Thank you Ashwani and Craig for inviting me. So I will kind of switch gears and talk more about the how to treat the addiction part in our patients. And the preface which Dr. Szabo alluded to in the previous session is as simple as it could be. We actually needed to treat these patients in terms of helping these people to achieve and maintain alcohol abstinence. We do know in fact that alcohol abstinence is the cornerstone in the treatment of alcohol-related liver disease, ALD. And in fact the abstinence may be critical at any stage of liver disease. And for example, we know that the 40% of people survive in five years with cirrhosis if they keep on drinking. But if we help these people to quit the drinking, actually survival almost a double to 77%. And the good news is that we have a treatment. That's actually a schematic from the NAAA website, the NAAA Treatment Navigator. So we do have treatments to help people with alcohol use disorder, AUD, including behavior treatment in the medications. However, the challenge, and I will talk more about that, is actually that data from the NAAA show that only 10% of people in the United States receive any type of treatment for AUD. That's not specific for AUD and ALD, but AUD in general. And only 4% of these people receive any prescription for a medication for AUD. So that's despite the fact, which I'm going to review briefly, that we do have both behavior treatments and medications effective in treating people with AUD. And starting with behavior treatments, we have residential treatments, but also we have effective treatments for outpatients, including brief interventions, which can be relatively easy implemented in primary care settings. And we also have more structured behavior treatments. I will here summarize the most effective kind of state-of-the-art behavior treatments, which include the Cognitive Behavior Therapy, CBT, Contingency Management, CM, and the Motivational Interviewing, which are kind of summarized in the next slide. CBT approach in particular have among the highest level of empirical support for the treatment of alcohol use disorder. And evidence indicates a relatively sustainable effect. However, limited use in the clinical practice. Ditto for CM, Contingency Management. The CM interventions have demonstrated efficacy and utility in improving outcomes in patients with AUD, and evidence indicates the ability of these interventions to promote sustained period of alcohol abstinence. And finally, for Motivational Interviewing, MI, MI interventions also have demonstrated efficacy in producing sustainable effects, also in contributing to counseling effects. It also did show that the results with MI are influenced by participant and delivery factors. So again, the challenge here is that despite that we do have behavior treatments, they are not typically implemented in clinical practice. And unfortunately, this also applies to the liver setting. There is not, for example, a common use of these behavior treatments in herpetology. And if we look at the publisher literature, we don't have a lot of studies to actually investigate the implementation of these behavior treatments in a liver setting. A recent, actually, meta-analysis from Dr. Khan and colleagues showed that actually the number of publisher studies is very low. And also, the systematic review indicates that in the patients with AUD and chronic liver disease, there is no robust evidence of any behavior intervention in maintaining abstinence. However, significant effects are suggested by this systematic review in both facilitating and maintaining abstinence when either CBT or MI are integrated with medical care. So, suggested, in fact, if we do integrate the treatment of addiction with the broader treatment of the liver in general medicine, actually, we may have significant effects on alcohol outcomes. Now, in addition to behavior treatments, we also have medications we can use for these patients. I'm not going to the details of this slide, but here the summary is that we have a much better understanding of the neurobiology of alcohol use disorder. And this knowledge is helping us to identify targets of developer treatments. However, what the slide on the right shows is also that there is a high, profound, if you will, heterogeneity of our population. And because of this heterogeneity, the response to these medications tend to be at the small effect size. But nonetheless, we do have medications approved by the FDA to treat alcohol use disorder. And these medications are accompanied with disulfiram and naltrexone. But again, as I pointed out before, data showed that only 4% of patients with AUD receive a prescription with any of these three medications. And then if we go to a liver setting, we don't actually have a clear data, but most likely the number is even lower because, in particular, disulfiram has the potential of giving hepatotoxicity. So, it's not commonly used to treat AUD in a liver setting. For naltrexone, actually, historically, naltrexone has been associated with the fear of hepatotoxicity, although decades of clinical practice in using naltrexone suggested that at the dose used for alcohol use disorder, such actually side effects seem to be very rare. And finally, for acamprosate, actually, except the one formal study conducted in France many years ago, where a single dose of acamprosate was tested in patients with child PUA and B, there are no formal data using acamprosate in AUD patients with ALD. But from a clinical, a pharmacological standpoint, there are really no reasons why acamprosate could not be used in the treatment of AUD and ALD. Nonetheless, the number of medications we are talking about is very small. We're talking about three medications. If you compare this number to numbers of medications we have for depression or for hypertension, diabetes, of course, the number is very small. The effect size tends to be small. So, the bottom line is that we need to develop a new treatment. So, there are efforts to actually identify new targets, and that's something my lab is doing, but I'm not going to cover it today because of lack of time. But also, there are many efforts in repurposing existing medications approved for other indications to be repurposed for alcohol use disorder. In phase 2 and some phase 3 clinical trials, support the potential efficacy of, in particular, baclofen, gabapentin, ondantroton, taparimethavarenicline. I'm not going to the details of each single drug. I want to emphasize that these are not approved by the FDA for alcohol use disorder. But one challenge, again, is that with one exception. These medications have not been tested in AUD patients with ALD. So, we are lacking former clinical trials where we tested these medications in people who have developed alcohol-related liver disease. One exception, which I'm going to use as a case study, is the baclofen. And, in fact, actually, baclofen, which is a GABA-B receptor agonist, was tested a few years ago when I was in training in Italy with Giovanna Dolorado in this clinical trial. Actually, we show that the use of baclofen compared to placebo was more effective in maintaining alcohol abstinence and reducing alcohol craving in AUD patients with liver cirrhosis, and there was also an improvement in the liver function test. After our study, which is back in 2007, there were two more clinical trials testing baclofen in AUD patients with liver disease. One study was done by Peter Hauser at the VA in Oregon in patients, veterans, with chronic hepatitis C, and this study did not show difference between baclofen and placebo. By contrast, another trial by Krista Morley and Paul Haber in Australia in AUD patients with liver disease did show difference between baclofen and placebo. So, actually, suggesting that these controversial findings may be due, maybe, that's our work in hypothesis, to difference in severity. As a matter of fact, the U.S. study, if we look at the paper carefully, show very low levels of drinking at the baseline. So, suggesting there was the potential for a flora effect. By contrast, the severity of alcohol dependence and the severity of liver disease was much higher in our clinical study in 2007 and in the Australian study published in 2018. So, overall, suggesting that the use of baclofen in AUD, including AUD patients with ALD, may depend on the severity of the dependence and on the severity of liver disease. Ashwani, actually, together with Ramon, Joseph, Han, and Patrick, and Vijay, actually, they recently published the ACG clinical guidance, where they indicated baclofen as a potential tool to use for patients with ALD, but with low level of recommendation or evidence, because, in fact, we do need more and larger clinical studies. The baclofen story in the AUD field is even more complex. If you want to know more, actually, recently, Roberta Gabbio and I led a group of 26 people, where we started together, and we worked for six months to develop a statement, a consensus statement, on the use of baclofen in AUD. And this was published a few months ago in the Lancet Psychiatry. But to summarize, baclofen basically is, again, a case example. So, some evidence shows its efficacy, some other studies do not, and the data remain preliminary. But nonetheless, baclofen can be seen as an example of how we could, hopefully, implement treatment, pharmacological treatment of AUD in liver settings. So, beyond this example, in fact, I point out before that a camposet, which is approved by the FDA for alcohol use disorder, could be used in patients with liver disease. Beyond the medications approved by the FDA, there are other medications that have been shown some efficacy, and I want to mention two examples, because these are gabapentin and vareniclin. I'm picking up these two examples because the pharmacology of both the gabapentin and the vareniclin does not suggest that there is any reason why these medications could not be prescribed in the patients, or used, at least off-label, in patients with liver disease. For vareniclin, in particular, which is approved for smoking cessation, there are a variety of human lab studies indicating that the vareniclin reduces alcohol craving and drinking, and a multicyclinical trial conducted by NAAA, led by Ray Leighton, shows that the vareniclin reduces a heavy alcohol drinking, this is in people without liver disease, and also that the vareniclin seems to be more effective in those people who are also smokers, and also that the vareniclin seems to work better in those people who are also reducing smoking. So, suggesting that maybe vareniclin could be used as a tool to treat both alcohol use disorder and smoking. Another example is gabapentin, which is approved by the FDA for epilepsy and neuropathic pain. Again, it is not approved for AUD, but a variety of human lab studies suggest its potential efficacy. In particular, Barbara Mason and Scripps show that the gabapentin reduces alcohol drinking and craving, and Ray Anton and colleagues at MUSC show that the effect of gabapentin seems more profound in those people with higher alcohol withdrawal syndrome. This data were replicated by Barbara Mason in a 2014 clinical trial. However, we at NAAA recently conducted a clinical trial. It was a 10-site clinical trial led by Dan Falk and Ray Litton. Actually, this clinical trial did not show a superior effect of gabapentin compared to placebo, which may question the efficacy of gabapentin, of course, although a working hypothesis is that, in that clinical trial, we used an extended release formulation of gabapentin, and the pharmacokinetics, the blood levels of gabapentin reached by these patients were lower compared to the clinical trials with the extended release formulation. And also, compared to the Ray Anton studies at MUSC, these actually studies tend to have, I mean, the multi-site clinical trial had a lower severity of patients, in particular patients with lower levels of alcohol withdrawal, which could be another factor why gabapentin was not effective in this more recent clinical trial. So, hopefully, there will be more data in the future to try to better understand whether gabapentin may still have a role in the treatment of AUD. Now, beyond the specific behavior treatments and medications that I have here mentioned as examples, what I really want to point out is these are just examples, again, and what is really critical is actually to work all together toward an integration model of addiction medicine and hepatology. And we think that this is becoming even more important now that we can cure HCV. So, what we are going to see more and more in the liver settings is pretty much people with obesity and or alcohol use disorder who will go to the liver doctors and who may need liver transplant. And one other important point is that, in fact, the treatment of addiction should be seen at any level of liver disease, including pre- and post-liver transplant. So, regardless of the severity of liver damage. And as a matter of fact, if we integrate the treatment of addiction in a liver transplant center, this actually may have profound effects. I will mention just one example, which was also led by Giovanni Dolorato when I was working with him in training in Italy. And here, what we did was to implement an alcohol addiction unit in a liver transplant center. And we found actually a profound reduction in the relapse in the patients who actually received the treatment with the addiction unit, compared to those patients who were not seen in the addiction unit. And also, the presence of the addiction unit extended survival in patients after liver transplant. And this data had been replicated by two other independent centers in Italy and also in France by Georges-Philippe Pegeot. Finally, last but not the least, what is really critical, it's actually to really work harder altogether to increase education and training in primary care in internal medicine. That's actually one huge challenge we have. So, to summarize, unfortunately, the treatments for AUD are not routinely used in clinical practice, despite the fact that we do have effective behavioral treatments and we do have effective medications approved by the FDA. And we also have some promising medications not approved, but with some evidence of efficacy to treat AUD. The two main challenges, in addition to discovering and developing new treatments, are also to integrate hepatology in addiction medicine, and also to increase at the medical school level and also at the residency level education and training in addiction. And thank you so much.

addiction treatment

alcohol-related liver disease

behavioral treatments

medications

patient outcomes