Dr. Jennifer Price from UCSF who is going to give us a tour de force of the best of viral hepatitis in the meeting. Thank you, Jennifer. Great, thank you. It is really my pleasure and honor to be delivering the viral hepatitis debrief at this year's liver meeting. My name is Jennifer Price. I'm an associate professor and transplant hepatologist at UCSF and I'm chair of the hepatitis C special interest group. Here are my disclosures. And I first want to give a huge thank you to all of the presenters who made their presentations available to me for inclusion in this talk. I also want to thank Dr. Chloe Teo and Dr. Marion Peters for their input on several of the abstracts that I reviewed. And finally, like the other speakers, I want to acknowledge that I just could not include all of the excellent science related to viral hepatitis that was presented during this meeting into the debrief. So I also have divided my talk into several themes and I'm going to highlight a few abstracts in each of these. So the first theme is hepatitis C epidemiology. There were several excellent sessions on viral hepatitis elimination and actually a comment came up in a couple sessions that our outdated surveillance estimates can actually hamper our ability to monitor our progress toward elimination. So it was quite timely that Dr. Hall and colleagues presented this late breaking abstract in which their goal was to update the estimated national prevalence of hepatitis C in the United States during 2017 to 2020. And they approached their prevalence models in two ways. The first way was that they updated the NHANES surveillance estimates and also conducted an updated literature review for estimates of hepatitis C prevalence among the population of individuals who are not sampled at NHANES. So for example, people who are incarcerated or people who are experiencing homelessness. And when they did this model they estimated that there are 2.46 million people in the United States living with hepatitis C. And then they took a second approach. They also did the NHANES and literature review but then they did modeling to account for the fact that while people who inject drugs are sampled in NHANES they're really underrepresented. And we know that people who inject drugs are overrepresented among people living with hepatitis C. So when they did this approach they actually found that there's an estimated 4 million people living with hepatitis C in the U.S. So these findings I think are pretty sobering because they show that despite years of effective cure the estimated prevalence of hepatitis C in 2017 to 2020 remains essentially unchanged from 2013 to 2016 when using comparable methodology. And it's actually substantially higher when accounting for the increased injection drug use in the United States. So I think this really underscores the urgency that we need our National Hepatitis C Elimination Program and it also shows us that we have a lot of work ahead of us. Now I think we can all agree that having curative hepatitis C treatment is a necessary component for elimination but is not sufficient and that innovative models of care delivery will be critical to achieving our elimination goals. And Dr. Talal and colleagues presented rigorous research of one of these models. So this study was really focused on people with opioid use disorder because we know that people with opioid use disorder are disproportionately impacted by hepatitis C and are also less likely to receive treatment for a variety of reasons. So this group aimed to determine whether a facilitated telemedicine based hepatitis C treatment model that was integrated into an opioid treatment program could alleviate many of these barriers to hepatitis C treatment. So they conducted a prospective randomized clinical trial using a stepped wedge design and this was conducted across several sites in New York State. And the way it worked was the patient at the opioid treatment program would get screened for hepatitis C and if they were RNA positive they were randomized to either off-site hepatitis C treatment or on-site treatment via telemedicine. And this wasn't just the regular telemedicine it was staff assisted telemedicine. So there was a case manager at the opioid treatment program that would assist the patient with the telemedicine encounter. The hepatitis C provider was off-site and would send the medications directly to the opioid treatment program where the patient could receive them along with their methadone. So they enrolled over 600 participants, 50% were non-white and 15% in rural areas. And on the bottom right here you could see their outcomes. The orange bars are those who had an off-site referral for hep C treatment and the blue are those who had telemedicine referral. Almost everybody had their first case manager visit which was done at the opioid treatment program but you can see here big differences in treatment initiation and completion. So in the intention to treat analysis there was significantly higher SVR-12 in the facilitated telemedicine group at 91% versus 35% in the off-site referral group. Other key findings was that there is a high satisfaction with the telemedicine model and actually among those who achieved SVR they noted significant declines in their illicit substance use. So I think this study really clearly shows how we as hepatitis C specialists can deliver high quality hepatitis C care to a broader population and I'm hopeful that this model will be widely embraced with our hepatitis C elimination efforts. The last theme for hepatitis C is hepatitis C treatment in special populations and I'm going to review three special populations. The first is hepatitis C in pregnancy. So we know that one-third of newly reported hepatitis C cases occur in women, particularly among women of childbearing age and that the prevalence of hepatitis C positive pregnancies has been increasing. But pregnancy is actually an opportune time for hepatitis C screening and linkage to care because it's a time when a patient is already very engaged in health care during the pregnancy. So this study that was presented by Dr. Menlowitz aimed to characterize the hepatitis C care cascade during and after pregnancy. They conducted a retrospective cohort study where they linked pregnancy data to hepatitis C testing records and administrative data in Ontario, Canada and they identified over 27,000 people who were hepatitis C antibody positive and also had at least one pregnancy. And what they found was that about half of them never got a hep C RNA test so there was a big drop-off right there. And then among those who did get an RNA test and were RNA positive, 44% of them were not treated. And then what they did which was really interesting is they identified missed opportunities for diagnosis and treatment, missed opportunities to prevent transmission to the infant. So I'll explain what that means. For example, if a patient was hepatitis C RNA positive but it had at least one pregnancy before treatment that was considered a missed opportunity. So if you look down here at the bottom, although over half of the patients who are RNA positive ultimately were treated, only 18% received treatment before a pregnancy and the rest either were never treated and subsequently had at least one pregnancy or they were treated but after at least one of their pregnancies. So this really shows that there's major drop-offs in the hepatitis C care cascade during pregnancy that can lead to missed opportunities to prevent mother-to-child transmission. Now a particularly opportune time to treat somebody during who is pregnant would be during pregnancy but unfortunately safety and efficacy data on DIAs during pregnancy have really been lacking. So I was really excited to see this late-breaking abstract that was presented by Dr. Chappell in which she presented the interim results of the STORC study. So the STORC study is a multi-center phase four open-label single-arm study in which they are evaluating the safety and efficacy of cephalospovir velpatysphere given between 20 to 30 weeks gestation. The study is still enrolling so these are just interim results but so far they've enrolled 26 participants. 24 have delivered and 17 have completed their SVR assessment. Everybody with an SVR assessment achieved SVR 12. There were three preterm births among the 24 deliveries and there were 22 AEs related to cephalospovir velpatysphere. All were maternal and they were predominantly nausea, vomiting, and fatigue and there were no SAEs. Importantly they had viral load testing among 15 participants at delivery and all of them were undetected and among the 16 infants who were tested 100% were also undetected and then you could see here in this figure that there was a very rapid drop in the viral load after initiating soft fell during pregnancy consistent with what we see in people who aren't pregnant. So I think these interim data provide preliminary reassurance regarding the safety and efficacy of cephalospovir velpatysphere administered after 20 weeks gestation and we really look forward to seeing more data with the fully recruited study. The next special population group that I wanted to highlight are the hepatitis C donor positive recipient negative solid organ transplant recipients. Since hepatitis C is so easily cured now with the DAAs giving a hep C positive donor to hepatitis C negative recipient has really become standard of care at many institutions. However most centers are treating with a full course of DAAs after transplant and this long duration may not be necessary. In fact the Toronto group previously showed in a clinical trial of 30 donor positive recipient negative non-liver solid organ transplant recipients that giving an ultra short course of glucapavir perprentisvir plus azetamide one before going to the OR and then seven days post OR prevented chronic hepatitis C and azetamide we're used to thinking of as a cholesterol medication but it actually also can block hepatitis C entry into the hepatocyte. So Dr. Aliata reported extended follow-up of this initial clinical trial as well as outcomes of the standard of care cohort after they established this protocol as standard of care in Toronto. So this ultra short protocol became standard of care in Toronto in early 2020 and they transplanted 59 recipients using this a quarter were lung transplant recipients and over half were kidney transplant recipients. I think it's notable that almost all of them completed the full treatment course before their hospital discharge so this is very short which makes it convenient to treat people while they're still in the hospital and none had hepatitis C RNA breakthrough and then when they looked at the combined cohorts there was no hepatitis C virologic breakthrough need for retreatment or hepatitis C related complications. And Dr. Aliata also really nicely explained how they were able to operationalize this as standard of care so they have a specific protocol where they notify the surgeons the house staff the transplant team etc as soon as there's a net positive donor. They have established in their EMR order sets for the ultra short medication course as well as for the hep C RNA testing post-op and they protocolize the follow-up with hepatology. So in summary this ultra short protocol can prevent chronic hepatitis C infection and is well tolerated and what I think is very important is effective when operationalized a standard of standard of care and I think that was very impressive. The final special population I wanted to highlight is the population of patients who have hepatitis C related HCC and this study Dr. Kam and colleagues aim to determine the proportion of patients with hepatitis C related HCC who received DIAs after 2014. So they conducted a retrospective study of patients with hep C related HCC using a nationwide insurance claims database and they identified almost 4,000 HCC patients with hepatitis C and they found that only 24% of them had their hepatitis C treated. When they looked at factors associated with treatment younger patients, patients with cirrhosis and patients who were seen in GI or infectious disease specialty care clinics were more likely to have been treated and although this wasn't the primary aim of their study they also looked at five-year mortality with DIA treatment and they found that DIA treatment was associated with lower five-year mortality in people with HCC which I think is really important because this is consistent with other retrospective studies that have similarly shown that hepatitis C treatment in HCC can improve survival. So the take-home point here is that DIA treatment receipt is associated with improved five-year survival in patients with hepatitis C related HCC but it's underutilized and I think it's really important for us to recognize that while treatment of hepatitis C in this population is a little bit more nuanced than most because you have to think about when to time the start of DIAs with the HCC treatment it's still really important and we need to continue to make efforts to reach this special population. So I'm going to shift gears and talk about hepatitis B and the first group of abstracts I want to highlight are three that focus on optimizing currently approved hepatitis B therapies. The first looks at the use of tenofovir in pregnant patients to prevent maternal child transmission. We know that antiviral therapy in pregnant patients with high hepatitis B viral load is a cornerstone to preventing hepatitis B vertical transmission, but the optimal timing of treatment discontinuation is unclear. So this was a study that was presented by Dr. Mack. It's a single center prospective study that was conducted in a tertiary hospital in Shenzhen, China, which has a very large obstetric service and they have estimated hep B surface antigen positivity of around 6% among their pregnant patients. And their aim was to compare the rate of maternal hepatitis B virologic relapse after early, meaning immediately after delivery, versus late, meaning at least four weeks after delivery, cessation of prophylactic TDF. They enrolled 330 participants, it was not randomized. None of the participants had other indications for TDF except for being pregnant. 83% were antigen positive and 2 3rds elected to stop the TDF immediately after delivery. And the results are shown here on the right. The green are the people who stopped immediately. The orange are those who stopped at least one month after delivery. And you can see here that virologic relapse was nearly universal, but there were no significant differences in the two groups. In virologic relapse, clinical relapse, there also was no significant difference in maximum ALT changes postpartum. So in conclusion, in this study, early compared to late postpartum TDF withdrawal did not adversely impact maternal outcomes. The second abstract I want to highlight focused on the group of patients with chronic hepatitis B who have high viral load, but mildly elevated ALT, so the so-called gray zone patients. And we know that some uncertainty still exists regarding the indications for antiviral therapy in this group of patients. So Dr. Xu presented an open label rollover study following a randomized control trial, the TORCH B study, that had had paired biopsies. So essentially, during the prior randomized control trial, patients in the gray zone were randomized to receive either TDF or placebo for three years. They had baseline and three-year biopsies. And this study showed that there was a decrease in fibrosis progression in the TDF group. The abstract that was presented at this meeting was the open label rollover. So after the three years, the people who were on TDF continued, and the people who were on placebo switched, and there was another biopsy after three years. There were 123 participants who had these paired biopsies. 80% were male, and 19% were antigen positive. At baseline, the people who had been on TDF already had lower fibrosis and lower necroinflammatory scores compared to those who had been assigned to placebo. And then after three years, with the three-year follow-up biopsy, I'm showing you here the changes in fibrosis. And this is first in the overall cohort. So the green are the people who had fibrosis improvement. So 60% had fibrosis improvement. The yellow are those who had no change, that was 26%. And the red are those who had worsening fibrosis, and that was 14%. And the people who had been on TDF for the three years prior, 52% still had fibrosis improvement and for those who switched from placebo, 69% had fibrosis improvement. When they looked at the proportion of participants who had significant fibrosis at the beginning of the rollover, that decreased from 27% to 10% at the end of the study. And necroinflammatory scores also improved in about half, more so in the placebo group. So the take-home point here is that there was a improvement in liver pathology with three years of TDF. The changes were more pronounced in the placebo switchers, but the people who had been on TDF already for three years did continue to have improvement. And this suggests that there could be benefit for antiviral therapy in these gray zone patients, at least in terms of histopathology. The final abstract I wanted to present in this section compared tenofovir versus entecovir in preventing HCC. So we know that hepatitis B antiviral therapy reduces the risk of HCC, but some controversy still remains regarding whether the choice of agent impacts the outcomes. So Dr. Vecsena and colleagues conducted a retro, Dr. Saxena and colleagues, excuse me, conducted a retrospective cohort study of all Kaiser Permanente Northern California adults with chronic hepatitis B who were treated with TDF or entecovir for at least one year and had at least 90% adherence by prescription refill data. And they did two analyses. They looked at the entire cohort for HCC incidents, and then they also did analysis where they matched TDF patients one-to-one with propensity score matching to entecovir patients based on multiple demographic and clinical factors. In total, they had over 3,300 participants. 30% were on tenofovir and 70% on entecovir. They found that the TDF patients had several more favorable clinical characteristics compared to the patients on entecovir, and they also overall had a lower risk of HCC. So the blue here is the entecovir group, and the red here is the TDF group. However, when they did the propensity score matching of tenofovir to entecovir patients, these differences in HCC resolved. So I think the take-home point here is that when propensity score matching is used, there's really no distinguishable advantage by agent, and these findings really support keeping both TDF and entecovir as frontline agents for chronic hepatitis B treatment. Now, several sessions during this meeting highlighted deficiencies in hepatitis B screening and linkage to care. I wanted to highlight one abstract that focused on this issue, and this was presented by Dr. Paromaswamy. And what she did was she aimed to identify barriers and facilitators of viral hepatitis and liver cancer screening in distinct Asian American communities across Michigan. So what they did is first they invited various external stakeholders, so people from state government, from local cancer center, association of case managers. They invited them to participate in a focus group to identify broad viral hepatitis and cancer screening determinants, and then they used that focus group to conduct one-on-one semi-structured interviews with two to three community leaders in three different Asian American communities in Michigan, Bangladeshi, Burmese, and Chinese. And what they found was that there were several shared barriers and facilitators to viral hepatitis screening identified, and I've listed some of them over here. So these include non-English language, transportation issues, loss of insurance, stigma. But what I thought was interesting was that they also identified barriers and facilitators that were unique within communities. So for example, in the Burmese community, they reported that they experience a lot of racism and discrimination when seeking healthcare. They also noted that there's multiple dialects within their community, which makes translation services challenging. And moreover, there's multiple religious affiliations that further silo their community. So I think this study really nicely demonstrates the importance of engaging stakeholders and community members when we're developing and also adapting interventions to improve viral hepatitis and hepatitis C screening. Now our current antiviral agents are very effective at suppressing hepatitis B viral replication, yet functional cure remains elusive in most. And by functional cure, we're referring to sustained off-treatment hepatitis B viral suppression with loss of hepatitis B surface antigen. There were several excellent abstracts presented of novel therapeutics to achieve functional cure. And unfortunately, due to time constraints, I'm not able to include all of the abstracts. So I just want to highlight a couple, but I want to encourage you all to listen to the presentations on the app while they're still available. The first study I want to highlight is the Be Together study. So Bepiravircin is an antisense oligonucleotide that targets all hepatitis B RNAs and leads to a substantial reduction in viral proteins. The B-Clear trial previously showed that when Bepi was given with a nuc for 12 or 24 weeks, three to nine percent of participants achieved S antigen and hepatitis B DNA loss that was sustained for 24 weeks after end of treatment. So the aim of this study was to determine whether sequential treatment, first with Bepi for 12 weeks or for 24 weeks, followed by PEG interferon, could reduce rates of relapse and also improve responses that were observed in the B-Clear trial. So this was a phase two B randomized proof of concept trial. They enrolled over 100 participants, 74% were E antigen negative, and 69% started with a surface antigen quant of greater than 1,000. And I've circled here for you the top line results, which are that nine to 15% of participants achieved the primary endpoint, which was sustained surface antigen and hepatitis B DNA, less than the lower limit of quantification, for 24 weeks from the end of PEG interferon. Now just as we saw in the B-Clear study, low hep B surface antigen levels predicted response. So the yellow bars here are people who had a baseline S antigen level of less than 1,000, and they were more likely to have an end of treatment response. Now most of the Bepi end of treatment responders did not relapse on PEG interferon, but only two of the Bepi end of treatment partial responders had PEG interferon end of treatment response. So a little disappointing that adding PEG to Bepi didn't appear to further reduce S antigen levels, but encouraging that it may prevent relapse in a subset of Bepi responders. And I think an outstanding question here is whether concomitant PEG interferon with Bepiraviracin rather than sequential may enhance the hepatitis B surface antigen loss. The other novel therapeutic study that I wanted to highlight was this late-breaking poster abstract, where they looked at AB729, which is a gal-nat conjugated siRNA, which, similar to the ASO, dramatically reduces viral proteins, in conjunction with VTP300, which is a targeted immunotherapy, which sequentially combines two different hepatitis B therapeutic vaccines. So what they did here is they first gave four doses of AB729 with the goal to reduce S antigen levels, and then they followed this with VTP300 with the goal to enhance hepatitis B-specific T cell response. And what you can see here is that there were robust S antigen declines after four doses of the siRNA, but what's interesting is that the mean S antigen levels in the placebo group, which is in red here, began to rebound about 12 weeks after the last dose of AB729, whereas, by contrast, all of the VTP300-treated patients maintained a low S antigen level less than 100 through week 48, and 60% maintained S antigen levels less than 10. The treatment was well-tolerated with few adverse events and no grade three or four adverse events. So the conclusion is that VTP300 treatment appears to contribute to maintaining low S antigen levels after AB729. Follow-up is ongoing, which will be important to see if this is really durable, and they've also added an additional arm where they've added low-dose nivolumab, the PD-1 inhibitor, to the VTP300. Last category is hepatitis delta, and I have just one abstract that I wanna highlight here. As many of you know, bilevitide is a novel hepatitis delta entry inhibitor that's not approved in the United States, but is approved in Europe. And the aim of this study was to determine whether continuing bilevitide in patients who had early virologic non-response or partial response could be beneficial. So this was an integrated analysis of two different clinical trials that included bilevitide at two or 10 milligrams as monotherapy, and they included participants who took this treatment for 96 weeks. There were 141 participants. You can see their demographics here. 43% had cirrhosis, 56% were on a concomitant nuke. And what they found was that week 24, 35% had suboptimal virologic response. However, 74% of the partial responders did end up having virologic response after 96 weeks of bilevitide, and nearly half of the non-responders had virologic response as well. So I think that these results are encouraging and provide evidence for continuing bilevitide therapy, even in our patients who have suboptimal early 24-week response. I just want to draw your attention to these two late-breaking oral abstracts whose data I didn't have time to include in the debrief. One evaluated VIR3434, which is a monoclonal antibody, and VIR2218, the siRNA, for treatment of chronic hepatitis delta, and the other evaluated zelnesirin, which is a siRNA in combination with immunomodulators in virologically suppressed patients with chronic hepatitis B. And with that, I want to thank you for your attention. I want to congratulate all of the presenters at the conference, and also congratulate the ASLD leadership and staff for a successful meeting. Thank you.

viral hepatitis

liver meeting

hepatitis C

telemedicine

hepatitis B

treatment options

research collaboration