today with three experts on the field of extrahepatic manifestations of hepatitis C, infection beyond the liver. Among, in a way, 71 million people worldwide are chronically infected with the hepatitis C virus, which accounts for about 400,000 deaths per year. The majority of those deaths are from cirrhosis and consequent manifestations of end-stage liver disease, as well as primary liver cancer or hepatocellular carcinoma. But some of the deaths are related to the often underappreciated extrahepatic manifestations, and many of those are immune-related or inflammatory-related events linked to hepatitis C, and it occurs in a large number of hepatitis C infections. Seventy-five percent or so have these extrahepatic manifestations. This classic paper now, some years old, is the REVEAL study. It's a prospective cohort study of approximately 24,000 adults in Taiwan, 1,000-plus hepatitis C antibody-positive, and two-thirds are more veremic. So looking at three groups, those who have no antibody to hepatitis C, those who are veremic in the blue with antibody, and of course, veremia, and those in the middle in the red, the folks that are antibody-positive but no detectable virus, with the presumption that the vast majority of these cleared the virus spontaneously, which we see in 15 to 40 percent of folks that are able to clear it. So important here is that hepatic disease, the mortality cumulatively over approximately 16 years of follow-up, that was the median follow-up, 13 percent died from strictly hepatic-related disease. But surprisingly, also in the veremic patients, blue on the right as well, almost 20 percent had a mortality strictly from the extrahepatic manifestations, and in multivariate analysis, the hazard of dying from extrahepatic disease was nearly one-and-a-half times that of patients that did not have hepatitis C veremia, and notice that those who had cleared the virus spontaneously were much closer to the numbers of those who had never had a hepatitis C exposure, which is reassuring to tell our patients that are able to clear it that their risk of dying is no different from patients who never were exposed. What's reassuring is, despite the increased mortality, and curing the patients with direct acting agents improves not only the liver-related mortality, but the overall mortality as well, and this really suggests that the effects on extrahepatic manifestations are important. This was referred to in a previous webinar, this largest prospective study of patients in over 30 liver centers in France, nearly 10,000 patients, 31 percent of whom had cirrhosis followed for a median of almost three years, curate, no surprise with antiviral therapy now we're always exceeding 90 percent, sometimes 95, and in multivariate analysis, the exposure to the DAs was associated with a decrease in not only liver-related deaths, but all caused mortality by about 52 percent, so showing that it wasn't just liver that's improving their outcome and lifespan is the extrahepatic effects as well. So with that introduction, I want to give you an outline of what we're going to cover in the next hour or so. We've broken this down into renal and rheumatologic, Dr. Molnar will cover that first section, followed by Dr. Negro who will discuss the endocrinologic and cardiologic manifestations, followed by Dr. Torres' presentation on neoplastic and neuropsychiatric manifestations, and we should have some time for questions at the end, but feel free to type in your questions in the written question box and we'll try to answer those perhaps during the lecture themselves, or of course after. So in the way of introduction, I want to tell you about Dr. Molnar, again very excited, all these gentlemen are extremely well qualified to speak, and his outline is as above, but the renal and rheumatologic manifestations will be his task today. Dr. Molnar is a Hungarian-American transplant nephrologist and an Associate Professor of Medicine at the University of Tennessee Health Science Center in Memphis, Tennessee. Dr. Molnar serves as Director of AST Transplant Nephrology Program at James D. Eason Transplant Institute in Methodist University Hospital, and he'll be presenting our first section on the renal and rheumatologic manifestations of chronic hepatitis C. Welcome, Dr. Molnar. Thank you so much, Brian, and welcome everyone. In the next 15-70 minutes, I would like to show some exciting data and some basic data about renal and rheumatologic manifestations of hepatitis C. This is my disclosure, I serve as an advisory board member in two companies producing DAA. This is the overview of the renal manifestation I want to discuss today. We're going to start focusing on glomerular diseases and then focusing hepatitis C virus infection effects of renal function, then shortly discuss renal disease manifestation of hep C liver transplant recipients, and finally I'll show you as a renal part some exciting data about new data about field of hepatitis C in renal transplantation. Let's start with glomerular nephritis. There is at least three different pathomechanism how hepatitis C, chronic hepatitis C infection can cause glomerular disease. The most commonly seen and well-known, the type 2 mixed cryoglobulinemia, which is an IgM monoclonal and IgG polyclonal antibody production secondary to hepatitis C, which can cause immune complex disease, so-called type 1 membrane plurifactive glomerular nephritis. This is what we most commonly see in the clinical presentation of type 1 MPGN is basically hematuria, non-nephrotic range proteinuria, sometimes can be nephrotic range, and renal impairment. As you will see in the next few slides, the pathophysiological presentation is subendothelial mesengyl immune complex deposition. This is what is well-known and we were taught in med school about this, so this is the most commonly seen GN, which is associated with hepatitis C infections. But there is at least two other mechanisms how GN can develop in hepatitis C infected patients. One of them is direct antigen and antibody immune complex disease, other than cryoglobulinemia, which can cause again immune complex deposition disease, which can present as a type 1 MPGN similarly to cryoglobulinemia, but can present as polyarteritis nodosa or membranous nephropathy with a clinical presentation typically nephrotic range proteinuria and renal impairment, secondary to acute tubular necrosis, and can cause also IgA nephropathy with clinical presentation typically microscopic, sometimes macroscopic hematuria and renal impairment. And there is a third mechanism how hepatitis C infection can cause GN, that's basically a direct tissue infection and the response to the direct tissue infection with a healing process and that can cause a secondary focal segment agglomerulosclerosis, which is typically present as a nephrotic range proteinuria. So we have at least three different pathophysiological mechanisms how hepatitis C can cause different glomerulonephritis. Let's talk about a little bit more common mixed cryoglobulinemia syndrome. It's typically a systemic vasculitis, non-specific symptoms, palpable pubera, arterialgia, fever, renal disease, and neuropathy. It can present as hematuria and proteinuria, which is typically non-nephrotic range, but can be nephrotic range proteinuria and renal impairment. The laboratory presentation is very typical with a low complement level, typically C4 is lower than C3, low C1q, and again type 2 mixed cryoglobulinemia, meaning polyglonal immunoglobulin G and monoclonal immunoglobulin M. And most typically it's a rheumatoid factor, which is a direct monoclonal immunoglobulin M directed against the FC proportion of the IgG. There are at least two different clinical outcomes of these patients. Typically after like 10, 15 years, one third, half of the patients regarded as they have C type 3 mixed cryoglobulinemia, which is a polyclonal IgG and IgM cryoglobulinemia, which really carries minimal risk of GM. But after a little bit longer time, 15 years, 10% of the subgroup can develop type 2 mixed cryoglobulinemia, which can cause the discussed GM. There is 6% of the patients who are developing B-sulinforma, that's going to be discussed in more detail by Dr. Torres in this webinar. The classical medical school teaching is if you treat the underlying disease with a direct active antiviral agent, plasmid chain steroid and rituximab, then the GM is going to improve as well. Although this is not always the case and I'm just supporting this statement, I would like to show here in KI reports. This is a biopsy proven refractory mixed cryoglobulinemia, opposite cryoglobulinemia MPGN. Again, this is a biopsy proven MPGN, which basically remained even after a sustained biological response. Even after treatment of hepatitis C infection, we see these changes. You see in the panel A, this is a typical picture of MPGN showing endopatternal injury with endocapillary hypercellularity, which is caused by monocytes. You can see in panel B, with the past positive pseudothrombi, again, this is the main cause of the renal impairment. You see a full-blown picture of immunofluorescence in panel C and D with IgG and IgM, as well as kappa, lambda, 3, 3 and C1q positive immunofluorescence picture. In panel E, you can see the ill-defined microtubules, which is again very typical with hep C as associated with MPGN. But the interesting thing in this case, this patient has been cured for hep C, but has several relapse with MPGN even after the hep C has been treated. So the take-home message is even with hep C treatment, MPGN and other GN can relapse in these patients. The other glomerulonephritis we discussed shortly, which we can see not as frequently as MPGN, is basically membranous GN. There is conflicting results about this, but 5% of the hep C positive patient had, actually sorry, 5% of the membranous GN patient has hep C. The other glomerulonephritis can be polyarteritis nodosa, which is typically associated with hepatitis B, but again 19 patients of the positive patient has infection or co-infection of hepatitis C. IG is more commonly seen in advanced end-stage liver disease patients, which can improve after liver transplantation. And as we discussed earlier, the secondary FSGS can be seen secondary to direct tissue invasion. After we shortly discussed glomerulonephritis diseases, I would like to show you some data how the hep C infection itself can cause renal dysfunction. This is our data published five years ago in Hepatology showing 1 million veteran results. That's 1 million VEA cohort with approximately 100,000 antibody and or RNA positive hep C patients. And we focused on different outcomes, including estimated GFR is less than 60 at least twice, or CKD, ESRD, mortality, or combined of those, or the slope of the GFR function, the estimated GFR and defined as a rapid CKD progress defined as the slopes is more than five milliliter per minute per year kidney function loss. And we did several models, but the model five is basically adjusted for important confounders. And as you can see in this slide, approximately 5% higher risk was in developing new onset CKD in hep C positive patient compared to negatives. The risk was doubled for ESRD and even with rapid CKD progress was seen 50% higher in patient who had hepatitis C versus those who doesn't have the infection. That was one of the epidemiological evidence that hep C itself can cause renal function and faster renal function loss. Obviously, the next question would be, if you're going to treat hep C, how it's going to affect the renal function. As of today, there is no published data in general population, although there is one paper in press right now, but here I want to show how it can affect the treatment in liver transplant recipients kidney function. Here we compared more than 200 liver transplant recipients who received the DAA treatment and those who didn't receive the cure. And we compared this patient renal function loss over time. And as you can see in the black line showing the GFR slope in patients who did not achieve SVR versus those who achieved treatment with the dotted line. And if you compare these two group GFR loss, the patient who has been cured lost their GFR approximately 0.89 per milliliter per minute per year, which is basically a healthy GFR function loss with aging versus those who didn't receive cure lost their kidney function almost three milliliter per minute per year, which is a pretty fast GFR loss. Hepatitis C infection can cause faster CKD and functional loss in treatment categories. Words about how Hep C infection can affect liver transplant recipients. This is a study done by UAAB for a while back, a case series including 30 patients who got kidney biopsy during the liver engraftment. This is a very unique study because of the biopsy results. And the result was surprising, at least for me, because 25 of the 30 patients, the majority of them had some kind of immune complex or nephritis found in the kidney biopsies. Majority of those as expected was type 1 MPGN, but 7 patients was seen IgA nephropathy and 6 patients found to have mesengial immune complex deposition. Please note that 10 patients of these had completely normal workup, classic clinical workup with normal serum creatinine, normal UA, and no quantitative proteinuria. And the long-term follow-up is questionable, but short-term follow-up showed IgA party resolution, MPGN also improved, but there was some relapse with Hep C as well as MPGN. A few, really few words about renal transplantation. This is the field which is changing fast right now regarding hepatitis C. So before the DAA era, before the new treatment era, it was well known, this is national data before 2014, the patient who received hepatitis C antibody or infected kidneys had worse kidney graft and patient survival. As you see in this slide, there was very early differentiation in graft survival and patient survival, and that remained the same over the years. So that was some concerning data, but this has completely changed with the new available regimen, and there was two feasibility trials, I'll just focus on form one, which was done at UPenn when they transplanted Hep C-infected patients to uninfected recipients and started the antiviral treatment and post-op day three. All of these 20 patients from this study achieved SVR12, and here I'll show you the graft function or kidney graft function of these patients comparing to those from the national comparison who received hepatitis C negative kidney transplantation. And as you see, this patient with the early treatment and successful treatment had very similar outcome at six months and one year after transplantation. So with early treatment, these patients who received hepatitis C-infected kidney behaved exactly the same who received hepatitis C negative kidneys, at least from kidney graft function standpoint. But that was a feasibility trial, basically sponsored by the drug company. So there was a question whether it can be done as a standard of care, and our center is doing this as a standard of care, transplanting hepatitis C-infected kidneys to uninfected recipients. And these are our results from the first 50 transplantation like this. And as you can see, we have excellent GFR outcome. This is on the funnel B, you can see the different time points in GFR after transplantation, the start of treatment, and then the point of SVR12. So our graft function was very similar to the national data for the previous trials. And all of our patients as of today, which is more than 90, is under treatment or already achieved SVR12. We didn't have any treatment failure at this point. So this is a new opportunity to expand the donor pool in kidney transplantation. Few words about rheumatological manifestations. We already discussed the mixed glioblastoma syndrome in the renal section. I just want to talk about a little bit with Sjogren's syndrome, Zika syndrome, and other arthritis which can be associated with hepatitis C infection. So the hep C-related Sjogren's syndrome is pretty common. More than half of the hep C-infected patients who refer to liver biopsy have symptoms of Zika syndrome. Older age, higher metabolism score is associated with worse symptoms. The pathophysiology behind this chronic lymphocytic sclerodonitis in this patient, very typical presentation with potential rheumatoid factor positivity, but anti-CCP activity will not complement. But the difference between Sjogren's syndrome, primary Sjogren's syndrome, and hep C-related population, usually the anti-SSA and SSB antibody cannot be found in this patient. There is a clear association with HLA-BQB1, and usually the treatment of hep C improves the symptoms. Finally, a few words in other arthritis which is associated with hep C. These are often non-erosive oligoarthritis. Again, very similar finding in lab than in Zika syndrome. This is less aggressive than classic RA and can be life-threatening side effects of the disease-modifying agents. So you have to always follow this patient closely. There are some questionable associations with different rheumatoid diseases like osteoporosis, myalgia, fibromyalgia, polio, dermatomyositis, Basel syndrome, lupus, or antiphospholipid syndrome. These are data basically based on mainly case reports. Thank you so much for your attention, and I'll try to answer the questions. Okay. Thank you, Miklas. That was great. And now the second of the three topics will be presented by Dr. Francisco Negro as professor at the Department of Medicine and or Pathology and Immunology of the University Hospitals of Geneva, Switzerland. He obtained his medical degree in 1982 at the University of Torino, Italy, where he also completed his postgraduate education in gastroenterology. He was a visiting scientist and then assistant professor at Georgetown University School of Medicine in Maryland from 1986 to 1989 and guest researcher at the Laboratory of Infectious Diseases at the NIH in Bethesda, Maryland. Dr. Negro will be presenting the endocrinologic and cardiologic manifestations of chronic hepatitis C. Welcome, Dr. Negro. Thank you, Brian. And I want to thank ASLD for giving me the honor of presenting this brief seminar about the endocrinologic and cardiologic manifestations of hepatitis C. And thank also all the people who are attending today this webinar. Disclosures. The outline of my talk, I will just give a very brief introduction, generalities about streptocytic manifestations beyond of what has been said already at the beginning. And I will discuss then the link between HCV and diabetes and finally cardiovascular disorders. The generalities I want to mention are very simply, first of all, you must keep in mind that the pathogenesis of streptocytic manifestations in HCV infections are multi-faceted. Of course, nobody's going to give a talk about the very dysfunction leading to portosystemic encephalopathy. That's not the topic of today. As been mentioned already, there is a direct infection of non-hepatocytes, which has been proven in very few cases to tell you the truth. But what is very important is that you do not need to have direct infection of non-hepatocytes to account for streptocytic manifestations. This may be easily be explained by either abnormal immune reactions or by secretion of substances with endocrine effects by the infected hepatocytes. And we'll come back to this point when we discuss diabetes. The second point I want you to remember is that these manifestations may or may not respond to antivirals. In some patients in very advanced disease, either liver disease or extrepathic disease, the disease has reached a so-called point of no return. So it's quite unlikely that even achieving SVR, you will revert to a normal state functionally and anatomically. And the last point, which is very important, when we're talking about diabetes and cardiovascular manifestations, is that these manifestations may coexist with comorbidities, which are not due to the virus, but nonetheless, they lead to the same or similar clinical picture. It's very important to keep that in mind, just to understand that a reversion to normal state may not be achieved in all patients due to just these coexisting comorbidities, which have nothing to do with the viral infection. So let's talk about, first of all, diabetes. The association has been noticed since the very beginning, since a few years after the virus was discovered. I just will mention just a few landmark studies. There are some cross-sectional analysis, some are clinic-based, but probably the most important ones are population-based. And I chose the DNA in three surveys, which everybody knows probably in this webinar. It was run in the United States. In this first survey, from 88 to 94, included about 1,000 patients. And these investigators from Johns Hopkins show very nicely that patients, or let's put it that way, persons followed during this survey, in age older than 40, had a higher risk of presenting with diabetes, if they, at the same time, have a hepatitis infection. And you see also the adjusted odds ratio for diabetes was about four times higher after adjusting for body mass index, age, sex, race, and family history of diabetes, suggesting that the virus had something to do with the pathogenic diabetes beyond the common risk factors. There are also several longitudinal studies, and I picked this one from the Reveal cohort, which has already been mentioned before. You see here about 17,000 di-HCV patients who were not infected. About 1,000 infected. They followed on a median period of time of 11 years. And you see that the incidence increases with time for presenting diabetes. So incidence of diabetes is increasing over time, incomes after infection. This is also very important to mention this point. The adjusted hazard ratio was about 1.50, which means a 50% increased risk of developing diabetes. And these investigators also adjusted for a proxy of liver inflammation. And the liver inflammation showed that it contributed partially to the diabetes incidence, but not completely. In other ways, the virus is directly involved in the pathogenesis without going through the step of inflammation. Clearly, many studies have also approached the issue of correlation with the biological parameters. It's never been very easy to show a direct relationship with the viremia. It's very difficult, even though there is some rough data correlating that. And also I want to mention that the association with HCV genotypes was not confirmed after a few studies initially mentioned that, suggested that probably genotype one were more insulin-resistant than the other one, especially three. But more recent work has shown there is no difference in terms of insulin resistance and diabetes according to viral genotypes, especially a very important large study from Greece published by Manolis Taxis about 10 years ago. When you carefully select patients with hepatitis C and insulin resistance without other risk factors, and you apply a direct antiviral, this pilot study by the Boisson Group in Paris, it was Danopervir, it was one of the early protease inhibitor, you will see that when you inhibit the viral replication, you also will witness a decrease in HOMA-IR, which is a score of insulin resistance. This occurs in patients who do not respond, no response virologically, will be no response in terms of insulin resistance. A good response will parallel a response in insulin resistance, and those patients who relapse will also have HOMA-IR score going up again. So there is a good relationship between viral replication and insulin resistance level as measured by HOMA-IR score. However, the most counterintuitive discovery which was done in terms of relationship between hepatitis C and diabetes was by two groups I am mentioning here. One of them are from Sydney, led by Jacob George and Kelly D. Miller. They show with the hyperinsulinemic and homoglycemic a clamp that when the insulin, sorry, the endogenous glucose production was suppressing low-dose insulin, high-dose insulin at two steps of a clamp, they showed that especially with the high-dose insulin, which actually implies a complete suppression of endogenous glucose production, the glucose extraction from the plasma was not the same in control versus hepatitis C patients. In fact, they had to infuse less glucose in patients infected with hepatitis C virus, suggesting that the extraction, which is essentially carried out by the extrepathic organs was less pronounced. This implies a very counterintuitive fact, as I said before, that insulin-resistant hepatitis C is mostly extrepathic in origin. In other words, it's not the liver, at least it's not only the liver, but it's essentially extrepathic organs. And we all know that extrepathic extraction of glucose is essentially done by muscle and to a lesser extent by adipose tissues. There is also a second study, which was done by my group. When you apply an antiviral treatment to patients who have no other reasons for being insulin-resistant, they are normal glycemic and they are not obese. In this case, we have a patient with Genotype 3. When you apply an interferon-free treatment, you will correct essentially the extrepathic insulin resistance, which was shown in the right-hand panel here, showing that the high insulin clamp phase of the clamp proved that the improvement of insulin resistance is essentially in the extrepathic section. So this leads us to pathogenesis, a potential pathogenesis of insulin resistance in patients with hepatitis C, which may, of course, involve partially insulin resistance due to the liver infection directly, but also, in fact, the hepatocytes may secrete substances. We don't know which ones, so we are trying to identify those hepatocytes, which may act at the periphery, in the endocrine level, especially upon the skeletal muscle and the tip of tissue, influencing the rate of glucose uptake of these organs. So there is extrepathic origin of insulin-resistant hepatitis C. So what happens when you cure these patients? We have seen that there is a parallel decrease in insulin-resistant state when you apply antivirals. What is very important, however, even if you cure hepatitis C, you will reduce the risk of incident type 2 diabetes, and the rate of incidence is reduced by about two-thirds. This is a very large study for a single hospital in Tokyo, published many years ago, showing that patients with SVR and threat of interferon-based regimens, those who reach SVR had a lesser degree of diabetes incidence, irrespective of other factors of diabetes, namely age, older than 50, cirrhosis, and prediabetes before treatment. Also in the era of direct-acting antivirals, it's been shown that you may revert insulin resistance, but it's also very interesting what happens in those patients who have hepatitis C and diabetes. It's important for the management, the practical management of these patients. This study from Egypt showed that the glycated hemoglobin was partially corrected in those who actually responded to treatment. What is very important to know is that there are increasing reports that you may even induce a kind of hypoglycemic state in patients with diabetes during hepatitis C treatment. It is important to mention that because you may have to adjust antidiabetic level of drugs in patients receiving antivirals because you may otherwise induce hypoglycemia due to the fact you are correcting very rapidly the insulin resistance state. Clearly, if you reduce the incidence of diabetes, it will also reduce the incidence of diabetes complications as is very important to mention. The checks cohort are shown in a very elegant way. You see here that after follow-up in groups who were balanced by the way after propensity score waiting for many factors, including factors of diabetes, the incidence of acute coronary syndrome and stage of kidney disease and ischemic stroke were all significantly reduced in patients who responded to treatment. So curing hepatitis C will result in a lesser incidence of diabetes over follow-up and also a lesser incidence of diabetes complications though already have diabetes on the stage. Let's talk now about cardiovascular mortality. The first observation was done in blood donors and it was a very important study by Guiltyman Diabetes in the United States. There is retrospective U.S. cohort study. You see that about 10,000 patients with hepatitis C were matched for Asian sex with hepatitis C negative blood donors and followed about eight years. You see the survival probability in terms of cardiovascular mortality was significantly reduced in those who were not infected. So in other words, the fact of being infected with hepatitis C resulted in increased mortality for cardiovascular diseases. And these data were subsequently also confirmed by the meta-analysis done by Salvatore Petta a group from Palermo, Italy published four years ago in gastroenterology. You see again the study by Guiltyman, the review cohort and the study from Sydney involving OST treated patients. And the odds ratio for the total meta-analysis at 1.65 showing that in other words, those who have hepatitis C have a 65% increased probability of dying of cardiovascular causes. It is important to mention that these increase in cardiovascular mortality is counterintuitive again because some classical risk factor for cardiovascular disorders are absent in hepatitis C infection. And especially referring to lipid profiles. Patients with hepatitis C are known for having total cholesterolemia, LDL cholesterolemia and triglyceridemia lower than those who are never infected or who have past infection controls which is shown by several studies. There are also studies showing that and the first one was a theory when I was showing that 20 years ago in the registration trial for pigmented interferon. But if you cure these patients cholesterol and LDL cholesterol may go up again. Luckily enough, this correction of the lipid profile does not result in an increased mortality for cardiovascular disorders. What is the pathogenesis? We don't really know. There is some unconfirmed studies showing that the hepatitis C virus may directly infect the arterial wall. Again, this was never confirmed. If there is only one study, some other studies showing that the cardiac function, myocardial function may correlate with the viral load. But the primary pathogenesis is probably due to the endothelial damage. This was suggested first of all via anti-endothelial antibodies. But the more recent data suggests that some marker endothelial activation may be elevated in hepatitis C but due to direct secretion either by the infected hepatocytes or by the chronic inflammation associated with the chronic hepatitis C. So there is a chronic endothelial damage, low level which may in turn lead to atherosclerosis. Clearly among the pathogenetic factors, we cannot forget that not only the direct infection of the arterial wall and endothelial damage mediated by activation factors are involved but also clearly also the diabetes accompanying the hepatitis C infection may contribute to these cardiac events. So we can come to the last few slides. What is the effect of antiviral treatment on cardiovascular outcomes? This is a Taiwan National Health Insurance Research Database is a huge database collecting thousands and thousands of patients. They were treated in this case with the pegylated different alpha-ribavirin compared to untreated controls. Which were matched by propagation discourse in the length of follow-up. It is quite clear that the cumulative incidence of acute coronary events and the cumulative incidence of ischemic stroke were reduced by the successful treatment. So curing hepatitis C will result in a lesser incidence of cardiovascular events. And there is also a serious prospective cohort study done in France is a very important serotic patient cohort showing that there is a significant reduction in cardiovascular events after eradication of ACV partially with interferon-based and partially with DAA-based treatment. You see here the data showing how this incidence was reduced by successful treatment. So I would like to conclude this simple seminar with my take-home messages. I hope I convinced you that chronic ACV infections is associated with an increased risk of developing type 2 diabetes via both hepatic but mostly extrepathic insulin resistance. There is a good data showing that chronic ACV infection increases cardiovascular mobility and mortality. But luckily that treatment-induced viral clearance reduces the risk of both insulin diabetes and cardiovascular disorders. And I want to thank you for all the attention and questions you may want to ask. Thank you so much, Dr. Negra. That was great. And the third, and finally, Dr. Torres, who will be presenting the neoplastic and neuropsychiatric manifestations of hepatitis. Dr. Harry Torres is Associate Professor of Medicine in the Department of Infectious Diseases and an Adjunct Associate Professor at the Department of Gastroenterology, Hepatology and Nutrition at the University of Texas MD Anderson Cancer Center in Houston. He is board certified in internal medicine and infectious disease with additional accreditations on HIV, AIDS, and tropical medicine. He is founder and director of the Hepatitis C Virus Clinic at MD Anderson, the first established clinic in the United States and likely in the world devoted to managing hepatitis C in cancer patients. And welcome, Dr. Torres. Thank you, everyone. Thank you for inviting me to speak today. I would like to thank ASLD and the Hepatitis C Special Interest Group for hosting today's event. I'm delighted to be here and actually give the opportunity to speak to all of you about this important issue of neoplastic and neuropsychiatric manifestations of hepatitis C. These are my disclosures. And I'm going to start by talking about the neoplastic manifestations of hep C. First, mentioning which are the most common cancers associated with hepatitis C. We know that there are three that are traditionally associated with hepatitis C. The first one is hepatocellular carcinoma, as we all know. Then the extra hepatic bile duct cancer. And then the B-cell lymphoma. Those are the top three ones that have been proven to be associated with hepatitis C in multiple studies. Now, more recently, we have data about head and neck cancer and also pancreatic cancer. In terms of the extra hepatic cancer, so the most common one is non-Hodgkin lymphoma. There is multiple studies has been reported on that. The first one in 1949, to give you an idea of how long this has been going on, on this association. And the relative risk on hepatitis C and non-Hodgkin lymphoma is around 2.5. It's associated with multiple types of lymphomas, B-cell lymphomas mostly. It's a diffuse large B-cell lymphoma, which is the most aggressive non-Hodgkin lymphoma, but also with some indolent lymphomas, like a marginal zone lymphoma and lymphoplasmositic lymphoma. The risk of developing lymphoma is 60% higher on patients who have hepatitis C compared to those without hepatitis C used as control. I also want to mention a recent association reported initially by us here in the U.S., but now being validated in Brazil and also in Europe, as well as Taiwan, which is the association between hepatitis C and head and neck cancer. It was an interesting observation because we have a clinic here for patients with any type of cancer and hepatitis C, and we're starting to see patients coming with, as expected, with liver cancer and non-Hodgkin lymphoma, but then we start seeing all these patients with head and neck cancer coming to the clinic. We decided to study this formally, and we found that association. We identified specifically that hepatitis C is associated with non-oropharyngeal cancers, particularly the nasopharyngeal cancer, but also with HPV-positive oropharyngeal head and neck cancers. The prevalence of hepatitis C in patients with cancer is similar to what we see in the community between 1.5 and 2.4 percent of all cancer patients, so it's maybe a little bit higher on those who have lymphoma and particularly higher on those who have solid tumors. This 10 percent is in patients with head and neck cancer. In Europe, it has been reported between 1.5 and 30 percent. Really depends on the type of the study and the design they use, but what is important to know is if you're practicing in a cancer center or any other institution where you see cancer patients, it's expected that you're going to see the most common type of hepatitis-infected patients having liver cancer. That is expected, but as you can see here, patients may have any type of cancer from either head and neck cancer, lung cancer, prostate, or any type of malignancy. That's why we're doing at MD Anderson, we're screening all patients with cancer coming to our institution, and actually that is the current recommendation of ASCO as well, which is screen all cancer patients for hepatitis C. In terms of how hepatitis C can affect hematopoietic stem cell transplant or bone marrow transplant patients, this is a prospective study from France, and what they decided to do was to compare patients who have bone marrow transplant with hepatitis C and hepatitis C without transplant. And what they found here, as you can see, very, very interesting finding is patients who have transplant and hepatitis C, they progress to cirrhosis in about 18 years compared to 40 years for those who have only hepatitis C without transplant. So when you add hepatitis C to immunosuppression, the patient's going to progress faster to cirrhosis, and we have seen that not only on bone marrow transplant, we have seen that on HIV patients as well as a patient with cancer without transplant. How can we help these patients? Well, the oncologic benefits of antiviral therapy are multiple. As you can see here, the antiviral therapy reduced the risk by 75 percent, 70 to 75 percent according to the most recent data, in patients who have hepatitis C-related cirrhosis. But we're talking about extrapathic manifestation, so what other benefits we have. So we have then that the vital elimination can reduce the incidence of lymphoma, and not only the incidence. I'm going to show you in a few slides for now how we can cure selected lymphomas by simply using direct antivitals. Also patients who have hepatitis C associated lymphoma who receive antiviral therapy have fewer cancer relapses post-transplant compared to those who did not receive treatment. And one of the most important points from our oncologists are that we can open access to clinical trials, cancer clinical trials when we treat hepatitis C. And also we can improve the survival and disease-free survival of these patients. What you see here is a study that was published in New England. And the reason why it was published in New England a few years ago is because this is the most common indolent lymphoma we can see, which is a follicular lymphoma. This is a patient from London who received direct antivitals only. That's all they did on this patient. The patient have cancer and hepatitis C. What they decided to do is treat the patient without interferon, but with DAAs only. And as you can see here, you have on the left-hand side how the patient, the PET scan of the patient, how all the lymph nodes were there. And then after the patient received treatment, the patient have a genotype 2, and he received treatment appropriate for that. And after that, you can see how the lymphoma improved, actually the lymphoma resolved on this patient. And that is actually what we have seen on several type of indolent lymphomas up to the point that is now on the guidelines from Cancer Care. This is the NCCN guidelines on how to treat this specific type of lymphoma, which is a marginal zone lymphoma. And as you can see here in red, if the patient have hepatitis C, what is recommended by oncologists now is check the patient have hepatitis C, call Hepatologist, your ID, whoever is treating hep C in your center, and if there is no contraindication for treatment, then treat the patient for hepatitis C first. And give the appropriate therapy and see the patient achieve complete remission or partial remission. If not, then the patient will go in the route of receiving cancer care as needed for this particular cancer. But as you can see here, so for this specific type of cancer, it's recommended to go first with hepatitis C treatment. And that's exactly what we see here in the Anderson for most patients who have indolent lymphoma. We also have the other type of lymphoma I mentioned before, the diffuse large B cell lymphoma is the most aggressive ones. So on this type of lymphoma, we cannot wait for the patient to receive DAAs for two to three months. The patient have to receive cancer treatment quickly, otherwise the patient is going to die. Then this is a group of patients with very aggressive cancer and what we decided to do is look at what's happened when we treat this patient with hepatitis C treatment. This patient received either interferon-containing or interferon-free regimen. And as you can see here on this graph, so the solid line is refers to patient who did not have hepatitis C. And you see this gray line here, very, very, very close to the other line with similar outcome. And these are the patients who have hepatitis C but receive treatment. Basically when you treat infected patients, you can achieve the same outcome that does without infection. And we're talking about patient with the DCL lymphoma. Also cases that never received antiviral treatment were more refractory to first-line chemotherapy compared to those who did not have the infection or did not receive treatment. And also those who have never received antiviral treatment have a more progressive lymphoma compared to those who received treatment. Overall, we can improve the survival of this patient and we can improve up to five times the survival of patient with diffuse large V cell lymphoma. That is the reason why these patients get treated at some point. Many times the cancer treatment will go first but we will treat these patients eventually to improve the oncologic, not only the hepatic and the virologic but also the oncologic outcome. I want to now comment about hepatitis C reactivation. We are very familiar with hepatitis B reactivation in cancer patients. But at this point I want to mention a few words about hepatitis C reactivation. Another chronic infection that can reactivate. This is a case of a patient who we have here at MD Anderson. This is a young gentleman who has a V cell lymphoma. Baseline we have an elevated ALT. We have a baseline vital log and the patient received condition and regimen with busulfan, melphalan and borinostat as well as gencytarin. As you can see here the vital log went up from 5.84 log to 7.97. More than two log variation of hepatitis C. We define hepatitis C reactivation on more than one log variation. So this patient have a two log variation. And as you can see at the same time the patient have a peak on the ALT. We wait. We watch this patient. No intervention. But then we have a second peak noted here on the ALT and the vital log remains persistently high. We were concerned that this patient was developing then fibrosis and cholestatic hepatitis and we decided to start to depend on this patient. And as you can see here see how the vital log and the ALT normalized on this patient in addition to having a cure cancer now. So this is a classic illustration of hepatitis C reactivation. How often we see this. You can see here on this paper published a few years back on how often we see and it's almost 25%, 23% to be more specific. We see hepatitis C reactivation. Again define a one log variation on the vital log accompanied by ALT elevation which is not always the case but simply having a change on the one log by anemia that defines hepatitis C reactivation. 23% of the cases you will see that most frequently on patients with hematology compared to solid tumor patients. What does this mean from clinical practice? So well we have that when the patient has hepatitis C reactivation they may also have flare of hepatitis. Define a three log elevation on the hepatitis C from baseline. 43% of the patients may have hepatitis flare compared to those without hepatitis C reactivation which is very important for oncologists because in reality when we talk to our colleagues of treating cancer patients one of the most important issues, how this treatment or how the hepatitis will affect my cancer care on this patient and this is extremely important for them. This continuation of cancer treatment have to happen in 26% of the patients. So this is very significant for the oncologist because they cannot use first line chemo. They have to go with alternative and that may affect the cancer outcome at the end. What is very different from hepatitis B reactivation is we don't see liver failure and we rarely see any death related to hepatitis C reactivation. We haven't seen any at MD Anderson by the way. There is only one case report in the literature but no one else has been able to replicate that. So the outcome of hepatitis C reactivation is not the same that hepatitis B reactivation. That's good. Then we'll talk about bone marrow transplant population. So we recently, well five years ago now, we published the guidelines of how to treat bone marrow transplant patient infected with hep C when they can go for bone marrow transplant. So it's out there already now for five years. So you can go and review the data. But in general what we recommend is the patient will go for transplant and after transplant is when we treat the hepatitis C. That's overall what we do. How do we treat this patient with cancer and hepatitis C? This is a recent paper that we published last year. So first we are containing regimens and we can do this with any other agent commercially available. So we treat this patient with the same drugs we use to treat patients without cancer. And as you can see here the response rate was around 91%. So it's very similar response rate to what we see on patient without cancer. And obviously the response rate is better in some populations and some groups compared to others. Serotics have a lower response rate compared to non-serotic patients but overall 91% response rate. One of the most important points from our oncologists is how can we help them? And one way that we can help them is by simply treating the hepatitis C. This is a paper that we published recently where we demonstrate after looking on 6,000 clinical trials registered on clinicaltrials.gov that 58%, 58% of the patients on clinical trials they are considered for clinical trials from cancer care. They are excluded if they do have hepatitis C. And we all know hepatitis C is curable so we simply recommend to treat these patients and eliminate hepatitis C as an exclusion criterion and these patients can move on and receive cancer care. That is one thing that we're helping our patients here. And in general what we recommend is stratify the patient according to what type of cancer treatment they are receiving. Are they receiving short-term cancer treatment? If that is the case cancer treatment will go first and we'll treat hep C later. Is the patient receiving maintenance chemotherapy or long-term cancer treatment? Then we try to treat these patients simultaneously with cancer treatment and DAAs. Or is the patient going for a clinical trial or eligible for a clinical trial? Those are the ones who we will treat as fast as we can to make them eligible for cancer clinical trial. It's a very difficult conversation to have with these patients when they are coming for cancer care and you have to tell them no we cannot treat you because you have hep C. That's really not acceptable anymore. Let's treat the hepatitis C and make them eligible for what they need. In terms of neuropsychiatric manifestation for hep C, so I'm going to focus only on one of those which is the most common one, the most prevalent extrepathic manifestation is depression. We have seen it has been reported on 24% of patients with hep C compared to 17% of those without hep C. Patients who have hepatitis C have two times greater chances of developing depression compared to those without hep C and it's associated with a significant cost worldwide. In summary, what we know is that hepatitis C is associated with extrepathic manifestation, neuropsychiatric, and also neoplastic manifestation. Some of these manifestations are associated with worse outcome and increased mortality, but if we treat the hepatitis C, we can improve the outcome. We can reverse those outcomes. DAA's regimens are preferred to be safe on patients with cancer and it should not be an absolute contraindication. You have a patient with hep C, that should not be a contraindication for cancer treatment and bone marrow transplant, and depression is the most prevalent extrepathic manifestation. Once again, thank you and I'm open for questions. Excellent, thank you Dr. Torres. So I'd like to ask you specifically, Dr. Torres, there was a question I'm not sure it was answered on the boxes. What are the genetic underpinnings of the malignancies? And then the second part is my own about if you could clarify the HPV issue on the oral pharyngeal cancers, is that a co-virus or co-infection in those cases or you were saying that's excluding the HPV related cancers? I'm going to start with the second one. The association was particularly strong when the patient had HPV positive oral pharyngeal cancer. Is there a synergism here between these two chronic viral infections? We don't know, but that's what we found in the association. In terms of the first question, well there are multiple papers trying to associate, trying to find out why these patients develop cancer. And I can tell there are multiple explanations for that. One is a persistent and chronic inflammatory stage of patient with chronic infection and that may lead to lymphoma down the road, the upregulation of P53 as well. There are some other, but these are only hypothetical. We don't really have a clear explanation when this patient develops cancer. But what we do know is we improve the outcome when we treat the hepatitis C. That has been found in lymphoma. That also has been recently found by our group on head and neck cancers. So we can improve the oncologic outcomes of these patients. Great. Thank you. And this is a question for all the panelists and that is, is there one particular genotype of the worldwide major genotypes 1 through 6 that seems to be in your area more prevalent in those with extrahepatic manifestations? For example, is genotype 2 or genotype 3 more related or it really is completely random or just variable? From the cancer standpoint, there are studies from Italy showing that genotype 2 is the most commonly associated with lymphoma. What we have seen here at MD Anderson is genotype 1A and genotype 3 are associated with lymphoma. In reality, there is not consistent findings about that. Good. And also, Dr. Torres, is hepatitis C reactivation more common with any specific chemoregimen? And that would include, I would add there, biologics as well. Thank you for that question. I should have mentioned that. Yes. The number one agent is rituximab. It's anti-CD20, well known to cause hepatitis B reactivation. It can cause also hepatitis C reactivation. The second most common agent is agents in general say high-dose steroids. But again, we don't contraindicate treatment so we tell oncologists proceed with what you need to do and we can control this infection. Most of these patients receive cancer treatment with chronic active infection and we treat infection after the cancer therapy. Dr. Torres, one more question that relates to that. Just to absolutely clarify for our audience. The hepatitis C that you say reactivation, again, you defined it nicely by greater than one log increase. But how about for those that have been cured in the past, recently or in the remote past, that are then getting agents like rituximab? Is there any cases that you've seen from people who had aviremia to then develop chronic hepatitis C viremia after or as a result of these chemo or biologics? Fantastic question. We looked that up a few years ago and we look at patients with hematologic and solid tumors. They were cured of hepatitis with either interferon or DAA containing regimens. None of these patients relapse after receiving cancer treatment. So when they are cured, are cured. Good. Dr. Negro, a question for you regarding the diabetes. What should a practitioner do then if they have someone, say, who's a diabetic out of control and happens to be hepatitis C positive? Is there a real clinical correlate? Would you expect to see A1Cs drop as you mentioned or should obviously the sugars be controlled first? But do you think it's an important part of diabetes treatment then? I would suggest that patients with diabetes who receive antiviral treatment are frequently checked, but they already actually do it. So I mean this is not really adding any extra exam or management to those who have diabetes at baseline because they already are used to check their own blood glucose on a daily basis, on a frequent basis at least. I would just reinforce this rule because antiviral suppression of ACV may actually improve diabetes faster than expected and we have seen really patients with hypoglycemia symptoms during treatment with antivirals who had to correct the dose of drugs, especially insulin. Good. And Dr. Molnar, this question is for you please. Is there any reason then for those who are getting transplanted from the liver perspective to also concurrently do these renal biopsies and are these then subclinical infections or sorry, subclinical gonorrheal nephritides such as MPGN, is it important? What should we be doing in those cases given that interesting or provocative study from UAB? Yeah, thank you so much for this question. So I would not recommend like a general practice to do kidney biopsy, liver transplant for obvious reasons like high risk for bleeding reason, but I would suggest like basically following this patient if there is any like long-term indication of ongoing liver kidney disease then I would definitely go with renal biopsy. Don't forget that after liver transplantation one of the most common cause of that is basically renal dysfunction, so we should be pretty aggressive to diagnose these GNs or other underlining renal disease in liver transplant recipients. Sometimes in practical life the point, the problem is you can really not do kidney biopsies because it's still like high risk of bleeding, especially in the early post-transplant period, but if it's doable that would be great. Okay, and then I believe this will be the last question. Back to Dr. Torres, could you comment on the treatment on hepatitis C patients who also have concurrent hepatocellular carcinoma? Thank you. This is a complicated question, but let me try to summarize what is now recommended by ASLD and AGA. So what we typically do is we see if the patient can be there for a curative hepatocellular carcinoma, either resection or liver transplant or ablation. So if that is the case, so we treat the patient either before the transplant or after transplant, the trend is to treat this patient after the transplant or after the resection. Is the patient not eligible for a curative approach of the hepatocellular carcinoma? That is the situation where we simply wait, it's now recommended by ASLD and AGA, to wait at least six months for the cancer to be stable on cancer treatment before we move on and give DAAs to this patient, and that has to do with these articles that were published a few years back about DAAs inducing growth of hepatocellular carcinoma. Just because of that, it's recommended to wait at least six months on cancer therapy with a stable cancer before giving DAAs for patients with incurable hepatocellular carcinoma. To reiterate that there is no evidence that the direct acting antivirals increase the incidence of hepatocellular carcinomas post-treatment because that was a controversy for some time. Anything you want to amplify on that? Yes, I fully agree with you and there is no data to support that and that's why we're treating those patients. Great. Thank you. Okay, I think we've gone over time. I appreciate everyone, excellent presentations, great panel, and I hope we all got something out of this for our own practices and knowledge. Thank you again for attending. We appreciate it.

hepatitis C infection

extrahepatic manifestations

hepatocellular carcinoma

extrahepatic bile duct cancer

B-cell lymphoma

pancreatic cancer

renal function

glomerulonephritis

cardiovascular manifestations

depression