Greetings, I am Dr. Carla Brady, Associate Professor of Medicine at Duke University. I have the honor of presenting to you today a summary of the high quality research in viral hepatitis that has been presented at this year's liver meeting. I have no disclosures that are financial, but I will disclose that this presentation will cover only a small proportion of the important research that is ongoing in viral hepatitis. I will review studies that have been presented in oral sessions, as well as studies that have been presented as posters of distinction. It is impossible to cover every study, thus I will attempt to offer a sample of the crucial investigations in viral hepatitis that have been presented this year. Let's begin with hepatitis C. In prior years, much research in hepatitis C presented at the liver meeting focused on strategies for improving rates of sustained virologic response with hepatitis C treatment. Since the development and institution of direct acting antiviral agents in hepatitis C management, this has shifted more toward challenges of access and optimizing treatment opportunities among those for whom successful treatment is challenging. To understand the magnitude of these challenges, let's first focus on the cascade of hepatitis C related care. In 2016, the World Health Assembly instituted a worldwide goal for hepatitis C elimination by 2030, with the achievement of this goal defined as a reduction in mortality by 65% and a reduction in the new incidences of hepatitis by 80%. Many countries have been working toward this goal. One question involves what progress has been made, particularly prior to the start of the COVID-19 pandemic. This first study by Black and colleagues aimed to evaluate national, regional, and global progress toward hepatitis C elimination. This analysis involved an integration of literature review and modeling to estimate the prevalence and cascade of care at the start of 2020. Country level Markov models were created for 110 countries, for which 80 were approved by country experts. The other 30 were estimated only on the basis of published data. According to this model, there are nearly 57 million viremic infections in 2020, which is a decline of nearly 7 million viremic infections. However, less than 25% have been diagnosed and only 5% treated in 2020 based on modeling. Whereas there is an estimated decline in hepatitis C infections, modeling data demonstrate that much work is to be done to increase efforts to screen for and treat hepatitis C. This study by Zhang and colleagues, recipient of the AASLD Foundation Abstract Award, focused on the 2019 hepatitis C cascade of care for children and youth in British Columbia, Canada, recognizing concerns regarding increased risk for infection due to the opioid epidemic and other socioeconomic conditions. These investigations examined the cascade of care for people younger than 30 years of age who were living with hepatitis C using data from the British Columbia hepatitis testers cohort, which includes all people tested for or who were diagnosed with hepatitis C infection from 1990. Hepatitis C cascade of care was constructed to display the proportion of young people in each of the six stages identified in this graphic, from testing to treatment with achievement of sustained virologic response. In 2019, 1,350 persons in British Columbia under the age of 30 were diagnosed as being hepatitis C antibody positive. Over 80% of them had undergone hepatitis C RNA testing to confirm active hepatitis C infection. Of those with confirmatory RNA testing, 673 people tested positive for hepatitis C RNA. Among them, nearly 80% received a genotype test. However, only 40% of those who received a genotype test had actually begun hepatitis C treatment. However, those that were treated represented only 32% of the total number of persons with detectable hepatitis C RNA, with 88% achieving sustained virologic response. Additional data indicated that many of these individuals with hepatitis C infection in British Columbia lived in urban areas, were socioeconomically marginalized, and had other health conditions, particularly mood and anxiety disorders. These findings suggest that having hepatitis C services co-located with other health and social services, particularly mental health, housing, and employment-related services, may benefit young people living with hepatitis C. Given concerns about the impact of these social challenges in hepatitis C treatment in young persons, Eckhard and colleagues examined the effectiveness of a randomized pilot trial of rapid hepatitis C treatment initiation in persons aged 18 to 29 years who were hepatitis C antibody positive, hepatitis C treatment naive, and with a history of injection drug use in the prior 30 days. Study participants were randomized to a rapid treatment arm, receiving same-day medical evaluation, confirmatory and baseline lab testing, and a starter pack of cefosbuvir or elpatasvir, or were randomized to a usual care arm, receiving same-day hepatitis C confirmatory testing, and if positive, being referred to local providers for treatment. The primary endpoint was sustained virologic response in hepatitis C RNA positive patients within 12 months of enrollment. 39 of 47 eligible participants were enrolled in the study. Results were similar in the two arms. 21% were women, 43% were Hispanic, 7% were non-Hispanic black, 14% were homeless, and 86% were on therapy for opioid use disorder. Results demonstrated that 64% of those in the rapid treatment arm achieved sustained virologic response, compared to 9% of those in the usual care arm. This suggests that care out in the community setting may be a successful strategy for improving access to and success of hepatitis C treatment. Another single arm study of hepatitis C treatment at the point of diagnosis in a larger number of marginalized patients was conducted by Morris and colleagues and was recognized as a poster of distinction this year. Demographics of this population are notable for a median age of 47 years, with 30% of this population being of female gender, 27% of black race, 11% Latinx, 72% actively injecting drugs, 61% unhoused, and 84% with income below the national poverty line. The aim was to assess the acceptability, feasibility, and effectiveness of delivering hepatitis C treatment at the point of diagnosis disclosure in a community-based clinic through targeted street outreach recruitment. Sophospivir-lipatisvir was administered following insurance approval for those actively insured. And for the uninsured, a two-week starter pack was provided through the study supply until transitioning to insurance-covered therapy. Transition to insurance-covered therapy in this study was led by pharmacy colleagues. Among 414 participants, 113 tested RNA-positive, with 73 of those having initiated treatment at diagnosis. 47% actually completed treatment, 89% had undetectable HCV RNA at the end of treatment, and among those who completed their 12-week post-treatment visit, 96% attained sustained virologic response. Another poster of distinction from colleagues in France reported on the use of respondent-driven sampling in which persons who used drugs recruited other persons who used drugs to enroll in hepatitis C screening with confirmatory testing, followed by FibroScan for fibrosis assessment, and Institution of Hepatitis C Therapy. 15 persons using drugs initiated the respondent-driven sampling, leading to 14 waves of recruitment and identification of 554 initial participants, most of whom were men with unstable housing. 181 were hepatitis C antibody-positive, with 49 being hepatitis C RNA-positive. 75.5% initiated treatment, and among those who started treatment, 81.1% completed treatment. 27 patients, which was 55% of all of those who were hepatitis C RNA-positive, achieved SVR. Vaccina and colleagues conducted a retrospective cohort study in patients who previously failed DAA treatment for hepatitis C, and who underwent sofosbuvir, glaucoprevir, parentesvir, and ribavirin as re-treatment, with re-treatment having occurred for 16 or 24 weeks. Half of these patients had child's A cirrhosis, and two were female, two were of Hispanic ethnicity, one was Black, and one was Native American. Multiple treatment failures per patient were common. Two-thirds of patients were started on weight-based ribavirin dosing at either 1,000 or 1,200 milligrams per day, and the remainder were started on 600 milligrams per day. Nine patients, which was 75% of this cohort, required on-treatment ribavirin dose reductions, but no patients required use of epigen, none had early treatment discontinuation, or experienced adverse events. All achieved sustained virologic response, offering this as a viable treatment option for those patients with a history of failed hepatitis C treatment. Now let's turn our attention to hepatitis B. Abstract 66 estimated the national, regional, and global cascade of hepatitis B care at the start of 2020, using country-specific hepatitis B disease burden and transmission Markov models with data collected from national registries and country reports. Models were created for 166 countries, indicating that the global prevalence of hepatitis B is estimated to be 3.63% at the start of 2020. This represents over 270 million infections. However, only a little over 6 million are estimated to have been on hepatitis B treatment. The modeling that was done in this study also did modeling for the pediatric population, in which additional estimates demonstrated that about 0.82% of five-year-olds globally were infected with hepatitis B, with 67% of these infections occurring in Africa alone. These data clearly demonstrate that to achieve viral hepatitis elimination, further efforts are needed to improve hepatitis B screening and treatment. To address the need to improve hepatitis B screening and management, the liver care screening program was developed within the Kaiser Permanente Northern California health plan to identify and manage patients with chronic hepatitis B using evidence-based care guidelines. Sedghi and colleagues reported on outcomes of this chronic hepatitis B management program. Over 15,000 patients were identified as eligible for enrollment in the program and outreach was conducted to facilitate enrollment. Comparisons between enrolled and unenrolled patients demonstrated that enrolled patients were more likely to have undergone hepatitis B related lab testing in the first year of enrollment and were more likely to have received hepatitis B treatment and to have undergone the paticellular carcinoma surveillance as per current guidelines. The question of whether existing hepatitis B therapies can be stopped is a question that continues to be examined. I would highlight two large studies presented at this year's meeting that address this question. Multi-Center Abstract 22, a nucleoside and nucleotide analog withdrawal in chronic hepatitis B patients was the recipient of a Foundation Abstract Award and it examined long-term virologic and biochemical response after nucleoside and nucleotide cessation, particularly in patients who did not achieve hepatitis B surface antigen loss. Results of this study demonstrated that the proportion that achieved sustained remission and or surface antigen loss at two years was 45%, but by four years was 31%. Overall, at four years off of therapy, 9.7% had achieved surface antigen loss and 36% had restarted therapy. Abstract 23 quantified risk of severe hepatitis flare and factors associated with it in a large cohort of greater than 10,000 patients in Taiwan. This study enrolled patients who had received Entecovir or Tenofovir at least one year before stopping therapy. Results demonstrated that 4.5% of patients developed a severe hepatitis flare at median follow-up of 2.15 years. And the risk factors for this were older age, male sex, cirrhosis, and history of liver decompensation. 0.42% of patients died within six months of flare. Risk factors for this were older age, cirrhosis, and hypertension. The four-year cumulative incidence of flare was roughly 31%, with a four-year cumulative incidence of retreatment of roughly 49%. These studies indicate that hepatitis flares post-treatment and need to restart treatment are not uncommon. Abstract 19, authored by Zhang and colleagues from China, assessed the safety and effectiveness of Tenofovir alafenamide for the treatment of chronic active hepatitis B in pregnant women. This was compared to treatment with Tenofovir TDF in pregnant women. Results of this study demonstrated comparable tolerability, safety, and effectiveness of Tenofovir alafenamide and TDF therapy in pregnant women. There were no differences in gestational age of infants born to these mothers, and no congenital defects or malformations were reported. Similar rates of hepatitis B e-antigen seroconversion in mothers were also seen between the two groups. What about novel hepatitis B therapies? One possible target involves blockade of the PD-L1 pathway, which can restore hepatitis B-specific T-cell function, and possibly lead to functional cure of hepatitis B infection. ASC22 is a subcutaneously administered monoclonal antibody against PD-L1. Wang and colleagues reported on a phase 2A clinical trial on the single administration of three ascending doses of ASC22 with three patients per dose across 12 weeks of follow-up. All patients had been on nucleoside analogs where hepatitis B e-antigen negative, and with hepatitis B DNA under 20 international units per milliliter. The primary efficacy endpoint was hepatitis B surface antigen reduction. Data demonstrated a trend of dose-dependent reduction in hepatitis B surface antigen as demonstrated in the figure in the top right-hand of the screen. In the patients with maximum surface antigen reduction, an increase in serum level of interferon gamma was seen, but no clinically significant elevations in ALT were noted. ASC22 was observed to be safe and well tolerated with only grade one adverse effects such as headache, weakness, and rash being noted. Given these results, a phase 2B clinical trial was conducted with results presented during one of the late breaking abstract sessions during this year's meeting. In this phase 2B clinical trial, 149 chronic hepatitis B patients were enrolled into two cohorts for 24 weeks of treatment of different doses of ASC22. In cohort one, 75 patients were treated with one milligram per kilogram every two weeks or placebo every two weeks plus nucleoside analogs. Those receiving ASC22 with nucleoside analogs had more significant hepatitis B surface antigen reduction compared to those receiving placebo with a nucleoside analog. 19% of patients with baseline surface antigen of equal to or less than 500 international units per milliliter obtained surface antigen loss and remained negative until the end of treatment. ALT flares were seen in four of seven or 57% of the study population and in two of three or 67% of patients with surface antigen reduction and loss respectively. No severe adverse events were identified. These early results offer hope for newer efficacious therapy and further analyses will be performed once all 149 patients complete treatment and planned follow-up. VIR2218 is a synthetic small interfering RNA therapeutic that has been in development as another potential functional cure for hepatitis B. Yin and colleagues reported on results of an ongoing phase two study of administration of VIR2218 every four weeks for a total of six doses, either alone or in combination with various doses of pegylated interferon alpha as demonstrated in the figure. Co-administration of VIR2218 and pegylated interferon alpha led to substantial surface antigen reduction by week 24. Two of the three patients who achieved surface antigen reduction to the limit of detection also had surface antibody seroconversion. Adverse events were typically grade one or grade two and consistent with known side effects of pegylated interferon. Next, we will review a few additional abstracts that focus on outcomes in pregnancy for both hepatitis B and hepatitis C, as well as studies on viral hepatitis D. Yin and colleagues assess pregnancy outcomes in hepatitis B and hepatitis C using National Inpatient Sample Database. This poster of distinction and winner of a Foundation Abstract Award reported data demonstrating that there is a rising incidence of hepatitis B and hepatitis C in pregnant women, that patients with hepatitis B had significantly higher rates of gestational diabetes, and that hepatitis C infection was associated with significantly higher rates of preterm labor, all-cause maternal mortality, and longer length of hospital stay. These results add important information and updated data that can help to inform women regarding hepatitis B and hepatitis C associated pregnancy risks. Alam and colleagues from Spain assessed adherence to the 2017 easel recommendation for hepatitis D testing in all hepatitis B surface antigen positive patients. A total of 8.2% of these patients were tested for hepatitis D with the proportion of testing having occurred in 7.5% of patients before the institution of the easel recommendations and in 9.4% after the institution of these recommendations. The majority of hepatitis D testing occurred in academic hospital settings with only 22% of such testing having occurred in the primary care setting. These data show that a large proportion of hepatitis B surface antigen positive individuals are not tested for hepatitis D antibodies, particularly in primary care settings, resulting in many hepatitis D patients remaining undiagnosed. Using paired liver biopsies, Alam and colleagues assessed the antiviral efficacy of the Levitide, the only approved treatment in the European Union for patients chronically infected with hepatitis Delta virus. They randomized patients into three treatment arms, administering daily subcutaneous injections and treatment arms B and C and providing delayed treatment in arm A. Paired liver biopsies were stained for hepatitis D antigen and for molecular analyses. At week 48, there were strong reductions in intrahepatic hepatitis D RNA and in the number of hepatitis D antigen positive cells in arms B and C of the study. This was associated with decreased as an inflammatory gene expression to suggest improvement in liver inflammation. Of note, intrahepatic hepatitis D RNA levels did not change in the delayed treatment arm and this did not reduce intrahepatic hepatitis B levels. I'd like to thank the AASLD Scientific Program Committee for the opportunity to share these highlights regarding viral hepatitis research presented at this year's liver meeting. Congratulations to all presenters and thank you for your attention.

viral hepatitis

Dr. Carla Brady

Duke University

research

hepatitis C

hepatitis B