To kick things off, I'm delighted to introduce our first hepatitis debrief speaker, and that's Dr. Mark Ghani from NIDDK, the Liver Diseases Branch. Mark is a clinical tenure-track investigator at the Liver Diseases Branch, and as you all know, Mark has made many, many contributions to our understanding of both hepatitis B and hepatitis C infections, so it's difficult to imagine a more fitting person to serve this task. Mark has been co-chair of the ASLD IDSA HCV Guidance Panel and has been a principal investigator of the NIH Hepatitis B Research Network. So, Dr. Ghani, the podium is yours. Well, thank you, Ray, for that very kind introduction. I'd also like to thank the ASLD for the opportunity to present here. It's truly an honor, and before I start, I think I'd also like to extend a deep debt of gratitude to the presenters who kindly provided me with their slides and also apologies to those presenters whose work I could not present due to time limitations. So, why don't we get started? So, the abstracts that I've selected to present today will cover the following areas for hepatitis B, the natural history, novel therapies to achieve functional cure, prevention, co-infection with delta virus, and for hepatitis C, models of elimination, therapy focusing on unique and challenging populations, looking at the benefits of SVR, and finally, organ transplantation. So, I don't have to tell this audience that non-alcoholic fatty liver disease and hepatitis B are two of the most common liver conditions, so it's not unexpected that they would occur together. And this analysis looked at the influence of non-alcoholic fatty liver disease and whether it worsens underlying liver injury using liver biopsies from a large cohort of North American patients. And what you can see here is that in individuals with steatohepatitis, this was associated with more severe perisinusoidal fibrosis and perhaps this is not a surprising finding, but also the presence of steatohepatitis was associated with more advanced fibrosis using ISHAC fibrosis score compared to no steatosis or simple steatosis. And this was shown and confirmed on multivariate analysis. So, for our patients with hepatitis B, I think it's important to screen and manage metabolic abnormalities to prevent liver disease progression. So, we know that antiviral therapy is associated with a reduced mortality from all-cause mortality as well as HCC risk, but the question has arisen, is there a difference in HCC risk between tenofovir and entecovir? And this is because of data coming from Asia suggesting that tenofovir was associated with a lower risk of HCC compared to that of entecovir, but the issue is controversial. At this meeting, two large presentations were shown suggesting that this may not be the case. The first was from the French NRS cohort study and importantly, this study included patients of all races and ethnicities who received tenofovir or entecovir and were followed for a mean of four years. And what you can appreciate here is that at four years, there was no difference in the cumulative incidence of HCC in those treated with entecovir or tenofovir. And similar results were shown by another large European cohort, the PAGE-B. This cohort only included Caucasian patients, but again, showed similar results. At eight years, the cumulative incidence of HCC was not different between tenofovir and entecovir. So, I think these two large studies provide very robust data suggesting that there's no difference in HCC risk between tenofovir and entecovir and hopefully, we can put this issue to rest. So, for our virally suppressed patients, is there anything that we can do to further reduce their risk of hepatocellular carcinoma? And we know there's emerging therapy beginning to show that platelets may be important for carcinogenesis. And we certainly know there's epidemiologic data suggesting that antiplatelet therapy may reduce the risk of certain cancers, but there's limited data with hepatocellular carcinoma. So, this was a retrospective study looking, in new suppressed patients, looking at the incidence of cancer among patients receiving or not receiving antiplatelet therapy. And what you can see here is that among those patients receiving antiplatelet therapy, this was associated with an almost 20% reduction in HCC risk. And in addition, compared to aspirin monotherapy, those individuals receiving dual antiplatelet therapy had a 30% reduction in HCC risk. So, these are very provocative findings. Of course, they need to be confirmed, but if so, may open new avenues of HCC chemoprevention. So, turning to therapy, and the goal of therapy is evolving and changing from not just DNA suppression, but also to try to achieve functional cure. So, we have defined a surface antigen loss so that we might have finite therapy. So, to evaluate the durability of surface antigen loss as an endpoint, this was a retrospective analysis looking at patients who stopped or continued nucleoside analog therapy after surface antigen loss. And to look at the value of this endpoint, they looked at the incidence of surface antigen stereo reversion, shown in the left panel, and also the cumulative risk of HCC after stopping treatment. And what you can see is that there was no difference in the cumulative risk of S antigen stereo reversion. It was less than 10% in two groups, and also no difference in HCC development in those who stopped or continued therapy. So, these data show that surface antigen loss is a durable and safe endpoint for stopping treatment. Unfortunately, current therapy, the rate of S loss is low. So, are there any things that we can do to try to refine how we use these agents to increase the rate of S antigen loss? And in this study, investigators looked at either a switch or add-on approach to ongoing nucleoside analog therapy to try to increase the rate of S antigen loss compared to ongoing nucleoside analog therapy. And what you can see here in the right panel is that the groups that received treatment with the interferon, either add-on or switch, did indeed have increased rates of S antigen loss, seven to 10%. However, this is only a marginal over that achieved with either of the approved agents. And there was another study from a Canadian-European trial showing that similar results, about 9% rate of S antigen loss. So, I think these two studies suggest that there's a little benefit to add-on or sequential approach to induce S antigen loss. But as you can see here, the groups that received peg-interferon therapy did have suppression of a hepatitis B surface antigen. And this suggests that there may still be a role for using peg-interferon therapy in combination with novel agents. So, what about novel agents? And on this slide here, I show you the HPV life cycle and the many targets of the agents in development to achieve a functional cure. Now, although there are many agents, conceptually, there are only a few pathways to achieving functional cure. Either to inhibit viral replication, to target not detected, to lower viral antigenal burden with the hope of trying to restore an immune response or to directly induce or boost the immune response. So, let's have a look at a few of these approaches. So, here's an approach using an antiviral approach using a core assembly modulator. And core assembly modulators are small molecules that inhibit pre-genomic RNA encapsidation or disrupt a nuclear capsid assembly and thereby inhibit viral replication. In this study, a core assembly modulator was administered to both, to naive E-positive and negative patients at different dosing schedules. And you can see that this CAM resulted in potent inhibition of HDV RNA as well as HPV DNA. However, there was little change in E-antigen and surface antigen levels and there were no safety issues noted. So, this particular CAM was associated with potent inhibition of viral replication and we await further studies on its effect on functional cure. Well, another approach that we can take is try to reduce the viral antigen burden by inhibiting viral transcripts using a liver-directed antisense oligonucleotide. And this approach was tried in nuke-suppressed patients. This was in a randomized trial comparing different doses and different dosing schedules. And you can see here that there was a nice dose-dependent decline in surface antigen levels and almost a one log reduction in surface antigen levels was achieved with the highest dosing arm compared to placebo. But however, this agent does not target the CCC DNA. So, when treatment was stopped, there was rebound of surface antigen levels back to baseline. So, these data tell us that these agents will either have to be used continuously or in combination with other agents to achieve a functional cure. Yet, another approach is to try to enhance the innate immune response using a toll-like receptor 8 agonist. And in this trial, a TLR8 was administered once weekly for 24 weeks in virally-suppressed patients, both E-positive and negative, and compared to placebo. And what I show you here are the surface antigen changes from baseline. And you can see that they were really minimal, only about 0.2 log. However, two E-negative patients cleared S, and one E-positive patient cleared E. There were dose-dependent increases in serum cytokines, shown here, but these did not correlate with the treatment response. So, this is a promising approach, and we do await further studies. Now, for many years, investigators have been trying therapeutic vaccines to break immune tolerance to try to treat hepatitis B, but they've largely been unsuccessful, perhaps because we've been using vaccines that contain only a single viral antigen that's not very immunogenic. This vaccine that was tested here in NASPAC contains two viral antigens, surface antigen and core antigen. In this study, it was administered intranasally 10 times biweekly, nasally 10 times biweekly in nuke-suppressed patients, as well as in active carriers. And you can see in the two upper panels that three-quarters of patients achieved at least a 20% decline in surface antigen levels. And in the lower panels, a third of patients developed anti-HBS. And two patients in each group achieved surface antigen loss. So, this is a promising immune therapy for achieving functional cure, and it does raise the possibility that we might be able to break immune tolerance with an appropriate HPV vaccine, and further studies are awaited. Well, we certainly learned our lessons from HIV and hepatitis C, that to achieve undetectable viremia, we are going to need combination therapy. And such approach was tried here. This was a dual approach using a cam plus a nucleic acid, sorry, a nucleotide analog in E-positive treatment naive, as well as a nuke-suppressed patients. And what you can see is that dual therapy led to superior reductions in both DNA, as well as RNA in the treatment naive group. And in the nuke-suppressed group, what you can see is that a higher percentage of patients achieved a target not detected using a research assay with a lower limit of detection of five international units. So, this particular combination resulted in deeper DNA and RNA suppression, and we do await the results on whether it can achieve E or S antigen loss. This was a very interesting study looking at triple therapy consisting of an RNAi inhibitor, a cam, and a nucleic acid that was tested among both E-positive and negative patients, both treatment naive and experienced. And the RNAi was administered monthly for three months in combination with daily cam and daily nuke for 12 weeks. And what you can see here is that this triple therapy resulted in significant S antigen reduction in all patients, regardless of their baseline level, and in those patients who were treatment naive resulted in profound suppression of HPV DNA. So, this triple therapy regimen resulted in marked declines in surface antigen, and we await further studies on if it can achieve functional cure. So, let me switch now from treatment to prevention, and data was presented on a trivalent HPV vaccine consisting of the pre-S1, pre-S2, and surface antigens, and this was compared to a monovalent vaccine in JAREX. And the trivalent vaccine led to greater induction of HPV seroprotection compared to the monovalent vaccine, but what was more impressive is that it led to higher response rates in the difficult-to-treat population, that is men, diabetics, those who are obese, and current smokers. Data was also presented on the impact of screening on liver cancer mortality in patients with hepatitis B, and this is data from a national health insurance cohort study in Korea, looking at the impact on regular follow-up on outcome of hepatitis B in patients who are either compliant or not compliant with screening. And what you can see is that individuals who were compliant with screening, there was a significant reduction in risk of death from hepatocellular carcinoma, 44%, but more importantly, those individuals who were compliant with screening were more likely to receive a curative therapy. So, notwithstanding the limitations of cohort studies, I think these data reinforce our need to screen patients with chronic hepatitis B. So, switching now to a delta virus. There's no currently approved therapy for delta virus, and Mercodex B is a entry inhibitor, blocks the entry inhibitor for the hepatitis B virus. And in this study, a high dose of Mercodex B was evaluated in combination with peganiferone alpha 2A or tenofovir, and what you can see is that in both combination arms, the combination led to greater reduction in HDV RNA as well as the higher rates of undetectable HPV RNA. More importantly, the combination of Melchidex B with peginiferon led to greater reductions in HDV RNA as well as greater rates of undetectable DNA compared to the combination with tenofovir. However, surface antigen levels were not greatly affected. So these are very promising and exciting results. However, the lack of effect on surface antigen suggests that this combination will likely require long-term administration. So you saw this data presented earlier this morning. This is a pernylation inhibitor, lornafonib, also being evaluated for delta hepatitis, and pernylation is critically important. Pernylation of the delta antigen is critically important for the viral assembly, and in this study, ritonavir-boosted lornafonib was used in combination with peginiferon lambda for delta hepatitis for 24 weeks, and you can see that the end of the dosing schedule, there was a median decline of 3.4 log of HDV RNA, and just over 50% of patients were able to achieve HDV RNA below detection or below the limit of quantification of the assay, and generally, treatment was well-tolerated, and we do await further studies with this combination. So if I can summarize this part of the talk, I've shown you some data that steered hepatitis worsens underlying liver disease. There are many promising therapeutic approaches to achieve functional cure, but it's likely that combination therapy will be needed, and the optimal combination is unknown. I've shown you some data that HDV surveillance reduces HCC mortality, and a very provocative study is suggesting that antiplatelet therapy may lower HCC risk in nuke-suppressed patients. In the near future, we should have a more effective vaccine for difficult-to-vaccinate populations, and promising therapies for delta are on the horizon. So switching now to hepatitis C, now that we have very effective therapy for hepatitis C, efforts are focusing on elimination, and one of the critical populations to treat to try to achieve elimination are persons who inject drugs. However, these remain a very challenging population to treat, and this study looked at the feasibility of treating persons who inject drugs in a public health setting. And in this study, primary care providers were trained to provide care using a standard algorithm and provided expert advice when needed. Over 3,000 patients were treated, and an impressive two-thirds completed treatment with an impressive SVR rate of over 90%. However, treatment interruptions were common, and this did result in a reduction in SVR rate to 78%. Now, at this meeting, many strategies were tried to improve the adherence rate in this population, including patient-observed therapy, using digital medical therapy, as well as using integrated addiction and hepatology clinics with varying success, and I direct your attention to these abstracts here. Now, one of the barriers to treating persons who inject drugs is the concern for reinfection, and this was looked at in a population-based cohort study that estimated HDV reinfection rates among DA-treated patients in British Columbia, Canada. Now, what you can see here is that the overall reinfection rate was low, but among patients who injected drugs, sorry, among persons who injected drugs, there was a three-fold higher rate of reinfection compared to those individuals who did not inject drugs. You can appreciate here that most of the reinfection occurred within two years after SVR, and on analysis, predictors of reinfection were male and young age. Interestingly, those individuals receiving uninterrupted use of opioid agonist therapy, no reinfection rates were observed. So these data suggest that the opioid agonist therapy should be administered before and after HCV treatment in persons who inject drugs to prevent reinfection. Now, our efforts to eliminate hepatitis C would be greatly enhanced if we had an HCV vaccine, and data was presented here on a study looking at a candidate prime boost vaccine among actively using injection drug users. Unfortunately, the incidence of infection was not different between those who received the vaccine and those who did not. However, there was a significant blunting of peak HCV RNA levels among those individuals who were vaccinated, and three-quarters of vaccinated individuals demonstrated an immune response against the vaccine. So although this study was negative, it did demonstrate that there is feasibility of conducting vaccine studies among persons who inject drugs, and clearly, more efforts are needed towards vaccine development. Now, direct acting antiviral therapies are yet to be approved in the pediatric population, and two studies were presented at the meeting, at this meeting, providing evidence on the safety and efficacy in the pediatric population. The first study I'll present looked at Glicaprovir and pibrantaspir for eight weeks in children aged three to 12 years. Dosing was based on weight as well as on age, and you can see that the overall efficacy was high, 96%, and treatment was very effective across all age groups. There was a single failure at post-treatment week four, and the side effect profile and tolerance was similar to that of adults and adolescents. The second study looked at the safosavir and velpatasvir, another pan-genotypic regimen, in children ages six to 18, and in this study, dosing in those aged six to 11 was half the standard dose, and in those 12 or older, it was the standard adult dosing, and you can see among patients aged six to 11 that the SBR rate was high, 92%, and in those individuals aged over the 12, it was 95%. There was one virologic failure in each of the two age groups, and the rest of the failures were due to non-virologic reasons. So these two studies, I think, now provide evidence that these agents are effective in children, and in the near future, we should have safe and effective treatment for children three years or older, and I think this will serve us well moving forward in trying to eliminate HCV in children who number up to five million cases. Now, last year, we saw data presented on a short course of glicaprovir and pibrantasvir for treatment in naive patients with compensated cirrhosis. However, data was not presented on genotype three, the most difficult-to-treat genotype, and data was presented at the meeting here showing in genotype three patients, we can achieve very high rates in this difficult-to-treat population, 98% in the PERP protocol analysis. There was only a single patient who relapsed at post-treatment week four, and interestingly, presence of the baseline resistance-associated substitutions known to confer resistance to this regimen did not influence response to treatment. So based on the results of this study, the U.S. FDA has approved this regimen for compensated cirrhosis across all genotypes. So we know the effects of the impact of a sustained biological response on all-cause mortality in patients with hepatitis C, but less is known about the impact on liver-related mortality, and to address this question, a large VA database was analyzed looking at treated patients and propensity score-matched untreated controls, and what you can see here is that among treated individuals, those who achieved an SVR response had a significantly lower rate of liver-related deaths, and in addition, those patients receiving a DAA regimen had significantly lower rates of liver-related deaths, so I think this study illustrates the benefits of SVR on liver-related mortality. Now, we tend to focus on the liver-related benefits of SVR, but I think it's important to also remember that there are extra-hepatic outcomes that may be reduced by achieving an SVR, and in this analysis, investigators looked at acute coronary syndromes, end-stage renal disease, and ischemic stroke in patients who were untreated or who received treatment and achieved SVR, and what you can see here is that the cumulative incidence of acute coronary syndromes, end-stage renal disease, and ischemic stroke compared to untreated patients was significantly lower in those individuals who achieved SVR, so I think these tell us that there are important non-hepatic benefits to achieving SVR. There was also data presented showing that SVR is associated with improvement in HCC survival, and this is data from a multinational propensity score analysis looking at the impact of HCV eradication on HCC survival, and you can see that both all-cause mortality as well as liver-related mortality were significantly reduced in those individuals with HCC who were treated and cured, so for HCC patients who are candidates for HCC therapy, consideration should also be given to treating these individuals because of the impact on overall survival, so now that we have very effective therapy and curative therapy for direct-acting antiviral agents, this opens the realm or possibility of using these agents in hepatitis C-positive organ donors to HCV-negative recipients, but there's limited data on the use of this approach in liver transplantation, and this was a retrospective analysis looking at the outcome of liver transplantation among 14 NAT-positive individuals, and what you can see here, not unexpectedly, is that viremia returned early within five days after liver transplantation, mean pretreatment viral loads were high, 25 million, and the median time in this analysis to restart of treatment was one month, and you can see that all patients achieved SVR-12, and there were no early complications, so this data suggests that liver transplants using grafts from HCV-viremic donors to HCV-negative recipients is possible with good, excellent short-term outcomes. However, while these data are very encouraging, I think we do need to have long-term follow-up on both patient and graft survival, as well as the effect on wait times. So we know that iatrogenic infection almost always occurs following transplantation of organs from HCV-positive donors to HCV-negative recipients, and this study, one of the issues is what is the optimal timing of treatment in this particular situation, and this study looked at a short-duration prophylactic therapy to prevent post-transplantation HCV infection amongst 10 hepatitis C donor-positive recipient-negative kidney transplants, and what you can see is that this particular approach prevented infection in 50% of individuals. These people had no detectable viremia at multiple time points, and among those individuals who did have detectable viremia, the peak was low, 161, suggesting that this was likely a donor virus. Thus far, of the nine patients treated, all have achieved SVR, and there were no safety concerns. So I think these exciting data suggest that short-duration prophylactic therapy appears effective at preventing post-transplant infection from HCV-positive donors to HCV-negative recipients. But with preemptive therapy, the question is, can we go with an even shorter duration of treatment? And in this particular study, the investigators took what I thought was a very clever approach, using combination DAA with an HCV entry blocker, and what they used was the HCV entry blocker, Estamibi, in combination with Glicapivir and Piperintasvir, which was administered perioperatively and then continued for only seven days. And what you can see here is that among 25 patients in whom this was done, three-quarters of patients had quantifiable HCV RNA, but viremia was low. It did correlate with donor viremia, suggesting, again, that this is a donor virus that we're picking up. To date, 18 patients who have been treated have achieved a sustained virological response, and there have been no virologic failures to date and no safety concerns. So I think this is a very exciting approach for this particular population, and certainly suggests that preemptive Estamibi and Glicapivir and Piperintasvir administered for seven days prevented or rapidly cured post-transplant HCV infection. So if I can just summarize this part of the talk, I think I've shown you some data suggesting that it is feasible to treat persons who inject drugs, but overcoming adherence issues remains a challenge. In the near future, we hope to have a pan-genotypic regimen that will be available to treat children, and this will greatly improve our efforts to eliminate the approximately three to five million children worldwide that are infected with hepatitis C. A short course of pan-genotypic therapy is available for treatment of naive compensated cirrhotics, and this data now, and this regimen is approved by the FDA, and this has been updated in the current HCV guidelines that were released last week, and I do refer you to that if you need further information on this particular regimen. I showed you that there are multiple benefits to achieving a sustained virological response in terms of lowering liver-related mortality, lowering both cardiovascular and renal outcomes, and improved survival after HCC treatment. And very excitingly, preemptive therapy for a duration of either seven to 28 days appears to either prevent or cure HCV infection post-liver transplant, and I do thank you for your attention. Thank you.

hepatitis B

hepatitis C

therapeutics

prevention

liver disease progression

HCC risk

elimination