at 2020 Digital Experience Liver Meeting. My name is Svetlana Rodaeva. I am a Deputy Director of Division of Metabolism and Health Effect at National Institute on Alcohol Abuse and Alcoholism. To set the stage for our discussion today, I will give you some background information and I will also introduce the seminar program and our outstanding speakers. But before I begin, I would like to thank ASLD and the organizers who make this important seminar possible. The seminar is titled Hepatology and Addiction-Integrated Care Models for Alcohol-Associated Liver Disease, Call for Action. I think this is a key question that will reshape the future of hepatology field. The purpose of our seminar is to share NIH perspective on growing demand for comprehensive care for patients with alcohol-associated liver disease and to discuss the opportunities on moving forward and improving outcomes for these patients. As all of you know, alcohol and drug dependence or abuse disorders are common. In 2018, 53 million people in the U.S. used illegal drugs or misused prescription drugs and nearly 140 million Americans over the age of 12 were regular alcohol users. Importantly, alcohol and drug use disorders are uniquely associated with liver disease. About 50% of cirrhosis cases are related to alcohol use and there's a strong association between IV drug and HCV. A large body of evidence shows that alcohol consumption represents the most common cause of liver damage in Western countries. Alcohol-associated liver disease is responsible for approximately 25% of deaths due to alcohol consumption, demonstrating the importance of this disease in general population. ALD is also one of the most common indication for liver transplant worldwide. Because abstinence is the single most important factor in improving survival from ALD, screening for alcohol use and behavioral health program integrated into routine practice are required, but haven't been adapted in hepatology practice yet. The implementation barrier includes lack of personalized care, lack of clinical training in addiction, refusal of alcohol use disorder treatment by patients and lack of insurance coverage. Despite this challenge, there have been many positive developments in the field of alcohol-associated liver disease, showing improvements in public attitude and growing interest to integrated healthcare. The new diagnosis and treatment of alcohol-associated liver disease practice guidance have been published. It provides many important updates and highlights the link between alcohol use disorder and alcohol-associated liver disease. Other positive development includes an effort to reduce the stigma. So let's get the hepatology field adopted the new name alcohol-associated liver disease that reflects a complex interaction that characterizes disease. And I would encourage all of you to incorporate this new name into your research and your practice. So now we move on to the program overview. The seminar will follow the agenda you see on your screen. We have four outstanding speakers today, Dr. Reshvani, Dr. Leggio, Dr. Blanca and Dr. Yang. If you have any questions, simply type your question in the chat box and click send at any point during the seminar. The speaker will type the answer. So with that, thank you and enjoy the seminar. At the outset, I would like to thank the ASLD for this opportunity and also to the NIAAA and NIDA for their time and efforts. My topic for today is time to call for integrated care with addiction teams and patients with alcohol-associated liver disease. I'm Reshvani Singhal from the University of South Dakota. And here are my disclosures and none of them is related to the talk I'm giving today. So let me start with two clinical cases. On the left-hand side, you see a patient, young female who's enrolling for alcohol use disorder treatment and her screening is found to have alcohol-associated liver disease with steatosis and hepatomegaly. And how we can identify this patient to be integrated with hepatology service. And on the right-hand side, we see a patient, young male coming with a more advanced disease with alcoholic hepatitis and how we can identify this patient to have alcohol use disorder to be integrated with addiction medicine and multidisciplinary care. And we'll come back to these cases at the end of the presentation to make up a point. So starting with magnitude and disease burden. And you heard very elegantly from Dr. Rediba in detail about the ALD epidemiology globally as well as in the US. And I'm going to give you here the salient points. For example, alcohol is a contributory factor to almost half of cases of cirrhosis and a quarter of cirrhosis-related deaths in the US. Alcoholic hepatitis is a subset of patients with decompensated ALD who present with jaundice and a very high short-term mortality. ALD is currently the leading indication for liver transplantation. And in 2019, over 3,000 cases in the US were listed due to ALD. And we all know that this disease burden from ALD is overrepresented in young individuals with higher disease severity, more hospitalizations, liver failure, and increasing liver transplantation need. Just moving on to clinical presentation. People at risk of getting liver disease can be defined based on the amount of alcohol intake. And NIA classifies it as three or more drinks in men or two or more drinks in women on a daily basis for at least last 12 months. And a drink by NIAAA is defined as either a can of beer or a glass of wine or about 1 1⁄2 ounce of hard liquor. When we talk about the spectrum of ALD, it can be an early disease where the patient has steatosis or state of hepatitis without symptoms and if fibrosis happens up to stage two. However, when the fibrosis extends to bridging or advanced fibrosis or development of cirrhosis or advanced liver failure, or development of cirrhosis, or symptomatic type of alcoholic hepatitis with jaundice, patient already has advanced ALD. And it has been shown in many, many reports that patients with ALD compared to other liver diseases more often present in advanced stage compared to, for example, an FLD and hepatitis C and other diseases. And moreover, once they present, their progression is faster and they have a lower transplant-free survival. And clearly, there is a need for identifying ALD individuals when they have early spectrum of the disease so that we can control the risk factor and put them into treatment for abstinence and reduce the development of advanced ALD. And this point was made by this Danish registry of over 36,000 individuals followed for about 15 years, where at the end of 15 years, the risk of liver disease in males was about 6%, and that of females was about 5% of cirrhosis and advanced liver disease. And going back retrospectively, there were many missed opportunities in majority of these patients where alcohol use disorder and early ALD could have been recognized and prevented the development of advanced liver disease. So clearly, there is a need for not only screening for ALD using biochemical liver tests and ultrasound in at-risk individuals, but even those who are identified to have liver disease, like our first patient, further testing should be done using serum biomarkers or fibroscan to develop the risk of advanced liver disease so that they can be integrated with hepatology for care of their liver disease. Similarly, patients who have advanced ALD identified based on this non-invasive testing should then be sent to a hepatologist for further care. So now let's talk about on the other side of the spectrum, which is advanced ALD. And we know that there are very limited options or medical treatments for patients who have advanced ALD, including alcoholic hepatitis. Corticosteroids, the currently available first line and the only treatment option for these patients remains suboptimal because almost half of these patients remain ineligible due to contraindications. And those who are eligible to receive steroids, they have a very unpredictable response and only about 60% which lasts only for about a month. Clearly, we need your therapies for this disease. And fortunately, in the last five to 10 years, NIAAA has funded a consortium in the US to develop drugs for treatment of advanced ALD and alcoholic hepatitis, targeting various pathways in the disease pathogenesis. Although so far we do not have any drug which is approved by the FDA, but there are certain strategies like fecal microbiota transplantation, interleukin-1 receptor antagonist or anakinra, interleukin-22 and growth factors like granulocyte colony stimulating factor, which seem promising in the treatment of this disease. Although liver transplantation is an accepted treatment for alcohol cirrhosis, especially those patients who have obtained six months of sobriety, we know that in the last 10 years or so, there has been a lot of data developed in this field in patients with ALD and alcoholic hepatitis who have not yet obtained six months of sobriety and early liver transplant for celiac disease. Early liver transplant for celiac patients has provided survival benefit. However, this modality of treatment in celiac patients with alcoholic hepatitis remains heterogeneous across the world, mainly because lack of protocol or uniform protocol to select these patients across various centers. But what we know that abstinence from alcohol is the single most important determinant of long-term outcome in these patients with ALD. For example, in the study on 400 patients followed prospectively, after surviving index episode of hospitalization and these patients were followed for up to five years, you can see that compared to abstinent patients, those who started drinking have a higher risk of dying on long-term follow-up. Importantly, those patients who were even engaged in moderate amount of alcohol use up to 30 grams per day were at 2.3 fold increased risk of dying compared to abstinent patients. And this risk of dying increases with increasing amount of alcohol use on follow-up. And therefore, abstinence should be the goal and these patients with advanced ALD, especially those with moderate to severe alcohol use disorder should be engaged with addiction medicine to target not only their liver disease, but also managing their alcohol use disorder. However, in clinical practice, it is extremely rarely used as shown in this study, retrospective study from veterans in Pittsburgh, where about 36,000 veterans were studied in a database followed for six months. And then you can see that everybody had a diagnosis of alcohol use disorder, but only about 14% were engaged in some kind of addiction therapy, either behavioral or pharmacotherapy. Importantly, pharmacotherapy was used only about 1% of the time. And it becomes more relevant to see that those patients who were engaged in some kind of treatment with addiction medicine had a reduced incidence of new decompensation over six months by about 40%. And the odds of time were reduced by 20% in those who were engaged in some kind of addiction treatment compared to those who were not engaging in addiction therapy. So clearly, providing a benefit of integrated care, we need to develop more and more strategies to implement these models in clinical practice. And this starts with screening these patients for alcohol use disorder using a IAUD identification test or audit, which is a 10-item questionnaire, as you can see here. And each question can be scaled between zero to four, which is self-reported by the patient. With a total score of 40, you can gauge the diagnosis of alcohol use disorder and its severity. As it is a comprehensive questionnaire, it is used mostly in research, but a shorter version highlighted in the box with three first questions can identify patients with alcohol use disorder with a total audit C score of three or more in women and four or more in men, and then increasing the severity of alcohol use disorder with a higher score. AUD can also be diagnosed using another tool called DSM-5 criteria, which are listed here based on alcohol consumption characteristics, tolerance, and withdrawal. And out of these 11 criteria, you have to have at least two to diagnose alcohol use disorder, and the increasing number of criteria increases the severity of alcohol use disorder. It should be recognized that these patients with ALD have other issues going on. For example, neuropsychiatric issues shown on the left in about 40 to 50% with anxiety, sleep disorders, and depression. And they also have other issues with other substance use, especially nicotine, marijuana, opioids, which become important in the current epidemic of opioid use and other substances. This also brings into another connection of alcohol use and ALD patients with concomitant viral hepatitis and hepatitis C, and this issue will be discussed in detail by Dr. Blankos in his talk later today. So coming back to our two cases, the first case shown on the left, who had been enrolling in alcohol use disorder treatment and then found to have liver disease, and this patient should have a serum biomarkers or fibroscan or a combination of both to identify an individual who has stage F2 or more fibrosis so that can be integrated with hepatology for further care of the liver disease. The second case shown on the right, who came with diagnosis of alcoholic hepatitis, should undergo screening for alcohol use disorder either through audit score or DSM-5 criteria. And those patients identified to have moderate to severe alcohol use disorder should then be integrated with addiction medicine and multidisciplinary care to take care of other issues. And manage both the pathologies with liver disease and alcoholism. So here are my takeaways and take home messages from today's presentation. So screening for alcohol use disorder should be promoted in primary care and those patients who have established liver disease. Patients with asymptomatic liver disease, with steatosis or elevated liver enzymes due to alcohol should be screened using fibrosis markers, either serum or radiological or combination to identify those who have advanced disease and be referred to hepatology for the care of their liver disease. Patients who already have advanced liver disease from alcohol should be screened for alcohol use disorder so that they can receive integrated multidisciplinary care. It is clearly the time that we need to promote strategies to implement these models in clinical practice and how we can achieve that will be discussed by the next speaker, Dr. Lorenzo. And I thank you all for patient listening and be happy to take questions. I want to thank ASLD for the invitation and NAAA and NIDA for hosting the NIH Corner today. As we heard from Dr. Singal, total alcohol abstinence is the cornerstone in the treatment of alcohol-related liver disease, ALD. So the clinical management of these patients include the treatment of both the liver, ALD, as well as the underlying addiction, alcohol use disorder, AUD. We do have treatments to help the patients with AUD, including behavioral treatments and medications. In particular, I'm going to provide some examples of behavioral treatments, specifically cognitive behavior therapy, CBT, contingency management, CM, and motivational interviewing, MI. CBT approaches have among the highest level of empirical support for addiction, and evidence indicates a relatively sustainable effect. However, the implementation of a CBT in clinical practice is limited. CM interventions also have demonstrated efficacy and utility for improving treatment outcomes in patients with addiction, and evidence indicates the ability of a CM intervention to promote periods of sustained abstinence. And MI interventions have demonstrated efficacy in producing significant and sustainable effects and in contributing to counseling efforts. However, the implementation of these behavior approaches in liver settings is quite limited. A recent systematic review in 2016 also shows that in AUD patients with chronic liver disease, there is not robust evidence for any behavior intervention per se alone in maintaining abstinence. However, significant effects were observed in this systematic review, both in inducing and maintaining abstinence when either CBT or MI was integrated with medical care for chronic liver disease. So indicating the importance of integrating the treatment for AUD with the treatment for ALD. In addition to behavior treatments, we also have medications that we can use to help patients with AUD. Specifically, there are three medications approved by the FDA for AUD, acamprosate, disulfiram, and nartrexone. Nartrexone can be oral or intramuscular formulation. However, the implementation of medications for AUD in a liver setting requires additional considerations, in particular from a safety standpoint. In fact, disulfiram may give hepatotoxicity. And so disulfiram is contraindicated in patients with ALD. For nartrexone, there is a potential risk of a hepatotoxicity. However, such a risk is not well documented at the doses used for AUD. And in fact, such a risk seems to come primarily from all the studies in obesity with higher doses. So overall, nartrexone is not contraindicated in an absolute way in a liver setting, although caution is important. It's also important to keep in mind that intramuscular nartrexone does bypass the first pass metabolism. And also recently, another medication, nalmorphine, whose mechanism of action is similar to nartrexone, was approved not in the US, but in Europe. And there are no known risks of hepatotoxicity for nalmorphine. The third important medication approved by the FDA for alcohol use disorder, AUD, is acamprosate. And acamprosate is contraindicated in patients with kidney problems. What listed the dose has to be adjusted because acamprosate is primarily excreted and changed by the kidney. But there are not known contraindications or symptoms of acamprosate. There are no known contraindications or side effects that prevent the use of acamprosate in patients with ALD. Of course, with the exemption of those patients with ALD and the clinically relevant kidney problems. So overall, acamprosate is safe in patients with AUD and ALD. Indeed, a 1992 French study showed a single day administration of acamprosate was safe and tolerable in child PUA and B patients with cirrhosis. So further showing the safety of acamprosate in the context of a patient with ALD. All that said, the number of medications that we have approved for AUD is very small. And there is clearly an urgent need to increase the armamentarium of medications that the clinical providers can use in a clinical practice. The good news is that there are in fact some medications that hold the promise for AUD. Specifically, these medications are not approved by the FDA, but Phase II or in some cases Phase III clinical studies support their efficacy. Although, I want to emphasize and make clear that they are not approved by the FDA. So their potential use for AUD would be an off-label use. And those medications include the Baclofen, Gabapentin, Ondansetron, Toparamate, and Vareniclin. Baclofen is particularly interesting in this context because Baclofen is the only medication that has been formally tested in AUD patients with liver cirrhosis. And overall, the clinical trials with Baclofen are conflicting. Indeed, in this recent consensus statement, we emphasize that the conflicting results from multiple clinical trials may reflect the heterogeneity of patients' response. And one of the main take-home messages from this consensus statement is that maybe Baclofen works better in those patients with higher severity of dependence, which include patients with more advanced liver disease. And that could indeed be the reason why Baclofen seems to work better in patients with liver disease. Indeed, in an old study in 2007, we showed the efficacy and safety of Baclofen compared to placebo in promoting alcohol abstinence in alcohol-dependent patients with liver cirrhosis. It's also interesting that the two follow-up clinical studies have partially replicated these findings. More precisely, a VA study by Peter Hauser and colleagues in veterans with Hep C failed to show a difference between Baclofen and placebo. But it's important to consider that in this study, the baseline drinking levels were pretty low, indicating a low severity of dependence in these patients. By contrast, a study in Sydney by Morley and colleagues showed the efficacy of Baclofen compared to placebo in AUD, but only in those AUD patients with liver disease. So replicating our previous findings that the efficacy of Baclofen may be limited to those patients with a higher severity of dependence, including patients with more advanced liver disease. Indeed, both the American College of Gastroenterology and ASLD have included Baclofen as a potential pharmacological tool for AUD to be considered in the liver setting. However, it's important to keep in mind that the Baclofen is only an example. There are many other medications that could and should, in some cases, implemented in liver settings to help patients to quit drinking. In particular, I already mentioned Acamprosate, which indeed is approved by the FDA. And there are no contraindications or safety concerns why Baclofen should not be implemented for patients with AUD and ALD. Of course, again, excluding patients with advanced kidney failure, including, of course, Hepatorenal Syndrome. Furthermore, some of the off-label medications should also be considered. And two examples I want to mention are Gabapentin and Varenicline, although I also want to make clear that those medications have not been formally tested in patients with AUD and ALD. Nonetheless, they hold the promise. Varenicline is approved by the FDA for smoking cessation. And based on the SAMI Human Laboratory studies, an NAAA randomized clinical trial led by Dr. Leighton and his team show that the Varenicline is effective in reducing heavy alcohol drinking. And also, Varenicline reduced cigarette use, despite these patients were not seeking treatment for smoking. And indeed, an additional analysis showed the effect of Varenicline was more pronounced in those AUD patients who also reduced smoking. That's important because smoking is quite common in patients with AUD, including patients with AUD and ALD. So Varenicline may be particularly promising in the context of patients with AUD and ALD who also smoke. The other example I want to make is Gabapentin. Based on the SAMI Human Laboratory studies, a treatment randomized clinical trial by Dr. Mason and colleagues at Scripps showed that the Gabapentin dose dependently reduced drinking as well as a craving indomnia and dysphoria in AUD patients. Furthermore, the same team also showed that the Gabapentin reduces cannabis use and withdrawal. And cannabis use is also frequent in patients with AUD. So once again, suggesting that this medication may be used beyond alcohol for substance use comorbidity. Now, based on these preliminary results, NAAA conducted a multi-site randomized clinical trial. This multi-site randomized clinical trial did not replicate the initial findings. This could pose the question of whether, in fact, Gabapentin is effective. But I also believe that the Gabapentin is, in fact, effective in AUD patients. But just like all other medications, only in a subset of patients. Now, first of all, this randomized clinical trial showed low blood concentrations of Gabapentin, which was indeed an extended release formulation. And that, in its own, could be a reason why this study was negative. Furthermore, patients involved in this multi-site randomized clinical trial had low levels of alcohol withdrawal. And Dr. Anton and colleagues at MUSC have recently shown that the Gabapentin seems to be effective only in those AUD patients with history of alcohol withdrawal and more withdrawal symptoms. Finally, a secondary analysis of this multi-site randomized clinical trial using machine learning and random forest methodologies showed that the Gabapentin was, in fact, more effective than placebo, but only in a subset of patients. So again, indicating the potential for its efficacy in a subset of AUD patients. Indeed, Gabapentin, as well as Tepiramate, which I did not talk about today, have been endorsed by the American Psychiatric Association as a second-line pharmacological treatment in patients with AUD. So to summarize, it's very important that we work toward the integration of addiction and medicine. And indeed, this is even more important now that we have effective treatments for HCV. So to summarize, we do have treatments for AUD. And however, we had to do a better job in integrating hepatology and addiction. Thank you so much. Good afternoon. I'm Dr. Carlos Blanco. I want to thank the American Association for the Study of Liver Disease for inviting me to participate in this symposium. The topic of my presentation is going to be liver and substance use research challenges and opportunities. I'm the director of the Division of Epidemiology Services and Prevention Research at the National Institute on Drug Abuse, which, as you know, is part of NIH. I do not have any conflicts of interest for this presentation. And I'm going to talk about three main topics. One is the prevalence of substance use disorders. The second topic is going to be hepatitis C. And the third topic is going to be how we can create teams or collaborations between researchers and clinicians that can develop research projects and funding opportunities that would be of interest to neither. The first topic is the prevalence of substance use disorders. And as you can see, I want to highlight three main disorders. One is nicotine dependence, which is now also called tobacco use disorder. The second is alcohol use disorders, including alcohol abuse and dependence. And the third is drug abuse and dependence, or drug use disorders. And within those disorders, I want to highlight three, cannabis use disorder, opioid use disorder, and one that has become or is becoming increasingly important, which is stimulant use disorder. And that would include cocaine abuse and dependence, amphetamine abuse and dependence, and other stimulants. Now, nicotine dependence is very, very important, because even though patients may come to you as a reason for consultation for their symptoms, obviously, about 13% of the population, and even higher in individuals who seek general medical care, have nicotine dependence. And tobacco use disorder or nicotine dependence, tobacco in general, is the main preventable cause of premature death. So by addressing tobacco, we can really prevent a high number of deaths. It's actually more than half a million deaths per year that could be prevented by addressing tobacco. So even though your patients may consult with you for another reason, it's important to really screen them for use of tobacco, and potentially recommend them to stop using. And if you don't feel able to treat them, then refer them to an appropriate expert who may do so. Alcohol use disorder, I'm not going to delve into it, because Dr. Kathy Yang and Lorenzo Alagio are going to address that topic. And then opioid use disorder is important for a couple of reasons. One is that even though the majority of individuals who have opioid use disorder acquire the pills through friends or family members and not through physicians, sometimes physicians are responsible for prescribing medications that can be either misused by their patients or diverted and then misused by other individuals. The other reason, of course, that opioid use disorder is important for you is because injection drug use, often injecting opioids, is the main source of hepatitis C, which is the topic of my presentation. As you know, the prevalence of hepatitis C is about 130 to 150 million individuals worldwide. Of those, about 4 million are in the US. So about a little bit over 1% of the US population is currently infected with hepatitis C. And if you think about it from the point of view of mortality, more than 20,000 people die every year from hepatitis C. And that's more than any other infection and, in fact, more than 60 other infectious diseases combined, including HIV and hepatitis C. For a while, the prevalence of hepatitis C was decreasing. You can see in the graph that until the year 2006, 2007, we were on the right path. The prevalence was decreasing. But then around 2007, 2008, the prevalence started to increase, both for men and women. The prevalence is always a little bit higher for men, but it's also going especially high also in parallel by women. If you look by race, also races are increasing in the prevalence, but the increases are probably more marked for Native Americans and for whites. One of the reasons why hepatitis C and opioid use disorder coexist, and also with HIV, is because they have shared risk factors and causes. At the same time that this is in a way the reason for this endemic, we can also take advantage of those shared risk factors to think about shared solutions or solutions that integrate treatments for both disorders or for three disorders in the cases of individuals who may suffer from HIV, HCV, and OPD. In terms of the route of transmission, blood-borne transmission is the main route of transmission. Until 1989, 1990, probably health care exposure was more common. But at this point, injection drug use is certainly the highest risk population. There are other modes of transmission that still remain, including sexual, especially homosexual contacts. Heterosexual is more rare and also perinatal in some cases. There are other ways of transmission, including non-injection drug use, household exposures, and unregulated tattooing that have been reported, but are much less prevalent and for that reason, in a way, less important from the public health point of view. In terms of risk factors, when we think about individuals who inject drugs, we can take into account or think about several potential risk factors. One is injection duration. Obviously, the longer people have been injecting, the higher the risk. Frequency of injecting is also a very important variable because every time you inject, you are increasing the probability. So as you inject more time, the probability is accumulating. Then equipment sharing in general, not just sharing needles. The case, the incidence of HCV has the decreasing part due to harm reduction in HIV, but not enough to counter the increases due to opioid use disorders. Overall, the prevalence of hepatitis C has been increasing as I mentioned in the previous slide. One thing I wanted to bring to your attention is this HCV cascade of care in the US, and the need to improve diagnosis and treatment at several steps. So what I like about these cascades of care is that it helps us isolate where the leakage happens, and by the same token, where specific places where we can intervene. So if you take a baseline of 3.5 million individuals, which is the prevalence into around 2014, when this study was conducted, you can see that only about half of them are diagnosed and aware of being infected by hepatitis C. Fewer, about 43 percent, access outpatient treatment, and a little bit more than one in four, 25-27 percent, get RNA confirmation of their diagnosis. Even fewer, less than 20 percent or less than one in five, get a liver biopsy, and about 15 percent get prescribed treatment. Maybe a little bit more right now, but still very low doses. So you can see that there are ways in which we can improve. The first way would be simply by improving the rate of diagnosis. So I would essentially funnel more people into treatment. We could get also better diagnosis, improve the quality of the diagnosis, and certainly we could improve the quality of the treatment, especially now that we have very efficacious treatments for hepatitis C. Some of the reasons why there are these leakages is there are the barriers that I cite in this slide. So many individuals are not diagnosed. There are specific groups that have lower rates of diagnosis, including individuals who are young, urban, and have injection drug use. There may be places where there's no treatment for drug use disorders, and so that's going to decrease the number of people who reach out for treatment, and the same if there's a lower availability for antiviral treatment. Of course, there's always going to be some individuals who are not interested in accessing treatment. Finally, I want to mention stigma, because stigma is a major barrier for all kinds of treatments, but particular for treatment that has to do with mental disorders and even more for individuals with substance use disorders. So to the extent that we address a stigma, we can remove an important barrier to treatment. I also want to point out that in addition to thinking of treatment as benefiting the individual, it's important to think of treatment as a way of prevention. So if we treat an individual, that individual is not going to be able to transmit the disease to other individuals, but by contrast, if we don't treat the individual, that person is going to be a very important vector of transmission. The other thing to take into account, of course, is that the individual gets treated but gets reinfected becomes again a source of transmission. Since many individuals who have hepatitis C have an opioid use disorder, it is important to treat not only the hepatitis C, but really to get individuals to get treated for opioid use disorder to prevent that they get infected, and enter again this cycle where they get infected, infect others, and then they get infected again. So it's important to think about integrated treatment when we think about the treatment of individuals with hepatitis C from the individual point of view, from the thinking about the individual patient, but also thinking in terms of population health. I also wanted to mention the crisis with the overdoses, which is an additional problem that we have with opiates. As you know, initially, the overdoses were due mainly to prescription opiates, then heroin, later fentanyl, and more recently, as I mentioned earlier in the talk, stimulants are becoming a very, very important issue. Then I wanted to devote the last few minutes of my presentation to talking about the kind of research that we are interested in NIDA. The kind of research that we are interested is really a dialogue between clinical practice and public health to generate research questions, and then ensuring that researchers address those questions so that clinical practice and public health. Traditional way of thinking about innovation, which is the Rogers model, is that some individuals would be the innovators and then there would be early adopters. Then more people would adopt the intervention and then eventually everybody would adopt the intervention. But as you know, it takes about 17 years following that model to really get people to adopt the intervention. That's a very, very long time. I think that one of the reasons at least why it takes so long is because when early innovators don't take into account the needs of the people for which they are innovating, it becomes a blaming game. In this case, researchers would tell clinicians what they have to do, but that's really responding to the needs of the clinicians. I think this is the model of the learning healthcare system in which we create this virtual circle where, as I was mentioning a little bit earlier, you get clinicians, administrators, patients to come up with the questions. These are the things for which we need solutions. They generate the questions. Then we have the researchers who are the individuals who have the training to really address the questions in a systematic and in a way definitive way. By having this collaboration and this dialogue between the question generators, if you will, and the people who can address the question, there will be more friction at the beginning. It can become a little bit more difficult to generate a good research. But once you have the research, because it has been really vetted and is responsible to the motivations of the people who have to apply the research, it is much more likely that this research will be adopted. It's going to be a cycle. You're going to develop an intervention or you're going to address a question. It's going to partially respond to this need or to this question, but it's not going to be perfect. When you evaluate it, you're going to see the things that are useful and the things that are not so useful. Then you can refine the intervention and go into another cycle. That's the way we can continue to do research, but most importantly, improve clinical practice and public health. Three takes away from this talk. First, corresponding to the first topic I addressed, substance use and substance use disorders are very common, particularly alcohol and tobacco. But at the same time, they are extremely treatable. We have medications and behavioral interventions that are very useful to treat these disorders. So don't be skeptical and don't be discouraged. And if you don't feel capable or you don't feel prepared or you don't have the time to provide the treatment, then refer them. Second, injection drug use is the main source of transmission for hepatitis C. And the third point I want to emphasize is the research, the interest that we at NIDA have in research that addresses clinicians and patient questions, particularly using the model of the learning healthcare system. And this is a high priority for NIDA. With that, I want to thank you for your attention and I'm looking forward to the questions during the chat section. Thanks very much. Good afternoon. I'm here to tell you about funding opportunities from NIAAA and NIDA. My name is Kathy Young. I'm a division director in the National Institute on Alcohol Abuse and Alcoholism. And our division, the Division of Metabolism and Health Effects, oversees the liver portfolio within NIAAA. I have nothing to disclose. I want to thank AASLD for inviting us to organize this session. And I want to thank my co-organizers for helping to put it together. You'll notice that NIDA's mission statement and NIAAA's mission statement are specific to our areas of focus, but they both reflect NIH's overall mission, which is to generate knowledge to help improve human health and wellbeing. Before I leave this slide, I want to make one boast, and that is NIAAA is celebrating our 50th anniversary this year. We were founded in 1970 and we're 50 years old this year. So in the earlier presentations in this session, you've heard an awful lot about the parallel diseases of alcohol use disorder and alcohol-associated liver disease. I want to assure you that NIAAA supports and encourages a broad range of topics and approaches to understanding and mitigating ALD, alcohol-associated liver disease. We support and encourage applications on basic preclinical research and translational research on mechanisms in liver disease, and also for any other gastroenterologists in the audience, anyone working on alcoholic paculatitis. We also welcome those applications. We support translation to treatment, and this usually involves the engagement of clinical researchers. We know about our interest in integration of treatment. And even pre-pandemic, there's been increased interest in telehealth and digital health, which has increased even more during the pandemic. I want to emphasize that we encourage you to contact a program officer as you begin to develop your application to confirm that the area you're working on is a priority for NIAAA. If we had all the money in the world, we would support all the high-quality applications, but we have forced to pick and choose among high-quality applications. So please check with us about your priorities before you start to develop an application. The web link there will connect you to the contact information from the program officers. If you're going to start to, if you're going to submit a basic research application, please start with the end in mind. Our goal is to improve human health and wellbeing. So be sure that the question you're asking is relevant to human disease. Be sure that the animal model and the protocol replicate human disease, and that the alcohol feeding model addresses physiological alcohol levels and reflects patterns of human consumption. For all of these applications, it's best for you to start with the Parent Funding Opportunity Announcements, FOAs, the Parent Program Announcements, or the PAs. So the Parent R01 and the Parent R21. There's a new wrinkle or recent wrinkle from NIAAA, and that is to let you know that for the Parent R01, for any R01 you submit, you've got to choose between three different PA numbers because they're now separated into clinical trial not allowed, clinical trial required, or basic experimental studies with humans required. And the PA number that you put on the face page of your application has to align with the topic of the research that you're proposing. If it doesn't, NIH will reject the application without even reviewing it. So choose the correct FOA number, and you can find those at the link that I show there. NIAAA also supports U mechanisms, U01s and others, and these are the type of thing that consortia and networks can use to establish a group of collaborators working together. These are collaborative agreements, and that means that NIH has a little bit extra involvement compared to normal grants. You can only get a U01 application funded if you are submitting it in response to a specific focused FOA released by one of the institutes at NIH because there is no parent FOA. And currently NIAAA has no focused FOAs for U awards. I will note that NIDDK has a very interesting two RFAs because their plan is to establish a liver cirrhosis network. And you know that liver cirrhosis has many etiologies, one of them being alcohol consumption. So we're actually quite enthusiastic about NIDDK's liver cirrhosis network. One other quick housekeeping item, there are fewer targeted program announcements, and these are being replaced by notices of special interest, or NOSIs. I want to emphasize you don't need to be responding to a NOSI. You can submit to the PAR, the parent announcement, without using a NOSI. But if you choose to use a NOSI, how you do that is you use one of the parent PAs, like an example here is PA 2185, which is the R01 for clinical trial not allowed. Any PA fits. And then later on the face page, enter the notice number that you're responding to. Okay, back to more substance. I want to explain that NIDA and NIAAA support the development and retention of early stage investigators. It's very important to us to promote and give every opportunity to early stage investigators, and also to, I'll tell you why. So one of the ways we do this is with career development awards. These are called K awards generally. And there are, I'll show you four mentored K awards and two independent K awards. So in general, a K award allows for the support, the financial support and salary support, I mean to say for three to five years for the applicant. And it's meant to have intensive supervised career development. So the mentored awards require a supervisor who will be intensively and actively involved and agrees to work with you. The K01 is the most general of these, and anyone can apply and look for development in any of the biomedical and behavioral clinical sciences that NIH might support. The K08 and the K23 are somewhat different because they are directed specifically for people who have a clinical doctoral degree, for example, an MD, DVM, one of the psych degrees. So these are people who have clinical training and for the K08, these people, this applicant would want to increase their knowledge of laboratory-based or field-based research. For example, they might be starting to want to look into bedside to bench research. The K23, on the other hand, while still targeted to medically trained people, focuses on patient-oriented research. The fourth mentored K award is the K25, which focuses on anyone with quantitative training in specialties in mathematics, computer science, informatics, so on, imaging science. So data science, for example, is really quite an interesting area right now. And if people with this kind of training want to get some biology exposure to be able to use their expertise to forward NIH-relevant research, they would look for a biology mentor, a clinical mentor, and apply for a K25 award for that. The other two awards are independent research development awards. The K02 is for someone who is newly independent, but just needs protected time to get a stronger foundation in research. And the K24 is for a mid-career clinician, an associate professor, who wants to devote time to patient research and can also willingly mentor junior faculty, clinical residents, and so on. One other mechanism that we have to support early career investigators are these two supplements. Now, these are administrative supplements and not grants, and they can be attached to someone who has their first R award, their first research award, or a K award. But these folks have had a critical life event, which caused them to lose time, to have to take time away from their research to deal with family members, childbirth, adoption, or primary caregiving responsibilities, for example. These awards provide a little bit of extra money for research and extra time for people to get caught up so they can be competitive in trying to get the next research award, go to the next stage. So what I've told you so far, the key takeaways are that alcohol use disorder and substance use disorders are major contributors to liver disease, and that mitigating alcohol-associated liver disease will not be possible until the parallel diseases can be treated. NIDA and NIAAA support research that addresses and seeks to alleviate substance use disorders, including alcohol use disorder. NIAAA supports basic preclinical and translational studies on ALD. And NIAAA and NIDA support early career investigators with multiple support mechanisms. If you have any questions, don't hesitate to reach out to me or to Carlos Blanco of NIDA. Thank you.

Digital Experience Liver Meeting

alcohol-associated liver disease

substance use disorders

integrated care models

hepatology

abstinence

pharmacotherapy options

funding opportunities

patient outcomes