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The Liver Meeting 2020
2020 Hepatitis Debrief
2020 Hepatitis Debrief
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Video Transcription
Hello, I'm Nancy Rowe from Rush University Medical Center, and I'm honored to have been invited to give you the 2020 Liver Meeting Viral Hepatitis Debrief. Here are my disclosures. I'd like to first focus on hepatitis C. The selected abstracts predominantly focus on the care cascade, working towards WHO elimination goals, and some of the new special populations. Dr. Adge and colleagues, in coordination with the CDC, presented data on the epidemiology and the care cascade. The left upper corner of the slide shows the NHANES population, which over time has been close to on track for elimination targets, but the non-NHANES population displayed next to it is woefully behind, and at its current rate will never be on track for elimination, and one could argue this is the group that's at highest risk for transmission. They used a model, which has been well validated, the components of which go into it are on the bottom part of the slide, and to judge incidence and prevalence from states, they used CDC reports as well as national rates, and they supplemented this with prison data. For screening analysis, they looked at three different options, status quo versus 80% of the NHANES population and 20% of the non-NHANES population, and then 80% of everyone. They also looked at these with various screening strategies. It's no surprise that universal screening will be needed in all states, however, the annual screening rate varied between 9% and 15%, with a national mean of 9.8%, and you can see that broken down by states in gray. They then turned this to look at treatment. They considered three different scenarios, and with universal screening, all three scenarios were actually effective in meeting treatment targets, however, they did not all make an impact on mortality. You can see from the left, with the status quo treatment, that mortality might actually even increase, however, if you increase treatment to 80% of the NHANES population and 20% of the non-NHANES or uninsured prison population, that will decrease mortality by about 17%. If you broaden that further to 80% of treatment for all, that will decrease mortality by 41%. They then used all of this data to develop a tool that states can use, and they provided the link for that, so that states can go in and use that online tool to help model different scenarios. So, in summary, current screening and treatment strategy will not meet WHO targets, but universal screening will be needed in all states to eliminate targets, with annual screening rates varying by each state. Safe, well-tolerated pan-genotypic therapies have allowed us to revisit some of the traditional algorithms. Sunil Salman, in the late breaker session, presented data on Keep It Simple and Safe, the MIN-MAN study, which was coordinated with the ACTG, or AIDS Clinical Trial Group. This included 400 participants from multiple countries and 38 ACTG sites. All individuals received 12 weeks of soft-Val, compensated serotics were included, but hepatitis B surface antigen, pregnant, and decompensated serotics were excluded. The approach is described there on the left-hand side. No pre-treatment genotyping was required. All 84 tablets were provided at entry. There were no scheduled on-treatment clinics or labs, and there were two remote contacts, one at week four and one at week 22. Baseline characteristics are in the center. Average age was 47, although there was quite a range. The majority were men. The majority race was white, however, 28% were Asian, reflecting the multi-country distributions. A lot had a history of injection drug use, either current drug users or previous drug users, and only 90% and only 9% had compensated cirrhosis, which was based purely on FIB4. There were also a large number of HIV co-infected. You can see from the right-hand side that the remote contacts were successful. At week four, 99% of individuals engaged in the remote contact, and this did decrease a little to 84% at week 22. However, overall SBR rate was excellent at 95%, lowest in the age group of 20 to 29-year-olds. There were very few unplanned visits, and only three people lost drug. We do a weight analysis to see if this group of non-responders were either related to relapse or reinfection. I next want to look at the HERO study presented by Dr. Litwin in the link breaker session. This is a multi-site randomized pragmatic trial of patient-centered models of hepatitis C treatment for people who inject drugs. This was a national study in community-based and treatment programs. All individuals were actively using, and they had onsite hepatitis C treatment. There was also considerable stakeholder support. The goal was to compare SBR-12 rates and those that received modified directly observed therapy or MDOT compared to a patient navigation model at methadone programs in community-based clinics. You can see the outline of the study from below. There was a period of randomization followed by 12 weeks of treatment initiation before treatment was actually started, and all individuals that engaged in treatment received soft Val for 12 weeks. There was then monthly follow-up with the termination of SBR-12. Some of the unique patient characteristics are described here. There were 755 individuals in the study. The majority were male. Most were young, 44% under the age of 40. There was a majority of white race, and 54% had unstable living, 65% were unemployed, and 18% were genotype 3, although the majority were genotype 1. You can also see that the last drug injection was within four weeks of initiating therapy and 75.9%. The graphic shows those that enrolled, initiated treatment, completed treatment, and then the SBR rates. Although the SBR rates in the entire study were relatively low at 54 and 56%, when you looked at the modified or the protocol population, which included those that were randomized, initiated treatment, had no crossover, and had SBR-12 outcomes, this was actually much higher at 88.7% and 90.6% between the two groups. The SBR rates were similar between the MDOT and the patient navigation models. 80% of enrolled people did initiate and complete therapy, which is incredible. Adherence was higher, though, in the MDOT versus the patient navigation, although this did not impact SBR rates. Just to outline the uniqueness of this population, 96% did have urine drug screens that were positive at baseline. Dr. Tatiana Kushner presented data looking at adherence to infant hepatitis C testing guidelines among pregnant women with hepatitis C-related cirrhosis. This is important because women with hepatitis C cirrhosis should be retained in care. This population was obtained from a cohort of women with cirrhosis from Ontario, Canada, characterized between the years 2000 and 2014. Among over 86,000 women with cirrhosis, there were 194 pregnancies with active hepatitis C, 26% of which were diagnosed during pregnancy. There were less than 3% that had hepatic decompensation during pregnancy. The characteristics of these women tend to be lower socioeconomic and predominantly urban, although this is changing over time. When we look at the right-hand side, hepatitis C testing in these infants was actually quite low, with just a little bit over 40% receiving hepatitis C antibody testing and very few having hepatitis C PCR testing done. It's also important to focus on the age when initial hepatitis C testing was done. Nearly all of the tests were obtained before the first year of life, with minimal done after the first year, recognizing that our treatment guidelines actually say that infant testing should first occur with antibody at 18 months of age, and then confirmation with hepatitis C PCR at the age of three. So ultimately, greater than 25% of individuals with hepatitis C-related cirrhosis were identified during their pregnancy. Only 32% of infants were tested after that first year of life, and less than 10% of those that were tested did end up being antibody positive, confirming our transmission rates, which are between 5% and 12%, and increased in those that are co-infected with HIV. Thankfully treatment options for our pediatric populations are available. I'm going to cover the DORA study, but it's important to recognize that Lidipisvir, Cefaspivir, Velpatisvir are approved for pediatric populations, soft-Vel to the age of six and above. The DORA study looked at Glucapivir propensisvir for pan-genotypic treatment ages three to 12. It's important to see that this is not only based on safety and efficacy, but also was dose-finding. The overall SVR rates are presented in the middle and are incredibly high in each age cohort. Because this is dose-finding, some of these individuals did receive doses that did not go forward. Treatment side effects were minimal, including vomiting, headache, and diarrhea. You can see the baseline characteristics on the right. It's important to show that 20% of the pediatric population was cirrhotic, and the majority was treatment-naive. Also, the majority had eight weeks of therapy. At the end, Glucapivir propensisvir for children aged three to 12 had SVR rates that were comparable to adults. There were no failures seen on the final dose, although it's important to state that one of the failures was in a trial that refused to actually take the drug, although it was in a dose that did not go forward, and the adverse events were minimal. There's no arguing that effective treatment decreases morbidity and mortality significantly from hepatitis C. However, there does remain a residual risk, especially for liver cancer. The study from the Asia Liver Consortium for Hepatitis C, or REAL-C, included individuals that achieved cure did not achieve cure after DAA therapy. There were 160 treatment failures, and they were matched to 612 individuals with SVR. The outline of the outcomes is on below. You can see that the cirrhosis subgroup especially had a significant decrease in five-year liver cancer incidence, which translated to an SVR reduction in liver cancer rates of nearly 60%. However, five-year cumulative HCC incidence remained at 8% after SVR and went up to 22% if the pretreatment alpha-fetoprotein was above nine. This study did outline that age, alpha-fetoprotein, and Albi grade were associated with liver cancer risk in those with cirrhosis, but only alpha-fetoprotein was significant in those without cirrhosis. Dr. Massimo Lovaro presented an elegant study profiling circulating microRNAs in cirrhotic patients treated with direct actin antivirals. In this group of 565 patients, 12 developed liver cancer. These were case-control matched to individuals that had cirrhosis that did not develop cancer. They profiled both pretreatment and post-SVR circulating microRNAs and found five unique circulating microRNAs in those with liver cancer after SVR. In addition, they found 26 unique pretreatment circulating microRNAs in those that developed cancer, of which five shared interactions in tumorigenic pathways. The next virus I'm going to turn to is hepatitis B, where we're not only learning to use our existing agents, but also looking at the tremendous scientific discovery as we work towards a functional cure. First, I want to address data involving existing antiviral therapy. Dr. Toureau presented results on protocolized withdrawal of antiviral treatment after either 24 weeks of pegaglita interferon in combination with 192 weeks of tenofovir or just tenofovir. The study design is below and did include compensated cirrhosis. Although safety amendments are noted on the slide, patients were eligible for withdrawal if hep B antigen was negative and hep B DNA was less than 1,000 international units per milliliter and they were non-cirrhotic. The number that required retreatment was not presented. However, there were defined criteria for retreatment. Primary and secondary outcomes were similar between the groups. You can see from the graphic that hep B surface antigen loss was similar, but it occurred earlier with combination therapy. ALT flares also occurred earlier with combination treatment, whereas they tended to occur at treatment discontinuation with just tenofovir. In those eligible for tenofovir withdrawal, 30-39% met criteria for inactive hepatitis B. That's a hep B DNA less than 1,000 international units per milliliter and normal ALT. The study does demonstrate that treatment discontinuation is possible, but should be protocolized with defined criteria for retreatment. Another trial evaluating clinical and virologic outcomes after cessation of nucleoside or nucleotide therapy was the retrospective multi-site study RETRACT-B, or response after end of treatment with antivirals and chronic hepatitis B. 1,541 predominantly male and Asian subjects with a mean age of 53 stopped therapy after three years. 77% were E antigen negative at baseline, 60% had been on anticovir and 29% on tenofovir. The graphic shows cumulative hep B surface antigen loss, which reached 14% after four years. On univariate analysis, investigators found that the rate of surface antigen loss was significantly higher among those patients that were 50 or older in Caucasians compared to Asians and in those that had received tenofovir. However, after multivariate Cox regression, only race remained significant with Caucasians having nearly a six-fold higher rate of surface antigen loss over Asians. 74% did have viral relapse by four years, with 56% of these showing an increase in ALT. 56% did resume therapy by four years with increasing age associated with retreatment. However, retreatment strategy was at the discretion of the clinician and not protocolized. As we strive to achieve functional cure, factors to predict success are imperative. Professor Breckenhoff and colleagues evaluated serum biomarkers, obtained in three studies utilizing palliated interferon with or without nucleoside therapy. The protocols are pictured below. FLIR was defined as an ALT greater than equal five times the upper limit of normal during the first six months after treatment cessation. These investigators found that higher levels of end of treatment quantitative surface antigen virus RNA, and core-related antigen were associated with flare, with 52% experiencing flare if both surface antigen and RNA were elevated, and none if both were low. Although studies have linked flare to favorable outcomes, in this analysis, flare was not associated with either surface antigen loss or sustained response, which was defined as a HIT-B DNA less than 2,000 international units per milliliter six months after cessation. Conversely, low-endotherapy biomarkers correlated with sustained response and surface antigen loss, which was seen exclusively in those with low-end of treatment biomarkers, suggesting that these could be powerful tools to guide treatment and discontinuation. Hepatitis B DNA integration contributes to liver cancer development and relates to replication. Dr. Chao and colleagues nicely demonstrate how long-term nucleoside and nucleotide analogs not only reduce viral load, but also decrease core-related antigen, interhepatic Hep-B DNA, and interhepatic CCC DNA. Integration was determined by inverse PCR, followed by a circulation of digested DNA and PCR amplification. Although baseline clone size did not correlate with E antigen status, age, or viral parameters, it did decrease with new treatment with a mean reduction of 42.5%. Although integration is felt mostly random, it did find that it was most prevalent on chromosome 16, 17, 21, and 22, and none on the Y. Five patients had 10-year biopsies, three of which had undetectable DNA integration after long-term nuc therapy. Nuc treatment did reduce clone size in infected hepatocytes and DNA integration. However, there was no correlation between clone size reduction and serum or interhepatic viral parameters. Dr. Hsu and colleagues also demonstrated a reduction in expressed viral integrations after three years of tenofovir treatment in 66 patients compared to 61 that received placebo. The method is shown below. Host-viral chimeric pairs reflected integration. As you can see from the graphic, Hep-B integration correlated with baseline Hep-B DNA, core-related antigen, and serum RNA levels. However, after three years of tenofovir therapy, this correlation was not significant, as all patients had viral suppression. There was a two-fold reduction in expressed viral integration versus placebo. Reduction in viral load with either tenofovir or natural history was associated with a reduced expression of viral integrations and dysregulated genes. Let's now turn to some of the exciting therapeutic developments. Hepatitis B surface antigen reduction after the nasal-administrated therapeutic vaccine, NASVAC, was first presented in 2019. Dr. Yoshida reports 18-month follow-up data at this year's ASLD 2020. NASVAC contains hepatitis B surface antigen and hepatitis B core antigen to induce production of hepatitis B surface-neutralizing antibody, as well as B core antigen-specific cytotoxic T lymphocytes, which then inhibit hepatitis B virus replication. NASVAC was given to 29 individuals on oral antiviral therapy, as well as 42 NUC-naive subjects. The dosing schedule is shown below. It includes 10 doses dosed at two-week intervals. Hep B surface antigen levels continued to decline over the observation period in both groups. In addition, there was a gradual increase in hepatitis B surface antibody titer, and six of the 72 subjects achieved functional cure. Prithvi Rawals' lab reports very interesting results, silencing the HBX gene by a CRISPR-Cas9 system. Hepatitis B DNA can integrate into the host genome. HBVX, or HBX, can be maintained and transcribed in human hepatocytes, even in the absence of complete hep B viral replication. HBX does not directly bind to host DNA, but affects processes such as epigenetics, cell differentiation, hep B DNA repair, and inflammation, which have a role in HCC development and progression. Silencing of the HBX expression using short interfering RNA or short hairpin RNAs and inhibition of the signaling pathways that are activated by HBX abrogate the functions of HBX. Rawals and colleagues designed a series of experiments to see if targeting HBX by CRISPR-Cas9 could impact tumor genicity and progression of HCC. The methodology is outlined on the left. Transfection of hepatoma cell lines with plasmids expressing CRISPR against the HBX gene was done followed by in vitro assays in three-dimensional cultures. I want to draw your attention to the first graphic on the top center. Here, the HBX knockdown reduced expression of HBX gene by about 80%. The next graphic shows the HBX treated cells led to the reduction in tumorigenic properties compared to non-treated cells. This includes reduction in chemotaxis, invasion, and cell colony formation, all demonstrated on the plates. The graphic to the center bottom shows the HBX knockdown reduced both copies of CCC DNA and hep B surface antigen secretion twofold, as shown on the right. Next, the group generated a three-dimensional HBB-HCC in vitro model, which showed that the 3D spheroid cultures transfected with HBX CRISPR formed smaller and fewer spheroids. Cell-cell adhesion was also decreased in spheroids formed by HBB-HCC after HBX knockdown. Although this is very early research, it's exciting to see a model that demonstrates reduction in both viral biomarkers, as well as tumorigenicity. Dr. Mirai and colleagues also presented data using a CRISPR-Cas9 system targeting the hepatitis B genome. Their methods are outlined in the graphic. They first identified a guide RNA. They selected three guide RNAs targeting the hepatitis B genome, which were then cloned into CRISPR vectors. They then virally transduced the guide RNA or control into hepatitis B genome integrated cells or primary human hepatocytes, PHHs, and humanized liver chimeric mice. Hepatitis B virus susceptible cells with inducible Cas9 expression were transduced with guide RNA. Cas9 expression was then induced by doxycycline. The next experiments demonstrated efficacy. The picture on the left shows indel formation was observed in all of the regions of the hepatitis B genome targeted by the three hep B guide RNAs. And the graphic below shows that transduction suppressed hepatitis B replication supported by a reduction in levels of hepatitis B DNA, hep B surface antigen, hep B E antigen, and pre-genomic RNA, which is not on this graphic. The middle picture shows that similar effects were demonstrated by PHH. The graphic on the top right then shows that even with dox induction, hepatitis B replication was suppressed. The group next looked at the efficacy of CRISPR-Cas9 in combination with inhibition of DNA repair pathways. After CRISPR-Cas9 induces a double-stranded break, the DNA undergoes repair. Homologous recombination repair involves PARP and BRCA. The group found that inhibiting BRCA1 had very little effect. However, inhibiting PARP offered additional effect. The last graphic on the bottom right demonstrates the additive impact of combining CRISPR-Cas9 in combination with the PARP inhibitor oliparib. Though I have not shown the data, the group did demonstrate that inhibiting PARP alone with oliparib exhibited no anti-hep B viral effect. This group nicely demonstrated that CRISPR-Cas9 targeting the hepatitis B genome suppresses hep B virus, and that this effect can be augmented by inhibiting hep B DNA repair. AB729 is a single-trigger pan-genotypic galnet siRNA, which inhibits hepatitis B replication. Dr. Yoon on behalf of the investigators reports findings from AB729001. Part two, which includes single doses in chronic hepatitis B subjects, and part three, repeat dosing in chronic hepatitis B subjects. All subjects in cohorts A, B, and C, and E were virally suppressed with nucleotide or nucleoside therapy and could not have cirrhosis. Baseline characteristics among cohorts were similar, although cohort C was slightly older and had a lower hepatitis B surface antigen mean. The graphic on the top right shows the effect of a single dose of AB729, which led to similar levels of hepatitis B surface antigen decline for the three doses, followed by a sustained plateau at week 12, the duration of which could be dose dependent. Several subjects even had a hepatitis B surface antigen decline to less than 100 international units per milliliter. The bottom right graphic shows the hepatitis B surface antigen decline after repeated dosing every four weeks. Surface antigen continued to decline with each dose. The presenter commented that it might be possible to further reduce dosing intervals to eight to 12 weeks, and that these intervals will be evaluated. 729 also reduces hep B core related antigen and hep B RNA to the limit of quantification or detection in most subjects, though I have not shown this data. 729 was well tolerated without discontinuations due to AEs or grade three or four AEs or lab abnormalities. There were, however, mild asymptomatic ALT elevations in 22% of the subjects. We do look forward to further data in the future on this interesting agent. Allogos Therapeutics has a rich platform of agents, including ALG133, a surface antigen transport inhibiting oligonucleotide polymer, or STOPS, that reduces hep B surface antigen secretion. Professor Hong presents a strong case that combination therapy will be essential to achieve a hepatitis B cure. You can see from the graphic of the Allogos comprehensive approach, hep B virus antisense oligonucleotides, or ASOs, or siRNAs are used to target hepatitis B RNA for degradation. Dr. Hong outlined steps to design a liver targeted ASO with reduced liver toxicity and high potency, resulting in the pan-genotypic ALG572. Data was presented showing hep B surface antigen decline in mouse models and liver chips supporting activity without transfection. The graphic on the top right shows the effect of combining ASOs, ALG572, which targets small S open reading frame, along with ALG576 targeting the X transcript region at two dosing regimens. Combination shows activity between the two ASOs. The next study shows the effect of combining ALG572 with hep B virus siRNA targeting the X region. Max Energy Software showed synergy between the two compounds in a hep G2.2.15 assay, while the middle graphic shows the in vivo experiment where the purple line confirms that synergy. In comparison, the blue line is the siRNA alone, and the green line is the ASA alone on repeated doses. Dr. Hong continues to build the story through additional combinations. Although I do not show the graphic, combining ALG572 with ALG133 at the stop has even stronger synergy without cellular cytotoxicity. The last experiment combines ALG572 with Entecovir or the hepatitis B CAM ALG184. The HPV DNA and the mouse serum is shown on the left, where the red and the green lines are single agents, and the blue line is both compounds combined. The right-hand graphic similarly shows the additive effect of the ASO and CAM. The authors concluded that this is possibly the best-in-class ASO, demonstrating additive to synergistic activity when combined with other anti-hepatitis B agents. Dr. Yoon also presented durable reductions in hepatitis B surface antigen levels after the synthetic GalNac double-stranded RNAi RG6346. Data presented included single-dose administration to group B, our nuke-naive patients, and multiple dosing for monthly doses to group C, nuke-suppressed individuals. You can see from the graphics, the decline of hepatitis B surface antigen after just one dose in group B, as well as the sustained hepatitis B surface antigen decline after four monthly doses in group C, which were followed up to 448 days. Impact on hepatitis B DNA in group B and RNA hep B core antigen and hepatitis B core-related antigen in group C are depicted on this graphic. 58% achieved a hepatitis B surface antigen in less than 100 international units per milliliter, and 92% greater than one log decline. AEs were typically injection-site reactions, though the graphics show an example of self-resolving ALT flare with decrease in surface antigen and biomarkers in group B. There were no ALT elevations in the virally suppressed group C. Last, I'm going to address hepatitis delta, or HDV. Around 20 million people worldwide are co-infected with delta, which increases their risk of cirrhosis, decompensated liver disease, and liver cancer. Dr. Christopher Koh presented results from the LIFT-HD study, a phase two study of weakly-pegylated lambda in combination with lonafarinib and rotonavir for 24 weeks, with 24 weeks of follow-up. The overall study design is below. 26 patients participated, of which 20 had paired liver biopsies. The median age was 40, and the majority were Asian. It's easy to see from the middle graphic the significant decline at both weeks 12 and 24 of therapy on delta RNA. The average decline was 3.2 logs at 24 weeks. 77 patients achieved the protocol-defined reduction of greater than two logs in 24 weeks, or greater than two logs in delta RNA, of which 50% were undetectable or below the limit of quantification. Adverse events did include GI side effects from lonafarinib, and there were four subjects that discontinued, all felt related to lambda interferon. After 24 weeks of follow-up, 23% of the total population, or nearly half of those that had undetectable or below the limit of quantification delta RNA, maintained this, three of which were undetectable. Of the five patients that had undetectable or below the limit of quantification decline in their delta RNA, there was a significant improvement of ALT, and those that had paired biopsies showed significant histologic improvement. I want to apologize for those scientists that presented incredible data that I did not have time to address. I would encourage you all to view the other debriefs from ASLD, and again, I want to thank the course organizers and for those of you that have listened to this debrief for the ability to present to you.
Video Summary
Nancy Rowe from Rush University Medical Center provided a detailed debrief of the 2020 Liver Meeting Viral Hepatitis research. Key topics included Hepatitis C, where strategies for screening, treatment, and modeling scenarios were discussed. Studies on new treatments like the MIN-MAN trial with a simplified approach were highlighted. The HERO study focused on treating Hepatitis C in people who inject drugs. In Hepatitis B research, studies on antiviral therapy withdrawal and functional cure approaches were presented. Exciting therapeutic developments such as CRISPR-Cas9 targeting the Hepatitis B genome were discussed. Studies on Hepatitis B surface antigen reduction, such as with AB729 and ALG133, were showcased. The conference also covered Hepatitis Delta research, including the LIFT-HD study on pegylated lambda combination therapy. Overall, the debrief emphasized the importance of innovative research and treatment strategies in combating viral hepatitis.
Keywords
Liver Meeting
Viral Hepatitis research
Hepatitis C
Hepatitis B
MIN-MAN trial
HERO study
CRISPR-Cas9
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