biggest barriers to hepatitis C virus elimination in both the US and globally is the identification of people with hepatitis C virus infection. So this is something that we routinely do in HIV programming globally where anybody who comes into a healthcare facility is screened for HIV infection. So I think a similar approach should be used for hepatitis C where anybody coming into a healthcare facility is screened for antibodies for hepatitis C. And anybody who tests positive for antibodies, we do reflex testing to HCV RNA. And anybody who's positive, we know that they have confirmed HCV active infection and so required treatment. And anybody who tests negative, we remember to counsel them for reinfection. The one thing I do want to point out is I've talked about HCV RNA but there are other tests that are being used globally such as the Cephe gene expert which is used in many countries in low and middle income country settings or the HCV core antigen which is also a good substitute for the HCV RNA and could help speed up the process of screening. The next thing I want to focus on is once we have someone with confirmed active HCV RNA infection, what are the different pre-treatment assessments? So you want to start with a clinical exam especially looking for signs of decompensated cirrhosis or other serious illnesses. And once you've completed that and you've ruled out decompensated cirrhosis, focus on laboratory testing starting with CBC, a hepatic function panel, looking at renal function, FIB4 and the CTP score if they have evidence of cirrhosis and also rule out pregnancy and hepatitis B virus infection. Once that's done, you can spend some time with the participant or the patient selecting what different regimens are available, what the patient would prefer, whether it would be a regimen of GP or soft well and also educating them about the need for adherence. So once that's done, based on the regimen selected, assess for drug-drug interactions following which you can initiate direct, initiate DAA therapy. On treatment, as I showed you, we really don't require any on-treatment laboratory or clinical visits. The only thing I would suggest or recommend that providers do is ensure that patients have a number that they can either call or they can text, especially the current generations. Most people prefer social media, either Facebook Messenger or WhatsApp or one of those channels to communicate with the healthcare providers. So in case they have any questions or concerns about their medications or even for you to contact them, to bring them back in for that SVR assessment, figure out what is the best mode of contact for that particular patient and make sure you have that information. And the one thing I would also recommend which has become routine during the COVID pandemic is all these telemedical and remote contacts. So really focusing on these different strategies for remote contact is something that is, is all that is required during treatment for most patients these days. So once you've completed treatment in the patient, the most important thing is to assess the SVR. So I think the way we assess SVR traditionally is at least 12 weeks after the end of treatment, we quantify HCV RNA. So I think one thing I want to point out here is we say 12 weeks post end of treatment, but that could be any time beyond 12 weeks. So there's no urgency or need to bring them back exactly at that 12 weeks or 14 weeks or 16 weeks. You could even bring them back in week 24 or week 36 after the end of treatment, and that would still qualify as the patient having achieved SVR. And the other thing I would recommend at this point in time is also using different modes of contact because we traditionally look at calling them on their mobile phone or the landline. But these days, as I mentioned earlier, a lot of patients prefer to be contacted using text messages or social media platforms. So really customizing how you contact patients to bring them back in for that SVR assessment to each patient who you're currently treating. That's something we should be thinking about going forward. So if the HCV RNA is less than the lower limit of quantification, the patient is cured. So you need to communicate with the patient that we have cleared your infection, but the importance on the risk of reinfection, and also if there are any other support services, especially when you're working with populations such as people who inject drugs, there are other needs like homelessness or economic opportunities or linking to harm reduction services. So making sure you really treat the patient as a whole at that point in time is something we should be looking at at the HCV RNA and the SVR visit. If the HCV RNA is detectable at the SVR visit, then it needs to be managed by either an infectious disease specialist or a gastroenterologist like a specialist. So the one special consideration I do wanna point out is DAA only cures the hepatitis C virus infection. So if there is somebody with compensated cirrhosis, that cirrhosis status needs to be monitored and managed either by infectious diseases physicians or primary care physicians. And if there is progression of cirrhosis, especially decompensated cirrhosis, then it needs to be referred to a specialist for further management of the decompensated cirrhosis. So I wanna end by saying that it really can be this easy. All we need is an HCV antibody test. You confirm that the participant has active HCV infection, do a little bit of clinical and laboratory exam like the FIB4, rule out decompensated cirrhosis, assess drug-drug interactions. And based on what the patient prefers, either give them soft-well one tablet orally for 12 weeks or Glicopravir and Fibroventusvir, three tablets orally with food for eight to 12 weeks, depending on what the participant's status is. So I think we tend to overcomplicate things, but if you really are looking at HCV elimination, we really should be thinking about decentralizing care and really improving access to therapy among different populations globally. So very rarely in infectious diseases do we have something where we have such an efficacious and safe regimen. We've never been able to eliminate or eradicate any infectious disease in the past without a vaccine. I think with hepatitis C, we have a fairly decent shot of actually eliminating hepatitis C without a vaccine, but for that to happen, we really have to simplify treatment and I know this only refers to compensated serotics and non-serotic participants, but I think one thing we need to recognize is almost 90% of the people, or even more, living with hepatitis C globally either don't have cirrhosis or have compensated cirrhosis. So it really is time we start simplifying and decentralizing care to really help achieve those WHO's elimination targets. I want to end by thanking people living with hepatitis C virus globally who participate in all these research studies that makes simplification and all these new protocols and management of patients possible. I want to thank the ACTG 5360, the Minmon team who really have helped me think through this whole simplification protocols. And I want to end by thanking Mark Salkowski and David Thomas and the entire team from the Hepatitis Group at Hopkins who really have been working with us all these years. Thank you for your attention. Hello, my name is Stacey Truskin and I want to thank the organizers of ASLD for inviting me to speak about this important topic today. We're going to be discussing HCV cure for persons who inject drugs. This is my brief bio and my disclosures. So let's begin by talking about the opioid epidemic in the United States. Roughly 70,630 people have died from overdose in 2019. 1.6 million people had an opioid use disorder in the past year and over 745,000 people have used heroin in the last year. 10 million people have misused prescription opioids and 2 million people have used methamphetamine. 50,000 people have used heroin for the first time. Unfortunately, this has led to a large number of overdose deaths in the United States. Roughly 48,000 deaths have been attributed to overdosing on synthetic opioids, and 14,480 deaths have been attributed to overdosing on heroin, both in the last 12-month period ending in June 2020. So, clearly, the U.S., as well as other places around the globe, are being highly impacted by the opioid epidemic. And because the most common way of transmitting hepatitis C infection is from injection drug use, we've seen a change in the number of cases that have been reported to the CDC of hepatitis C. And so, these are newly reported chronic cases of hepatitis C. And you can see here that younger individuals aged 20 to 40 are now making up the majority of individuals who are reported with chronic infection and predominantly male as well, which is also reflected in what we're seeing with the opioid epidemic. The good news, however, is that hepatitis C is treatable and that there is no difference in clinical trials and in real-world studies in how people respond to DAA treatment, irrespective of whether people are using drugs or not. And so, here are two Sentinel studies. The first is C-EDGCOSTAR, looking at the effectiveness of Elbazvir Grzoprevir given for 12 weeks. This study looked at treatment-naive people who use drugs who are on medication for opioid use disorder. More than 80 percent had been adherent to their MOUD visits, and about 50 percent, though, also had a positive urine drug screen for other illicit drugs. During the study period, you can see that irrespective of this, cure rates were greater than 90 percent. And similarly, the SIMPLIFY study looked at Sofel for 12 weeks and roughly 103 people. Active drug use among 74 percent of participants throughout the study course or in the past month at the time of study initiation, about 59 percent were on medication for opioid use disorder, and you can see here that 94 percent or more individuals achieved an SVR. Results of a 2018 systematic review and meta-analysis support these same outcomes, that recent injecting or non-injecting drug use led to an SVR in greater than 87.9 percent. Similarly, those receiving MOUD or with recent drug use had cure rates above 87 percent as well. And it's important to note that even clinical trials may underestimate SVR in people who inject drugs. Just in the same as real world, people sometimes don't come back for their SVR checks. That doesn't mean that they haven't cured or they haven't achieved an SVR 12, we just don't have the blood to document it. And so the guidance, the ASLD and IDA state guidance recognizes the fact that people who use drugs cure at just as high rates as people who don't. There are annual HCV testing recommendations for people who inject drugs, and then depending on the level of risk, more frequent testing may also be indicated. There's a recommendation that substance use disorder treatment programs and needle and syringe exchange programs should offer routine opt-out HCV antibody testing that reflexes to confirmatory testing and linkage to care for those who are impacted. And of course, people should be counseled about measures to reduce the risk of transmission to others. And people who inject drugs should also be offered linkage to harm reduction services. And perhaps most importantly, within this guidance, we see that active or recent drug use or concern for reinfection is not a contraindication to treatment. Similarly, we now are recommending that individuals who have acute hepatitis C infection are also, should also be treated. And this really reflects the fact that people who use drugs are both at greatest risk for acquiring new infection, but also passing it along. And the guidance is now recognizing the fact that not only does it benefit the individual to be treated for hepatitis C, but there's also a public health imperative to treat individuals who are at greatest risk of transmitting the virus itself. And so this concept, which is also called treatment as prevention, because you can't pass along something that you yourself do not have, is a key to elimination. And so there have been many modeling studies that have been published. This one was published in 2018, and you can see here, there was an examination of what the mean prevalence at the end of a 10-year simulation model would be. And what the authors found is that if we have a very high baseline HCV prevalence, greater than 85%, it is very difficult to use treatment as prevention. There'll be little impact on a decrease in HCV prevalence. But if you have a baseline prevalence of 75% or 60% or 30%, treatment as prevention will decrease the HCV prevalence. You could treat, for example, 120 individuals per 1,000, and you would drop the HCV prevalence and support HCV elimination considerably. And we see this in the real world. Colleagues in Australia have done this in real time. You can see that there was an increase in the percentage of individuals attending a syringe program in Australia. There was an increase in the number of individuals who received treatment. And you can see that commensurate to that, there was a decrease in the percentage of individuals who are HCV RNA positive. And this is a critical thing to realize, because if you can decrease the percentage of individuals that are carrying RNA, you're decreasing the community viral load. And then those that are injecting drugs are going to be less likely to come into contact with individuals who are carrying the virus and will be less likely to be reinfected after they are cured. So let's talk a little bit about reinfection. Reinfection happens, and it will happen until there is nobody left to reinfect somebody if they were to be injecting drugs with them. And so a couple of critical things have emerged from the literature, and there have been multiple different publications that have estimated what reinfection rates would be in different communities. There are a couple of trends that I think hold true. Individuals who are younger, born after 1975, are going to have higher rates of reinfection. And this particular publication showed four per 100 person years. Individuals who are using drugs more recently are going to have higher rates of reinfection, not surprisingly. And then also individuals who are using daily opioid agonist treatment or medication for opioid use disorder will have lower rates of reinfection. And so overall, rates of reinfection are relatively low, but it does happen. So in addition to treating people aggressively for hepatitis C, both chronic and acute infection, we need to be looking at harm reduction. So harm reduction is any positive change as defined by the person at risk for harm. It really is about meeting people where they are and providing the tools and information they need to keep themselves and those around them healthy. And so harm reduction in general will provide non-judgmental care. It's meant to fight discrimination. It does not require abstinence, although it is not against abstinence. And it does not attempt to minimize or ignore the real and tragic harm and danger that's associated with drug use. And so we all practice harm reduction in our daily lives. I'm sure those of you that are listening today have sped or gone above the speed limit at some point in time. That's not good for you, and it's not good for the people who are on the road with you. But unfortunately, many of us do this. Would it be better if we didn't speed? Absolutely, it would be better. However, in order to reduce the harm when we speed, we buckle up and put on our seatbelt. And I think that really is an analogy to what we are talking about with our patients, is that it would be better, obviously, for their health and for the health of others if folks didn't inject drugs. But if they themselves are not in a space where they are ready to stop, what kind of seatbelt can we give them to keep them safer? So one of those options is something like a syringe service program. Unfortunately, syringe service programs do not have great coverage across the U.S. There are roughly 29,000 individuals with hepatitis C as published by this group. And what you can see here is that if each red dot is one HCV case, there aren't a lot of triangles which represent the syringe service programs nearby. And so there's a median distance of 37 miles for individuals to travel in order to get to the nearest syringe service program, and more than 80 percent live greater than 10 miles away. And so without good access to harm reduction programs, we're going to have a really hard time eliminating hepatitis C. Another type of harm reduction or treatment is medication for opioid use disorder, and there are multiple benefits here. Methadone, buprenorphine, or buprenorphine naloxone, either in single tablet or injection form, is both safe and effective in suppressing opioid use. And retention in MOUD care has led to substantial reductions in the risk for overdose mortality, risk reduction in all-cause mortality, and then combined MOUD and syringe service programs can reduce HCV incidence by up to 80 percent. And MOUD alone can reduce HCV transmission from anywhere from 53 to 61 percent. So there are great health benefits here. This is an example of one study that looked at MOUD uptake and the impact on HCV cure. And so this study had about 100 people who injected drugs that were started on HCV treatment, and there were about 67 of those patients who were not on MOUD at baseline, but 79 percent were started on MOUD as part of this study. And 70 percent were retained on MOUD at week 24. And for those who were retained on medication for opioid use disorder, they were able to achieve, 91 percent of them were able to achieve SVR. However, if somebody was not able to be maintained on MOUD at week 24, there was a much lower rate of SVR there. So in addition to these other tools, how else can we be thinking about supporting cure in individuals who inject drugs? Well, the traditional referral model of HCV testing and treatment would require individuals to be tested in the community-based settings, whether it was a sexual health clinic, a drug and alcohol clinic, perhaps at their primary, maybe at a needle and syringe service program or a prison or a community health center, and then they would be referred to a tertiary care system for treatment. That does not work as well as the alternative, which is embedding both the testing and the treatment where the patient already is. We need to be bringing the HCV care to the community where a patient accesses those services. In addition to making sure we're embedding programs in places like methadone programs or prisons, sexual health clinics, making sure that treatment is offered everywhere, we also need to reduce additional systematic barriers to treatment. And some of those barriers include sobriety restrictions. So particularly in the United States, there are still payers that are not allowing individuals who have substance use disorder and continue to use drugs to be treated for hepatitis C. And so there's been great progress made in this area, but we still have a ways to go. So right now, 46% of states have no sobriety restrictions for their Medicaid programs. 28% of states do still require documentation that screening and counseling for substance use has occurred prior to treatment. 2% of states require one month of sobriety, but 12% of states require three months of documented sobriety, usually through a urine drug screen and sometimes a testimony by a provider that in order to qualify for treatment. And unfortunately, another 12% of states require six months of sobriety prior to treatment. So all told, there's about 24% or about a quarter of states are still requiring individuals to achieve sobriety before they'll be treated for hepatitis C, which is counterintuitive and counter to the data that we need to be treating individuals aggressively, that people who are actively using drugs are not only at highest risk for acquiring hepatitis C, but also transmitting it. We should not be creating additional barriers for individuals to be treated and requiring them to prove sobriety in order to access lifesaving treatment. So let's talk about some key takeaways here. So the ASLD and IDSA treatment guidance largely supports the testing and treatment of acute and chronic HCV in people who inject drugs. Direct acting agents for HCV in people who use drugs is highly effective. There's really no difference in SVR rates between those who are using drugs and those who are not. And reinfection will continue to happen, and we have to accept that as fact, until we treat a critical mass and scale up harm reduction. I think of this the same way as I think about my patients that come in with syphilis, reinfection, gonorrhea, chlamydia. We would never think about denying those individuals treatment. We have to treat people and meet them where they are. Recommending here that treatment is prevention as well. Treatment benefits not only the patient, but also the larger community. And we need to be thinking about integrated models of care, breaking our historical construct of requiring people to travel to where the care is, and instead bringing the care directly to where the patient is, and integrating services, desiloing healthcare so that you can get physical health services in a drug treatment program setting or vice versa. And the last thing is that if you are living in a jurisdiction where there are still sobriety requirements or provider requirements that would restrict the type of provider who is able to prescribe hepatitis C treatment, thereby making it impossible for an addiction specialist to provide hepatitis C DAs, advocate. Make sure that you're calling the Medicaid office and advocating for a different way forward. And you can also join the National Viral Hepatitis Roundtable, the Physician Advocacy Workgroup, to lend your voice to a larger cause as well. So I want to thank you all for your time and attention today. It's been a real privilege to be able to talk about this important topic with you. And I hope you all will consider treating people who are actively using drugs if you are not doing so already. Thanks. Hello everyone and welcome to AASLD. My name is Dr. David Wiles. I'm a professor of medicine at the University of Colorado and Chief of Infectious Diseases at Denver Health. I'd like to thank the AASLD and the hepatitis C sick for the opportunity to talk to you today about achieving cure after DAA non-response. These are my disclosures. We're going to start off with the case. This is a 59-year-old African-American gentleman with diabetes, hypertension, and genotype 3A hepatitis C infection who's being referred to you for evaluation of retreatment. You can see his prior treatment here on the slide. He was treated with pegylated interferon and ribavirin in 2008, but did not attain an early virologic response and treatment was discontinued. He had a biopsy prior to that treatment, which indicated at least advanced fibrosis. In 2014, he was treated in a clinical trial with sofosbuviravil patasvir for 12 weeks. At week four of treatment, you can see the HCV RNA was 23 IU per ml. After treatment at week four, so SVR4 time point, he had documented recurrence with, again, genotype 3A antiviral over 73,000. Resistance sequencing was done as part of the study, and you can see here in the NS5A, he had the Y93H RAS. He's back to see you today. His exam, there's no evidence of decompensated liver disease. You can see his medications listed there, including atorvastatin from Modadine, which he takes PRN. Updated labs are listed below with an albumin of 3.3, a total bilirubin of 1.4. You can see platelets of 89,000. If you work that out, that's a child's puA6, and he does have evidence of portal hypertension. An updated ultrasound didn't show masses or ascites, but he did have splenomegaly. So I want to start by just thinking about the broad considerations for DAA regimen failure, and I put them into these buckets here. You want to look at prior therapy. So for our patient, what classes has he been exposed to? In this case, sofosbuvironucleotide plus an NS5A inhibitor, but no protease inhibitors. Was the duration and use of ribavirin maybe appropriate? He did get 12 weeks of sofopatosphere. That was in the context of a study, but now we would say in the patient with genotype 3 prior treatment experience and cirrhosis, you probably would want to add ribavirin for that 12-week duration. Any other patient characteristics? Again, our patient has cirrhosis with evidence of portal hypertension. I didn't tell you, but he doesn't have risk for reinfection that we're aware of, and he is genotype 3A again. The other bucket is kind of everything else. Were there any issues with adherence, potential drug interactions? His famotidine could potentially lower the exposure of elpatasphere some, so that may be something we consider on a retreatment. And then we're going to spend the next few slides talking about DAA resistance specifically. So I've listed here on the table the most common resistance profiles after DAA failure. For the sake of this talk, I'm going to narrow in on the sofopatosphere and glaucapavir-pibrentosphere, the pangenotypic regimens, and specifically highlight genotype 3. What you can see here with sofopatosphere in NS5A, the most common resistance is the Y93A mutation. You can see the dual A30K and Y93H together. And as we've come to expect with sofosburi NS5B nucleotides, it's very rare to see the sofosburi signature resistance mutation S282T. Glaucapavir-pibrentosphere, a little different regimen, now combining an NS3 protease inhibitor with an NS5A inhibitor. In genotype 1A, there tend to be more complex resistance profiles. I will make the note, and it's listed here below, that most of the RAS profiles included in these analyses were patients who had failed multiple DAA regimens. And then in genotype three, again, Y93H predominates in NS5A after glucapavir prevents a sphere exposure with the A30K Y93H double mutant. Because glucapavir is a protease inhibitor, you do see resistance in NS3 protease as well. But in genotype three, the Q168 position would be the most common place to find RASs, although these tend to be less fit and don't tend to persist as long after treatment is withdrawn. And again, a reminder for our patient, NS3 resistance testing was not done and he had a Y93H in NS5A. So I've alluded to this, but I've got listed here NS5A on the left and NS3 protease RASs on the right. And again, I want to draw your attention really just to, for the NS5As, belpatisphere and plebrantosphere, parts of the modern pangenotypic regimens. And you can see there is a significant difference, at least in vitro, with plebrantosphere having a higher tolerance for different RASs without any conferring high level resistance in terms of single position RASs in genotype 1A or 3A. For the protease inhibitors, voxelapivir and glucapavir, again, the pangenotypic kind of most contemporary regimens, you see here a little bit of difference in genotype three with the Q168R, which causes intermediate level of resistance to glucapavir, but voxelapivir retains near wild type activity. So there are certainly some registrational or kind of phase three studies of retreatment. The Polaris studies looked at soft valvox for 12 weeks, and you can see in patients with NS5A inhibitor experience previously in their DAA regimen, and you can see overall a 96% SVR with a major determinant of SVR really appearing to be the cirrhosis status of the patient. 99% achieved SVR in non-cirrhotics, whereas it was 93% in those with cirrhosis. I have the genotypes listed below, and you can see genotype three, 95% SVR as well. Only one patient, only about 60% had failed a previous regimen. On the right is the Magellan 3 study that looked at retreatment of only glucapavir plebrantosphere failures, and again, you can see overall high SVR rates with 12 to 16 weeks and using ribovirin in this regimen. I want to take a little closer look now at specifically the details of the genotype three patients in these two studies. Again, on the left is the Polaris study, and you can see of the failures, four of the seven failures in this study were genotype 3A. They all had cirrhosis. They were treated with various regimens, but you can see in terms of the RAS profiles, Y93H or A30K in three of the four. If we look specifically at genotype three with cirrhosis, the SVR rate again was very similar at 93% in that group. In the Magellan studies, there were 14 patients who had genotype 3. Some of those had only failed GP before. Those are considered treatment naive previously, and some were treatment experienced before. You can see again, overall 100% SVR rate with this regimen, although the minority had cirrhosis. You can see only 20%. Everybody with RAS has obviously gotten SVR in this case, including six of six patients with the dual A30K plus Y93H. There's one more study I want to just highlight. There'd been questions about whether soft fail box could be used for GP failures since it can include a protease inhibitor and NS5A. Maybe it would be harder to retreat those patients. There's a little bit of real world experience here, just over 30 patients, all failed GP, retreated with soft fail box for 12 weeks, no ribavirin. You can see 94% SVR rate. I've highlighted the genotype three experience, which again, overall 94% SVR rate, 17 out of those 18 patients with only a single relapse in a non-cirrhotic patient. If we take a more detailed look at the RAS profiles and any impact they might've had in the Polaris 1 and 4 studies, this was led by Christoph Sarasin. You can see here on the left in this pie chart, I'm looking at only box and bell specific RASs. Those RASs that confer at least a 2.5 fold shift in vitro, really no apparent difference in SVR, 98% in both cases. On the right, looking at it in a little different fashion from just Polaris 1 now, if we gradate the RASs by no RASs, those that cause intermediate level resistance, 2.5 to 100 fold, or those in the darkest blue, greater than 100 fold shift in vitro to velpatasphere. Again, by genotype and genotype three, we maybe see a slight decrement, nothing that was significant. If you look at the numbers, these differences are often represented by only a single patient or two. So again, a hint that maybe RASs have some small effect when combined with genotype three, and many of these patients had cirrhosis, but nothing definitive. Moving on now, even a little more detail, again, within the Polaris 1 study, now looking at just the genotype 3A patients and what their baseline RAS profile looked like, you can see why 93H was the most common RAS encountered, about 30% of the cohort that had RAS testing done and had RASs had that mutation, and you can see here 93% SVR in that group. All the other RAS profiles, only a handful of patients, and all of them responded. On the right there in the table is what the in vitro fold shift is for velpatasphere and pebrentosphere, and you can see all these RAS profiles really cause a high fold shift to velpatasphere and more variable to pebrentosphere. There were really no patients included within genotype 3 that had complex or high level resistance RASs to voxel apavir. So now I want to take you through a few of the real world experiences with using softball boxes retreatment for DAA failures. The first and largest is the U.S. veterans cohort on the left, and what I've tried to do is just highlight the unique aspects of each of these cohorts. So in the VA cohort, the most unique finding was what you see here that in patients previously treated with cephalosphere velpatasphere, there was a statistically significantly lower SVR rate regardless of genotype, and you can see here right around 85% across genotypes 1, 2, and 3. The next one is the Spain multicenter cohort, which is a prospective cohort, about 140 patients. The Spanish cohort is a little different in that it was predominantly genotype 1b. There was very little use of soft or GP softball or GP in this cohort. You can see here the main determinant was genotype 3. So non-genotype 3, the odds ratio for achieving SVR was 16, and that was statistically significant. And then finally, an Italian prospective multicenter cohort, findings a little different here. Cirrhosis, the biggest discriminator between SVR and not with softball box retreatment. Baseline RASs did not appear to have effect in this cohort, nor did the use of ribavirin. And then this last issue of use of HCC onset during treatment, very small numbers, but seemed to portend a worse response. And then finally, this cohort did have a lot of soft valve prior use, and there was no indication in this cohort of a lower response with soft valve. The most recent then is an Australian early access program, about 100 patients, almost 72% had genotype 3. They were almost all cirrhotic or post liver transplants. This is a really difficult population to treat. And again, the SVR rate in genotype 3 was 89%, including 90% in those with genotype 3 and cirrhosis. So, suggesting similar rates and not really highlighting a profound effect of genotype 3 and cirrhosis. Those were similar SVR rates to, for instance, the U.S. veterans cohort. So, coming back to our patient, in the capsule here on the right, I have a summary of the case. Again, he's genotype 3a, child's puke A6. An updated fibro scan showed liver stiffness of 19.3 kPa, so certainly has cirrhosis. He had failed PEG riba and soft valve for 12 weeks. His RAS profile is listed here, a Y93H and MS5A. You can look at the choices here and decide for yourself what you might use for retreatment, soft valve box with or without ribavirin, soft plus GP, with or without ribavirin, or maybe something else. So, now that our patient, I'll update you again. He's now been treated in 2019 with soft valve box. He got 12 weeks. Ribavirin was not used. At week 4, he was less than 15, but detectable in terms of HCV RNA. He's genotype 3a at recurrence again. This is four weeks after treatment has finished, and the viral load was 57,000. We'll come back to whether resistance testing should be done again, and again, he has cirrhosis with a recent fibro scan. You just review with the patient, his pharmacy repeals were on time. It doesn't seem like he had a lot of issues with non-compliance. He had had updated hepatocellular carcinoma screening with no masses, and a recent EGD had shown maybe portal hypertensive gastropathy, but no obvious varices. So, now what would you do? Would you repeat resistance testing in this patient who's now failed 12 weeks of soft valve box? And if so, what would your answer be? First, no, it's not going to impact what I do on retreatment. Yes, and then there's various options here. I'm curious. It's going to impact which NS5A inhibitor or regimen I use. It's going to impact whether I do ribavirin, or I also want to do soft resistance testing with NS5B resistance testing. So, there's very little experience now with patients who have also failed soft valve box. This is from the European Resistance Study Group, led by Julia Dietz, and this is a very large group of Julia Dietz. And they looked at soft valve box failures, 40 of them, including about 45% that had failed genotype 3, which is the most common genotype that had failed soft valve box. And this is the RAS profile in those patients. You can see just over half had NS5A RASes both before and after soft valve box failure, dual RASes in about a third. The main point of this is that after soft valve box failure, there's generally little evolution further in resistance profiles, so you don't tend to select for a lot of additional resistance. In this case, maybe an increase in double RASes in NS5A, but not a profound increase, and generally not much change in NS3 profiles from before and after soft valve box failure. So, I put it back to you. Again, the capsule on the right, he was resequenced after this. NS3, he did not have NS3 RASes after soft valve box failure, but now does have the dual A30K plus Y93H RAS in NS5A. So, what would you use as treatment? You can see your options listed here. I'll just pause for one second as you go through those. I won't read them all, and then the final option would be you're going to do something else. Well, now, in the European resistance study group, they did look at soft valve box retreatment and the efficacy. Again, very limited data. Of the retreatments, you can see here, this was an updated rate of SVR they included in a letter to the editor as follow-up. You can see here for soft plus GP with or without ribavirin, 12 out of 15 attained an SVR 80%, and then four were treated with soft valve box for 24 weeks with or without ribavirin with 100% SVR. The main issue here, and you see the asterisks, is that of those three failures with soft plus GP, two of those died on treatment or in follow-up before SVR 12. So, I think a more accurate representation would be to take those out. So, I've combined the data here on the right with two additional reports that were written as letters to the editor highlighting five and six patients treated in single centers consecutively for soft valve box failure. They were all treated with GP plus soft with ribavirin in those instances for 16 weeks. So, if you combine all that, you see about a 96% SVR rate with 24 patients treated. The lone failure was a genotype 3A with hepatocellular carcinoma developing during retreatment and a complex RAS profile post-treatment. And then again, those four out of four with 24 weeks of soft valve box. So, that's really about the extent of the clinical data we have with retreating soft valve box failures. So, I just want to highlight here, there's some in vitro data that essentially selected high-level resistance to protease inhibitors. Those are the dotted lines in all these cases, and then did retreatment with either GP or box valve soft. And the only thing I'll highlight is once you have resistance, all the dotted lines with GP, either single using glucaptor or prebrinster or the combination, you see rebound relatively quickly on therapy. There's no case where you remain suppressed when you start with high-level protease inhibitor resistance. The only way you can do that on the right is if you have a triple combination with a nucleotide involved. So, again, this is loose in vitro data that, again, backs up the thought that you probably need a nucleotide or a high barrier drug, two additional drugs that are active in the regimen, at least based on in vitro data. And then, finally, what about ribovirin and increasing duration? So, this is a retrospective study from the CHECS cohort led by Stuart Gordon's group that looked at the impact of extended duration, addition of ribovirin, or genotype 3. And what you can see here is that for every month you extended treatment duration, you had about a two-fold increased risk of attaining SDR. If you have previous DEA failure when you add ribovirin compared to not, about a five-fold increased rates in success. And then, specifically in genotype 3 as well, when you add ribovirin, over a 13-fold increase in the odds of SDR. Of course, all the caveats with regards to retrospective data and ability to control for other factors, but suggesting that increasing duration, adding ribovirin are of value in cases like this. So, in my last slide, I want to talk about what the guidelines offer. You can see here both the ASLD-IDSA guidelines and the ESL guidelines and how they approach regimens for initial NS5A failure. I really want to focus in terms of the discussion just on the bottom row here where our soft valve ox failures are what are called very difficult to cure and the ESL guidance, which may be multiple failures of regimens or very complex RAS profile. And you can see here in both cases, both guidances are relatively aligned recommending soft plus GP and ribovirin for 16 to 24 weeks. ESL specifically in the case of soft valve ox failures really advocates for using 24 weeks of soft plus GP with ribovirin. And I certainly think that's very reasonable. Soft valve ox that would be used for somebody who previously failed soft valve ox certainly I think should be given with ribovirin and extended really to the kind of the maximum duration that's been used is 24 weeks. So, now I want to come back to our patient. So, in his case, the fourth time was the charm. He was retreated as we just discussed with soft plus GP and ribovirin. He did require ribovirin dose reduction during therapy down to 800 milligrams and did attain SBR-12. So, again, now I'm going to come back to our final slide, which are our take-home points. So, I think despite the tremendous efficacy, a significant number of DA failures will be realized just because of the sheer number of people being treated. Genotype 3 and 1A, along with cirrhosis, are predictors of DA failure. Retreatment of initial failures is really similarly efficacious, 90 to 95 percent, with those same predictors of non-response, particularly genotype 3 and cirrhosis. There's limited data, most with soft valve ox on soft valve ox failures, but it appears they can be successfully retreated. I would say for almost all those cases, you need to use ribovirin if you can and extend duration. A clear picture of the impact of RASs on DA treatment remains elusive. I've just highlighted a commentary that Mark Sulkowski and I did after the Papaluka study in CID, which highlights a lot of these issues in more detail. And then what we think…I think we really need is really an international collaborative on collecting resistance data and treatment outcomes, and this is something Anita Howe has led, and I just want to highlight it, the shared international resistance collaborative cohort. You could go to their website and possibly join shared to upload resistance data and participate in that collaborative. I think that's a great thing that we're probably going to need if we're going to be able to get more data on how RASs impact these responses. And with that, I'll just present some acknowledgments. Again, I'd like to thank the ASLD and Hepatitis C SIG for this invitation, ASLD and IDSA for their support of the guidance, and then my guidelines panel co-chairs, Tim Morgan, Andrew Aronson, and Devika Bhattacharya, and then Stuart Gordon and John Scott, who really led the resistance and retreatment section revisions. Thanks very much. Well, great. I'd like to…thanks for joining us for this recorded session. We're now fortunate to be joined by our speakers that have a panel discussion about the topics, so we're pleased to have David Wiles, who you heard speak about how to manage patients after daily failures. Dr. Sneel Solomon, who told us Hepatitis C treatment was easy and we could simplify with minimal monitoring. And finally, Stacey Truskin, who spoke to us about this critical population of people who use drugs in the quest for elimination of Hepatitis C and how we have the best outcomes in this population. And of course, my co-moderator Jenny Price is here as well. So, let's kick this off. Sneel, how do we…you talked about minimal monitoring, yet we also heard about a patient population of people who use drugs who have a lot of unmet medical, psychosocial needs. How do we put those two together so that we can both simplify treatment but also prevent overdose death and other complications? Thanks, Mark. I think that's a great question. I think one of the challenges is there has been very limited data on minimal monitoring approaches in people who inject drugs and people who use drugs. But if we really want to achieve elimination, I think we need to focus on that population. Without that population, we're never going to achieve elimination. So, that being said, I think there are a couple of things that we need to consider. And so, when I presented on minimal monitoring approaches, I talked about ways where you could reduce the frequency of testing, but also strategies where you could dispense the entire course of treatment at one point in time. So, in people who inject drugs, I think what we should be focusing on is really getting rid of all that testing. We don't need genotyping. We don't need on-treatment monitoring. We don't need a lot of the other tests that we do on treatment. But I think we should still have some kind of a remote touchpoint. It doesn't have to be in person. It could be remote, where we do keep that contact with participants, especially ones who are actively injecting drugs because you tend to lose those populations. So, I think that is something that's very critical. And I think what's also very important is these drugs are expensive and insurance, and it's already challenging to get treatment to patients who need them. So, I think what is also critical is that it's not just about treating the hepatitis C, but it's about treating the individual as a whole. And people who inject drugs have several other complications besides hepatitis C. For example, overdose, as you mentioned, is like a big challenge. So, it's not just about managing the hepatitis C, but also ensuring that they have access to harm reduction services to minimize reinfection, making sure they have access to support services, housing instability. So, it really is looking at the individual as a whole and trying to incorporate all these minimal monitoring strategies in terms of reducing the frequency of tests and the number of tests, but also trying to address all the other social issues that are required to really treat the person as a whole. So, keep the hepatitis C treatment simple. Give the patient the kind of care they need. I know Stacey and David, I'm curious what your thoughts are about resistance, but I'll come back to you. Stacey, how are you putting these two together, simple treatment, complicated patient? Yeah, I think what it's important to remember that minimal monitoring doesn't necessarily have to mean minimal contact with our patients, that we can still connect with them in ways that feel best for the patient, whether as Sunil said, remote sort of telephone calls, telehealth, sort of less formal visits in the clinic to just check in, outreach work. There are lots of different ways that we can continue to care for our patients without having to have them undergo phlebotomy or unnecessary medicalized testing. And David, just to finish the thought about kind of putting these two together. I mean, one concern might be, I recall you had a paper early on where people who took NS5As, that NS5A resistance persisted. So let's say we take this approach and the person falls off treatment after four weeks. My take on the data that you presented and others is that they'll have a virus that's resistant and that is entirely transmittable. Do you have concerns about simplified therapy and a growing pool of people who are non-responsive urologically? Yeah, I think it's a great question. I guess the short answer is I don't have concerns for the majority of patients. Yes, if you fail a regimen and select for NS5A resistance, it does seem that those resistance mutations or RASs persist for, at least in the majority, 70-80% out to two to three years, was about as long as we had looked. But as we'll discuss in the presentation, you know, taking the next step to say, do those resistance mutations really impact their future therapies? Right now, really the answer is generally no. Now, that's a complex question. It depends a lot on other things besides just the resistance mutation, the genotype that we probably would get at that point. I also agree with Sunil that up front, you don't really need genotype testing with the pan-genotypic regimens. But once you've failed, you're going to get those. You may take a look at the RASs, but for the majority of patients, we are then retreating. The resistance mutations they have don't really materially affect what you present for the majority. Again, there are exceptions to those that we kind of discuss in the cases. And then four weeks, you know, yeah, as you alluded to, you know, if they fall off after four weeks, so they get their first dispensing and you lose contact with them and don't manage to get them. One way around that is as Sunil studied and give them all of it up front, where at least they still have those medications and can take them, even if they don't make it back to clinic or don't make that check-in. And I think we're all really for that, empowering the patients more to kind of complete their treatment and not have us dictate whether they complete necessarily. But if they do get a short course there, there's really limited data. It does appear there was some recent data just with a publication of a short course of Glucapri or Pembrentisphere. They did see resistance develop. It doesn't seem to be as high percentage as those that fail after eight to 12 weeks, but there is some that's selected after four weeks. But again, probably does not impact their retreatment for the majority. So sort of piggybacking off of that, we're still restricted by the insurance restrictions and have to do the two-week or the four-week refills. And where I practice, a lot of my patients also have challenges just holding on to a full treatment course. So they prefer to get one or two weeks to spend some time. But I'm wondering for these patients that we may not see exactly when we want to see to give them their next set of refills, is there a point where you stop treatment if you don't see them again within a certain amount of time? Do you just, if they've already done eight weeks of treatment, just stop then if they were supposed to do 12 weeks? How do you manage those nuances when people are following up at sort of unpredictable intervals? And I guess I'll ask Stacey first. It's such a good question because this is really what we deal with all the time in our health centers. And I think the answer really depends on how long they've been without medication. If somebody comes in after missing three or four days to pick up their refills, we just keep on going and prevent, pretend like it didn't even happen and just keep our head down to finish. But if you have somebody that has disappeared for two weeks, three weeks, four weeks, it may make sense depending on how far into their course they are to stop and take a check, see what the viral load is, see if they're undetectable, and then just kind of cross your fingers. In some cases, I've had patients that have been seen in about four weeks will do a viral load. If they're undetectable, that's an SVR4 in some cases. And then we'll just wait and follow up again in eight weeks. And in many cases, individuals may cure. That's really a great point. I think it's important to remember that the durations of eight and 12 weeks were selected to try to get as close to that 100% as we could. But some people are cured with markedly shorter courses. We all have this anecdotal experience of a person who took two weeks of therapy and was cured. But in the trials, a fair number were cured with dramatically less treatment than the full course, if you will. So it's a great point, Stacey. Just to build on that, I feel like Stacey was in the room when we tried on the ASLD-IDSA guidance to come up with a new section on adherence to help guide clinicians. Because this is one of the most frequent questions we see come in. Of the panel, folks can write in and add. So there is a new section that should be live now on the guidance site that Devika Bhattacharya really led. And it was a challenge to try to be useful but not be too restricting in terms of how you define things. Because there's always got to be room for clinical interpretation as you decide, am I going to stop? Am I going to give them another refill? And things like that. I think just to follow up on what David also mentioned earlier, I think one way to deal with this is really empowering patients by giving them the entire treatment goals up front. So we had SMART-C and we had MinMon. So in MinMon, we did have people with substance use disorders where we did see suboptimal adherence was associated with substance use. But like Mark already pointed out, suboptimal adherence wasn't necessarily associated with SVR. So I think giving them that entire treatment goals up front and working towards that and getting insurance and other companies to approve that gets you to that point where you don't have to worry about treatment interruption because they're not able to come back in for the refills. And really leveraging some of the things COVID has taught us. Like telemedicine has become standard of care. We're texting people, we're using WhatsApp, Twitter. So we should start using these to actually get in touch with participants and try to make sure that they complete their treatments. So I think that is something we should start thinking about is dispensing the entire treatment goals at one point in time. We do this routinely for other infectious diseases. For HIV, we dispense six months at a time and don't worry about it. So I'm not sure why we're struggling with 84 days of 84 tablets in the case of hepatitis C. So I have a follow-up to that. One of the challenges also has been confirming SVR-12. And I'm wondering your thoughts about do we really need SVR-12? Is SVR-4 sufficient like Stacey said? Because I think most of us, if we see that SVR-4, we'll feel really good that if we don't see our patient again, they've been cured. Dave? Okay. Yeah, I mean, we see the same issues about getting them back. I think it's probably more provider hang-up than necessarily needed for good patient care. We all love to see all that final zero and know that they're okay. But I do think we probably don't, we don't really need it. If the patient didn't have a complicated kind of disease characteristic cirrhosis or something else where they need continued follow-up and where the SVR rates are maybe slightly lower, it's probably not really medically necessary. You know, I think you could extend that even to SVR-4, frankly. If we don't really think we need SVR-12, we probably don't need SVR-4. I think, you know, and I'll say Mark was involved, I think, and say, you know, they looked at the concordance between SVR-4 and 12 and it's what, about 70, 80% concordance. But I don't think you necessarily need either with these cure rates for an uncomplicated case. So you're suggesting that you don't need post-treatment confirmation of outcome because now, are you limiting that to people where you're confident they took the full course of therapy? Yeah, I would. I guess we, I mean, to be honest, I don't think we need it. We still do it for most of our patients too. So, but I would agree with that, Mark. Yeah. You know, if they only got eight weeks of their 12 weeks of soft palate sphere, I would probably be a little more interested in seeing, because we know eight weeks didn't fare as well. And I wonder if I could ask a question about, so we've talked a lot about that things like genotype are necessary. Sunil has eloquently advocated for giving the entire treatment course, which I would agree. We've tripped over that, you know, refill so many times that the greatest cause of treatment failure in our clinic is the refill required by the third-party pair. But is it realistic? I mean, when I talk to people in our own clinic, we're still doing genotypes. We're still dispensing medications four weeks at a time. David, to your most recent point, we're still checking for SVR-12. How do we get there? In 2019, before the pandemic, the guidelines panel had published this beautiful simplified algorithm, several studies, as Sunil talked about, proved it's the right approach. So how do we get this evidence to change our actual practices? I mean, I would say that, and where I am, some of the pairs no longer require genotype, and I'm still getting it. However, I will order the meds before the genotype comes back. And I think once it's no longer required by pairs, I won't order it anymore. We won't need to order it. I typically order it because I'm just not sure if it will be required. And now we've been increasingly getting approvals while genotype is still pending. So I think once we're no longer acting upon it, we probably won't check it. So is that true in other parts of the U.S.? San Francisco has been known to be more progressive than other parts of the United States and world. So I'm curious if that's true of other panelist practices. And maybe ask Sunil, I would imagine genotype in places like India, where you've done a lot of your work, are just impossible to do for clinical practice. And it's probably already standard not to do it. Is that the case? It is, Mark. So I think there are two different things. I think one thing COVID has taught us is if there's an epidemic in one part of the world, it's going to go everywhere. So we really should be looking at global equality. I really don't think we need a genotype anywhere. In India, for example, if you take India, a 12-week course of soft-well costs $170 versus one genotype, if available, but if available is a very big if, is about $150. So it just makes no sense. So I would just forget about the genotypes. We don't do genotypes in India. We just use soft-well or soft-tac. We don't have GP available in India, but if GP was available, then we would be using soft-well or GP. But right now, as a standard of care in India, we do our Fib4, stage the patient, give them treatment. And SVR, like David said, if they come back in, we do the SVR. But I think one thing to remember is many of these patients, we are going to be monitoring them for reinfection. So that SVR really isn't that important if they're going to come back in 24 or 48 or 72 weeks later. If someone is undetectable 48 weeks after treatment, they definitely were undetectable at SVR4. So there's no need to bring them back in a week 4 or week 12 post-treatment. Just bring them back in whenever you think it's time to look for reinfection. And that's good enough for me. And I think it really is about simplifying treatment. And especially as we move towards the younger generations, they just don't want anything to go anywhere. Everything should come to them. I think that's the generation we're moving to. So it really is about simplifying things. So you mentioned reinfection, which is certainly something that we all deal with and think about in terms of our patient care. A lot of different places to ask about that. But one thing that comes up, David, I'll direct this to you, is this idea. So you treat somebody, they have recurrent detectable HCV RNA. They have risk factors for reacquisition of a new infection. And then you get into this, is it the same infection with a virologic relapse, in which case you might take first-line therapy to repeat it, or is it a reinfection? Or would you use, which part of the guidelines would you follow, new infection versus retreatment of a virologic failure? Yeah. So how do you sort that out, right? And I was thinking about that when Sunil was talking, and I completely agree for most people who don't need a genotype. And I was talking about this within our group. And there are occasions where I've been glad to have a pretreatment genotype because you see a genotype switch, and then you know in some maybe of our higher-risk patients for reinfection, you really have evidence that it is a reinfection. You can treat them as treatment naive. The other thing you can obviously use is timing. And Sunil kind of alluded to the long end of this. If you know they got SVR12, and then 24, 48 weeks later, now they have recurrent viremia, same thing. That is overwhelmingly likely to be a reinfection. So there are these cases where I've been glad to have that information. But again, that's an individual patient, clinician mindset versus a public health mindset about how do we get all the impediments out of the way to achieve global elimination. And that's where those things can really get in your way. So it's kind of weighing both sides of the coin, I guess. Well, so we said no genotypes and potentially no post-treatment. So Stacy, let me ask you, in your practice, how have you been handling patients who come back in with active hepatitis C after what you felt was curative therapy? Yeah, it is a complicated situation when you don't have that SVR12. And I agree with David that SVR12, it's really a vestige of the interferon-based clinical trials. And it's unclear if it has a role from a public health perspective and an elimination perspective in treatment now. But it is helpful sometimes to have that when you have a patient come in who you're uncertain if they have reinfected themselves or they failed treatment. With that, I think we try to take a really good history and create an environment in the clinical setting that patients feel comfortable telling us the truth. If they were not using drugs during their initial treatment course, which for us is certainly not a requirement for treatment, but if they had had a period of abstinence or really safe drug usage with special attention to making sure that they're using clean syringes, then we take that under advisement. We try to piece together what the risk was of reinfection versus the likelihood that they really adhered to their medication. Because if they did, and they report that they took all of their meds with no problems, they completed the 12-week course, well, there's a 95% chance that they would have cured. And if they relapsed with their addiction after that, then there's probably a pretty good chance that this is reinfection and you can treat it as a novel infection all over again. So I think taking a really great history is critical and feeling comfortable talking to patients about the nitty-gritty of their drug use is an important piece of this too. Do you think, David, there's any role for RAS testing in this sort of scenario? Like, let's say you didn't have the pre-treatment genotype. Yeah, if you don't have a... RAS testing kind of as a phylogenetic, essentially. In other words, if there's no RASes, then they could be treated as naive again, like a new infection. It's probably likely that would be the case if you think they took most of their regimen and they got soft filpatysphere and didn't have any RASes, but it was the same genotype. I haven't used it that way in general as the real arbiter for whether somebody's got a reinfection versus a relapse. Maybe just to follow on that, how important is it? So let's say it's not a reinfection, but I go ahead and prescribe the first-line regimen. I say, okay, I'm just going to use the same thing you used before. I'm going to repeat it. Am I going to do harm to that patient or to that virus? Am I going to create a variant we need to worry about, the delta of hepatitis C? Good question. So there's a little bit of data from Target. Gary Wong looked at whether they have single, double, triple, and whether they're linked mutations, doing special sequencing. So you can see if all these mutations line up on the same RNA genomes. There's a signal in Gary's data that if you have two or three and they're linked, that you do start chipping away at the response rates. I think that intuitively makes a little bit of sense to us from an HIV background or something else. So those are clearly different diseases with different mechanisms to archive resistance. So there may be something to that. I think the fact remains that when you look at like using now triple-based therapy, so if you're going to go to soft valve ox and say you did, you used soft valve twice and then went to soft valve ox, there's really no data with the triple combinations that necessarily says you're not going to do as well. It would probably be more problematic if you somehow had high-level NS3 and MS5A as opposed to multiple in just one of the genomes and sequences. So that makes it even more important to follow the approach that Stacy outlined. And if you think it might be a virologic relapse and failure, use triple therapy, as you said. So what I suggest is just retreating, take that history, spend some time sorting it out. That's the solid advice from Stacy's practice. And at least in our insurances we deal with most commonly, like our Colorado Medicaid or our specific Medicaid, the barrier to getting soft valve ox seems to really have decreased for us anyway. It really is almost no different, at least in my experience, to getting another course of soft valve. Well, we are running a bit short on time. It is kind of funny for a recorded session to run out of time, but nonetheless, we are. We've talked about a number of topics on hepatitis C, and I really just want to remind our audience, I know this group is on board with this, that although we have simplified hepatitis C treatment and we have great tools, we really are far from hepatitis C elimination, both in individual populations, but also in the world. In fact, we've lost ground, as we've seen in many models and publications during the COVID-19 pandemic. I think it's really important that as we think about the tools that minimal monitoring gives us, we think about the types of individuals that we need to really target and figure out how to get at them. We've really covered those issues, and certainly, I think, I'm reassured that we've got successful second-line therapies if needed. So, I think one of the topics of today we discussed really fit in well to a toolbox of getting back on track with elimination, which is a really tall order, particularly pandemic. So, I want to thank all of our panelists and my co-moderator, Jenny Price, for this discussion, and thank you for joining us.

hepatitis C

medical experts

direct-acting antivirals

simplified testing

treatment strategies

individuals who inject drugs

HCV care

harm reduction programs

resistance profiles

retreatment strategies

reinfection

global elimination