Thank you. How many of you treat people who inject drugs actively? Can you just raise your hand? Yes, thank you. When one of the medical students two or three years ago asked me, would I treat someone actively injecting drugs, I could not answer him with the data. I said, I normally don't. I gave a lot of reasons, reinfection rate, noncompliance. So I thought I would look into this in a little more detail. And that's what I'm going to present to you today. Just look at it. I will briefly discuss the epidemiology of PWID, effectiveness of treating hepatitis C in that population, the challenges, and the role of treatment of PWID to achieve the global elimination of hepatitis C. It is estimated that about 15.6 million people who actively inject drugs. About 3.2 million are women. In Asian countries, it is much lower, about 3.2%. One fourth is younger than 25 years. One fifth had recent homelessness. 60% were incarcerated recently. About one in six is HIV positive. And one in 10 hepatitis B positive. When you look at the world map, the prevalence of PWID varies from countries to country. And when you look at the incident rate, it ranges from 5% to 45%. But in general, half of the PWID will have hepatitis C. And in high income countries, such as Europe and North America, PWID is the most common source of infection, more than 80%. And it is becoming a common source of infection in low income countries as well. So this is an old treatment, interferon ribavirin. One would have thought that interferon ribavirin will be ineffective in this population. But these are selected patient population, patients who have history of PWID. When you treat them with interferon ribavirin, compared to the control, they seem to have similar SVR. So what about the new drugs? There are some small studies. The first two studies are registration studies. And there were a few patients who are actively injecting drugs on opioid substitution therapy. And when you look at the SVR, the delta, the estimated and the observed, it's very small. And the last study is an Italian study. They have a significant number of them actively injecting drugs. They still got 95% SVR. Recently, a study was published in J-HEP, a large cohort of patients, 1752. Some of them were actively using drugs. Some of them were on opioid substitution therapy. And some not. So when you look at their SVR, again, the delta is very small. The only major difference was in people who were actively using drugs. But that was mostly because the patient lost for a while. So when you do protocol analysis, there was no real difference. And meta-analysis confirmed that of 11 primary articles and 12 conference abstracts. When you look at the patients on opioid substitution therapy, pool SVR was 90%. People who actively inject drugs, 88%. So when you adjust for all the variables, there was no real difference between those who are using drugs and controls. So the next question is, what about the reinfection rate? They are likely to go back to drugs or use drugs. So this is one study published recently, last year, from Canada. They defined PWRID as either recent, that is less than three years before SVR, or remote, more than three years. And majority were men. And 83% were born after 1975. And opioid substitution therapy was received by 19%. So when you look at the reinfection rate, there were only 40 reinfections. When you look at the crude reinfection rate per 100% person years, it was higher in those who were recently using drugs compared to those who were former users compared to controls. But yet, the actual number was much smaller. So there is a definite increase in reinfection rate, but it's not as high as we expected. And they found that those who are younger and those who are infected with HIV are more likely to be reinfected. But in that study, only one patient who was receiving OST developed reinfection. So why are we not treating those patients? So one of the reasons is there is a low hepatitis C testing and awareness in the PWRID population. And there is a dogma against treating them among us, the physicians. And more importantly, there is inadequate harm reduction services in most parts of the world. And there are no national strategies or investment to treat these patients. So let's look at how many patients are aware of their hepatitis C status if they were actively using drugs. Let's look at Sweden, high income countries. They looked at 1,500 consecutive PWRID and asked them how many of them knew they had hepatitis C. 76%, for instance, they were hepatitis C positive. But those who thought they never had hepatitis C, 25% were RNA positive. Those who said they didn't know about it, 47% were hepatitis C positive. So this is a high income country from Europe. What about India? This is a study done by School of Public Health in India. They looked at young Indians, rural parts of India with poor education. Look at the numbers. Majority, less than 5%, were aware of their hepatitis C status. Only 3% had seen a doctor for hepatitis C. And only 1.4% taken hepatitis C treatment. So they again went back and looked at, is there any improvement? So what they found was centers which provided the integrated services. That means they got needle substitution or needle exchange, opioid substitution. They treated HIV, hepatitis B and S. They were more likely to be aware of their hepatitis C status. And they're more likely to be treated. So I think when we look at the elimination of hepatitis C by 2030, we may need to go outside our traditional views of treating these patients in our hospital clinic and may have to think of treating them in integrated care centers devoted for these patients. So how good is this harm reduction? One could argue that these services are a waste of resources. But this is a Cochrane database review published in 2017. So OST is associated with the reduction of HCV transmission, especially when it is used in combination with needle share, needle exchange program. Using just needle exchange program is more beneficial in high income countries, not so much in low or middle income countries. So there are data to support harm reduction services based on the published literature. This is a study published in Lancet Global Health in 2017. When you look at the availability of harm reduction services, on the left hand side, the needle syringe programs, NSP, even United States is far behind of the goal. Only 50 syringes are given per year to these patients. On the right hand side is the OST. Except for Australia and some European countries, it is dismal, very poor. We need to have at least more than 40% coverage to have significant effect if you were to eliminate hepatitis C from this world. So it is poorly distributed. So they concluded that HIV hepatitis C prevention coverage in this population remains very poor and likely to be insufficient to prevent hepatitis C and HIV transmission. And we need to scale up our intervention if you are going to halt HCV and HIV epidemics. So let's look at harm reduction services. Most pharmaceutical companies would ask you to treat more patients with hepatitis C. And they'd say that that will reduce the transmission risk and reduce the mortality and incidence. So on the top part, it is you just continue what this is our model. This is a paper published in J-HEP last year. Only 0.1% in Finland, there were a reduction by 0.1%. We continue the current practice of treating them without harm reduction services. There is no OST or NSP. But look at the bottom half. If we complement that, if we continue at the same rate as we are treating and increase harm reduction coverage to 80%, we can reduce the incidence prevalence by 50%. So just treating hepatitis C, we are not going to change the natural history and epidemiology of hepatitis C. So finally, our goal, WHO hepatitis C elimination goal by 2030, how feasible it is. So WHO defined the elimination goal by 80% reduction in incidence rate and 65% reduction in mortality. They didn't say you're going to eliminate it 100%. And they identified that injection drug use is the primary route in most high-income countries and some low- and middle-income countries. To achieve that target, we need to increase treatment of BWID. So this is, again, a mathematical model published recently in Lancet. The global prevalence of hepatitis C is about 71 million. And if we were to reduce the harm reduction by 40%, we will reduce the new infection by 14.1 million. And if we treat those who are identified by direct acting antiviral drug, we will reduce death by 640,000. But if you go a step further and have a comprehensive program, we will reduce it by 15.1 million and mortality by 1.5 million death. This is where we might reach the WHO goal. This will reduce it by 82% incidence and 61%. The goal was 65%. But this is just a mathematical model, which is pretty good when they looked at all the data. This graph is taken from their paper. On the left-hand side is the number of deaths on the top left-hand corner. And this one is the incidence. The top two lines, if we just continue the status quo or no direct acting antiviral drug, the death is going to slowly creep up. The incidence may come down a little bit on the right-hand side. But if we complement with harm reduction services, especially in less low-income countries, the most important route of transmission is not PWID. It is through the contaminated blood products and medical instruments. And if you do that, the yellow line, you will reduce the death. But we won't reach the WHO target. But the red line on the left-hand side, if you have a comprehensive service, we will reach the target. And the bottom panel is something you have to look at very carefully. If you just look at the countries where PWID transmission is a major transmission route, none of them are going to achieve the goal of WHO elimination. Most of these countries belong to the high-income countries. That is because 80% of the reduction, 80% of transmission, is through PWID. So you would have argued that high-income countries have a more likelihood of achieving the WHO goal, but it is not going to happen unless we were to treat the PWID. So where will you see the maximum benefit? If you have a comprehensive program, not treating the PWID, just reducing the risk from blood products and other things, you will see a dramatic decrease in hepatitis C-related infection in countries such as China, India, Pakistan and Egypt. This will happen only if they implement a comprehensive package. The main reason is only more than less than three percent of hepatitis C in those countries is through PWID. So what does the global mathematical model tell you? Let's assume the blood safety and infection control by 95 percent around the world, which is an achievable goal. You will reduce the incidence by 72 percent in 2030. But let's assume that we reduce the harm reduction coverage to more than 95 percent of PWID. We are going to reduce incidence by 33 percent. The gain is not as much as in the less developed countries. And if you give only treatment, you just forget about all these things and you follow what our pharmaceutical companies say, you need to cover more than 90 percent of the population to have any benefit. So to achieve the WHO goal, we need to have harm reduction services at least to cover more than 40 percent of PWID. Currently only one percent of PWID live in such countries with more than 40 percent harm reduction. So in summary we can say that it may be reasonable to treat PWID if we believe in the global elimination of hepatitis C. Since 50 percent of PWID are hepatitis C positive and incidence is very high. Treatment of DAA, I showed you the data, show that it is effective. And also there is some evidence that they may change their lifestyle after treatment or the way they use drugs. But the treatment discontinuation rate is quite high, seven to nine percent. Part of the reason is many of them do not have transport, they are homeless, many of them incarcerated intermittently. So there is a high discontinuation rate, but it's only seven to nine percent. Re-infection rates are definitely higher, but it's not as high as one would have suspected. It's only marginally higher. Challenges are much bigger because hepatitis C awareness is very low among people who inject drug. That applies to high-income countries and low-income countries. It is more exaggerated in low-income countries. And to achieve the WHO target of hepatitis C elimination by 2030, we need to reduce the transmission rate among PWID. That will require comprehensive programs that includes harm reduction services, opioid substitution, and needle syringe program. And we need to increase the screening and treatment. Thank you. Thanks Paul. I'd like to invite the speakers to the podium and we'll have about under 15 minutes for Q&A. So if you have a question, feel free to come up to the microphone. So go ahead. Dr. Carter, that was a great talk. The guidelines for the size of the liver biopsy are obviously subjective. We know from our cardiology colleagues only 10% of the guidelines are based on hard fact. And as a hepatologist who has looked at literally thousands of liver biopsies myself and has done liver biopsy conferences with pathologies for decades, I can say that nobody gets 14-gauge anymore. And in the old days when I was using the classical needle, which was 16- gauge, that made a pretty big hole. And the complication, mainly pain, was pretty high. And I think that at Ohio State, we use actually transjugular quite frequently. And our radiologists are able to get 11 portal tracts virtually every time, at least 90% of the time without fragmentation. And you know, I'm old enough to remember when the pathologists wanted wedged liver biopsies, which is we now know are worthless because they have so much fibrosis. So I think the night, I will admit, seeing the 19-gauge with our EUS biopsy seems pretty small. But I bet you over time, your brain can adapt. So I don't think we should be limited by a guideline which is so subjective. And the pathologists always want more. Yeah, no, it's an excellent point. And I was trained by Marshall Kaplan, who was trained by Jerry Klatskan. And so I am a believer of the Klatskan needle. And unfortunately, the Klatskan needle is not even made anymore. I give you my old ones. I was trained by Jim Boyer after experiencing with Klatskan, so I'm in the same school. Right, so we are from the same lineage. But I agree with you because the Jamshidi needles, which we use for suction biopsies, even though they're 16-gauge, they're not a Klatskan needle. They're not as long and they're not as wide. The one thing I'm impressed with, in the interest of time, I didn't have time to show you video, etc. The U.S. obtained samples are extremely long. So they can be 3, they can be 4, 5, 6, 7, 8 centimeters. And the ability to obtain biopsies from both lobes is extremely helpful. They seem to get intact cores. The main question for me is if you have a 19, you know, the challenge is I don't think they can get a gauge bigger than a 19 gauge. And whether that will be adequate for staging NASH is not clear to me. But your comment is good. I think the biggest question with the 19 gauge, you begin to get fragmented. You may get 11 portal tracts, actually you get more, but the portal tracts won't be intact, so it'll be difficult to gauge them. But in terms of the amount of liver tissue, the lack of fragmentation is also crucial. I mean you get these things that look like hamburger, it's very difficult to interpret. And when you get biopsies, I always retrieve the biopsies from these outlying centers that make diagnoses, and you can't see anything. They got two portal tracts, you know, most of it is subcutaneous fat, and that's impossible to make an accurate diagnosis. So I think that anything we do that is not fragmented, that's long, that has more than 11 portal tracts, that's fair game for an intelligent interpretation. Good point. Microphone in the back. Hi, thank you for your talk. This is a question for Professor Cowdery. So I think it's great to be moving away from biopsies and non-invasive methods, and I wondered if you could comment on the impact of iron on non-invasive techniques like MRE. There's a recent paper currently showing that MRE is impacted in terms of diagnostic accuracy in anemic patients and patients with iron overload. So have you got any suggestions about what to do in those cases? Yes, so iron is a key confounder for both MRI-derived stiffness measurement, but also for transient allostrography. The same features that drives iron to make the liver stiffer that you see in MRI also affects allostrography. So what we know is that if the score is low, then you're fine. It's not going to falsely lower the score, which is good, but we probably have to have a higher, a lower threshold for proceeding to a biopsy in those patients. Whether we can remove the iron as a factor I think is unlikely with MRI just because of the the properties of relaxation times being affected significantly by iron, but that's another discussion. Thank you. Thank you. Great session. I have a question about the statins. That seems to be the hottest thing out there in clinical practice. Do you have, first of all, do you use it routinely in your serotics? And the second question is, how do you know you're giving enough of it? And are there any markers or anything that we can follow to keep these patients under treatment? I'll start by the second. We use a standard dosage, not extremely high, the more intensive dosage, but the standard dosage. And as far as we know from animal studies, the more effective one in stimulating KLF and enosynthesis was simvastatin, and probably second is atorvastatin. And from indirect evidence using, comparing the lipophilic and hydrophilic statins, probably lipophilic such as simvas and artos are the better ones to obtain the desired delivery effects. So I will use 20 milligrams of atorvastatin or 20, 40 milligrams of simvastatin and 40 milligrams of atorvastatin at regular dose. In a child C patient, I will use only 20 milligrams. The other question, whether I routinely recommend that, well from an academic point of view, you cannot, you are not justified to do it until the evidence is class A. We are close to that for portal hypertension, but I would like to have a second trial confirming the results of our trial, and probably this will come soon enough. But if you ask me what I recommend a patient that is worried about his probabilities and ask me, doctor, what else can I do? I say, well, I recommend always a safe lifestyle. This is almost important and it's something that is frequently neglected. And then I tell him, if you were one of my family members, although the evidence is not overwhelming, I will take on the statin. And if there is anything in your safe health profile that can make it recommendable for another issue, this will be fantastic because we both will be more confident that this advice is sound. And for males, it is very frequent to be on the safe side by suggesting a statin therapy. For females, if it is postmenopausal, you are also on the safe side. In premenopausal women, probably we are still a little bit more far away from that because they are protected by the statins. But postmenopausal, for sure, I will recommend. I am very positive and in patients with NASH, I am very much in favor. So when you do decide to give it, you give it at one dose, you monitor the patient, and you just leave it at that one dose? Yeah. And we start with a low dose, for instance, with the statins. We start with 20 milligrams, and at two weeks, we check. The transaminases have increased to 40. But you know that the policy nowadays endorsed by the task force in the States and the FDA is no longer to do that. It is just to test the transaminases before starting to know whether they were already high or not. And don't look ever again until the patient has symptoms of myalgia or something like that, and then you have to withdraw the statins. Go ahead. Thank you. That was a great session. I have a question for Dr. Norta. In your talk, you talked about the risks of endoscopy, but what about... Perhaps I missed this, but what about liver biopsy? Is there a cutoff for INR that you would say, or this one is for transjugular, or maybe even avoid, totally avoid the liver biopsy? I don't do a liver biopsy in general unless I really need it. So, you know, I think if you're staging disease in child CPE, you know, you do it without a biopsy. I think that it doesn't often come up that a patient with an INR of 2.9 needs a liver biopsy except for acute liver failure, autoimmune disease, what have you. Those are often done transjugular in our institution. We are often held to other societies' practice guidelines, as you know, and our interventional radiology guidelines are not written for cirrhosis. They're written for warfarin and other anticoagulants, but they have some INR guidelines that they follow. So it's always a negotiation. I don't have data that show that a higher INR raises the risk for bleeding, and that wasn't shown in the HALT-C post hoc analysis as well. So in general, we have the platelet negotiation, and we don't worry too much about INRs in those patients that we really need a biopsy on. Thank you. I have a question for Shiv. Can you comment on when you would consider splenic artery embolization in this kind of algorithm? You mean for gastric variceal bleeding or something? Yeah. It's not in the routine algorithm for splenic artery embolization. Of course, it will decrease the arterial flow and the venous flow, and it is very good for hypersplenism. But for an acute or active bleed from gastric varices, it may not be very helpful. So we do not use it unless it is for hypersplenism. But do you have any idea if you have used it before? Yeah. I've used it in a situation where the patient already had some sort of rebascularization procedure, has a very large spleen, and is continuing to bleed, but sort of a low-grade bleeding, not the acute management. And it seems to have been effective. That way it will certainly help. If you reduce the blood flow by 30% or so, it may be of immense help. Well, I agree with you. All right. Well, this concludes the session. I want to thank the speakers and the audience.

hepatitis C treatment

integrated care centers

harm reduction services

iron overload and MRE

statins in liver disease management

cirrhotic patients

splenic artery embolization