Faculty Bibliography

Background and aims: Globally, the prevalence of non-alcoholic fatty liver disease (NAFLD) is rising. It is imperative to identify high-risk patients whose disease may progress to significant liver fibrosis (>=F2). The American Association for the Study of Liver Diseases (AASLD) has no firm guidelines for non-alcoholic steatohepatitis (NASH) screening in high risk individuals due to inadequate data cost effective and treatment options.
Method(s): This cost-effectiveness analysis was developed to compare the value of screening in type 2 diabetes (T2D) patients for NASH against not screening. A Markov model was used to conduct a costutility analysis of 3 NAFLD screening methods consisting of combinations of ultrasound (US), alanine aminotransferase (ALT) determination followed by (1) liver biopsy alone, or (2) transient elastography for detection of patients more likely to have significant fibrosis (>=F2) followed by liver biopsy or (3) transient elastography alone. Post-detection, patients were hypothetically treated with weight reduction induced by intensive lifestyle intervention (ILI). Data provided by Vilar-Gomez et al. showed that 10% of patients who received the ILI were expected to lose over 10% of their bodyweight in 12 months. Costs (USD) and quality-adjusted life years (QALYs) were discounted at 3%; the time horizon is lifetime. The threshold incremental cost-effectiveness ratio (<=$100,000 as well as <=$50,000 per QALY) used is based on that favored by the Institute for Clinical and Economic Review.
Result(s): Screening >=55-year-old patients with T2D/NAFLD using US and ALT, followed by transient elastography, to detect significant fibrosis (>=F2) is a cost-effective strategy versus no screening, when detected patients were immediately treated with a 1-year duration with ILI. Screening with liver biopsy was not cost-effective, because of disutility associated with biopsy. [Table presented]
Conclusion(s): Non-invasive screening patients with T2D/NAFLD in the U.S. is cost effective and can be considered to decrease the burden of the disease.
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Background and Aims: TAF provides similar efficacy to tenofovir disoproxil fumarate (TDF) but with an improved safety profile particularly for bone loss and renal injury. However, continued benefit with longer-term TAF has not been sufficiently studied. Here we evaluate virologic suppression rates, eGFR, fibrosis, and ALT at 48+ weeks of TAF therapy in US clinical practice.
Method(s): TRIO has developed a national HBV network consisting of 6 academic and 4 community-based centers serving 17 US States to understand real-world HBV treatment. Of the 1037 patients enrolled from Jan 2017,270 patients initiated TAF and remained on therapy for 48+ weeks as of Jan 2019. Lab measurement data at baseline and at or after (but nearest) 48 weeks of TAF therapy were collected. Elevated ALT was defined as >35 U/L for males and?>25 U/L for females, HBV suppression was assigned for HBV DNA measures <=2000 IU/ml. Comparisons between baseline and 48-week measures were made using McNemar's test (for dichotomous variables), Bowker's test (for multi-level variables) or t-test (for continuous variables). To identify variables associated with elevated ALT, eGFR >0 ml/min, or FIB4 >1.45 at 48 weeks, logistic regressions were conducted with adjustments for multicollinearity of variables.
Result(s): The study population (n = 270) was mostly male (59%), Asian (89%), and under or normal weight (60%) with a mean age of 53 years. Prior to initiating TAF, 81% of the patients received TDF, 8% entecavir, 6% were treatment naive, 2% TDF/emtricitabine, 1% lamivudine, and 1% adefovir dipivoxil. As of Jan 2019, mean (median) TAF duration was 508 (512) days and ranged from 338 to 803 days. In paired analyses (Table), statistically significant changes were reduced mean ALT and increased DNA suppression; changes in FIB4 and eGFR were not significantly different between baseline and 48 weeks. Variables associated with elevated ALT and eGFR >0 ml/min at 48 weeks were baseline elevated ALT (p < 0.001) and baseline eGFR >0 ml/min (p < 0.001), respectively. For FIB4?>1.45 at 48 weeks, significantly associated variables were baseline FIB4 >1.45 (p < 0.001) and Medicare as primary coverage (p = 0.010, collinear with Age >=50).
Conclusion(s): This study of HBV-infected individuals receiving TAF for 48+ weeks found that statistically significant improvements occurred in ALTand HBV DNA suppression. Continued monitoring is ongoing to understand changes in these and other measures with longer term TAF.
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Background and Aims: Nucleos(t)ide reverse transcriptase inhibitors (NrtI) are the standard of care for the treatment of chronic HBV (CHB) infection. While these agents achieve viral suppression in most patients (pts), sustained response is rarely achieved following cessation of treatment. The HBV core inhibitor ABI-H0731 (731) in combination with a NrtI is currently being evaluated in Phase 2 clinical studies.
Method(s): ABI-H0731-201 is a double-blind, placebo (Pbo)-controlled study in NrtI-suppressed pts with CHB. Patients were randomized 3:2 to receive 731 (300 mg QD) +NrtI or Pbo+NrtI for 24 wks. Eligible pts had HBV DNA <=LLOQ for >= 6 mos, HBsAg >1000 IU/mL, ALT <=5x ULN and Metavir F0-F2. HBV DNA was measured by COBAS TaqMan 2.0 (LLOQ = 20 IU/mL) and an in-house (ASMB) semi-quantitative PCR assay (LLOQ = 5 IU/mL). HBV pgRNA was measured by an ASMB RT-qPCR assay (LLOQ = 35 IU/mL). Safety was assessed through reporting of adverse events (AE) and laboratory abnormalities. This report summarizes the antiviral activity and safety for the HBeAg-negative pts only.
Result(s): Of the 26 HBeAg-negative pts enrolled in the study, 16 received 731+NrtI and 10 received Pbo+NrtI. Overall, the mean (range) age was 48 (34-64) years, 16 (62%) were male, 21 (81%) were Asian. Results are shown in the table. Treatment with 731+NrtI resulted in a higher proportion of pts achieving TND by the ASMB HBV DNA assay compared with Pbo+NrtI. At baseline and throughout the study, the pgRNA and HBcrAg levels were low and the HBsAg levels did not change. The safety profile of 731+NrtI was similar to Pbo +NrtI. Both treatments were well-tolerated, with no serious adverse events or discontinuations due to AEs. All AEs and lab abnormalities were mild or moderate in severity. Only one pt receiving 731+NrtI reported a Grade 1 rash that resolved on study without treatment interruption. No Grade 3 ALT elevations were observed. [Table presented]
Conclusion(s): In 24weeks of treatment, a higher proportion of HBeAg-negative pts receiving 731+NrtI achieved HBV DNA TND by highly sensitive PCR methodology compared to Pbo+NrtI. 731 has a favorable safety and tolerability profile. These data suggest the contribution of 731 to the standard of care in achieving deeper viral suppression and support continued treatment with 731+NrtI in the open-label Phase 2 study ABI-H0731-211.
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Objectives: Here, we describe changes in HBV treatment in the 24 months after TAF approval as observed in a US network of 10 HBV-care centers.
Method(s): Data were retrospectively obtained from patient records through an electronic registry at enrollment (Nov 2016) with further collection at each patient visit. Of 1037 enrolled patients, 725 patients with 24-month follow up were included in this study.
Result(s): 7% (50/725) patients were untreated at enrollment and throughout the observation period (Nov 2016 to Dec 2018). Reasons for non-treatment: 82% (41/50) low HBV DNA, 54% (27/50) normal liver function, 8% (4/50) patient decision, 6% (3/50) HBeAg negative, 2% (1/50) does not meet guidelines, and 2% (1/50) unspecified. In Jan 2017 (end of enrollment), 58% (418/725) patients received tenofovir disoproxil fumarate (TDF), 23% (168/725) entecavir (ETV), and 2% (14/725) TAF. In Dec 2018 (end of the observation period), 30% (218/725) received TDF, 21% (152/725) ETV, and 35% (254/725) TAF. 37% (271/725) patients switched therapies for reasons of safety/side effects (58%, 156/271), physician preference (25%, 69/271), efficacy (8%, 23/271), or insurance/cost (6%, 17/271). Most switches were to TAF (91%, 246/271) from TDF (88%, 217/246). Rate of switching differed by site of care; compared to community practices, academic sites had a lower switch rate (26% [114/441] vs 55% [157/284]). Treatment switches in both academic (81%, 92/114) and community (98%, 154/157) sites were mainly to TAF, but the therapies prior to TAF were more varied in the academic sites.
Conclusion(s): In this study, 7% of patients were untreated while 37% received >1 regimen during the observation window. Reasons for non-treatment were mainly low HBV DNA and normal liver function. For the population receiving treatment, initial regimens were mostly TDF and ETV. Switches away from initial therapy was mainly due to safety/side effects concerns and were predominately to TAF.
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BACKGROUND:Despite significant morbidity and mortality among patients with decompensated cirrhosis, reported rates of advance directive (AD) completion and goals of care discussions (GCDs) between patients and providers are very low. We aimed to improve these rates by implementing a hepatologist-led advance care planning (ACP) intervention. MEASURES/METHODS:Rates of AD and GCD completion, as well as self-reported barriers to ACP. INTERVENTION/METHODS:Provider-led ACP in patients with decompensated cirrhosis without a prior documented AD. OUTCOMES/RESULTS:Sixty-two patients were seen over 115 clinic visits. After the intervention, AD completion rates increased from 8% to 31% and GCD completion rates rose from 0% to 51%. Women (P = 0.048) and nonmarried adults (P = 0.01) had greater changes in AD completion compared to men and married adults, respectively. Needing more time during visits was seen as the major barrier to ACP among providers. CONCLUSIONS/LESSONS LEARNED/UNASSIGNED:Addressing provider and system-specific barriers dramatically improved documentation rates of ACP.

Background: Standard of care nucleos(t)ide analogs (Nrtl) are effective in chronic HBV (CHB) infection, but achieve low rates of sustained responses off therapy. The combination of the HBV Core Inhibitor ABI-H0731 (731) with a Nrtl has demonstrated potent antiviral activity in prior clinical studies and is being evaluated in a long-term treatment study.
Method(s): Studies ABI-H0731-201 and ABI-H0731-202 were 24-wk double-blind, placebo (Pbo)-controlled studies in CHB patients (pts). After 24 wks of treatment, pts could enter the open-label extension study ABI-H0731-211 and receive 731+Nrtl for up to an additional 52 wks. The study diagram summarizes study design, patient flow and monitored parameters. This interim report summarizes data for HBeAg+ pts only.
Result(s): Final Wk 24 results confirmed greater mean Iog10 declines in HBV DNA (5.27 vs 3.99; p=0.017) and RNA (2.34 vs 0.61; p<0.001) are achieved with 731+ETV vs ETV in Study 202. By Wk 24 in Study 201, the proportion of pts on 731+Nrtl vs Nrtl achieving DNA "TND" was 69% vs 0% (p<0.001), and the proportion of pts achieving RNA <35 U/mL whose baseline RNA > 35 U/mL was 52% vs 0% (p=0.0013) respectively. There are 64 HBeAg+ pts currently on treatment in Study 211, having received an overall treatment duration of >32 wks. Among the 27 HBeAg+ pts receiving 731+Nrtl in Study 201, 41% (11/27) have now achieved DNA TND along with RNA <35 U/mL and HBeAg <1 lU/mL At their last timepoint, Study 202 (Rx naive) pts now in Study 211 (n=22) have demonstrated mean DNA and RNA declines of 6.1 and 3.0 logs, respectively, with observed mean log changes of >0.6 for HBeAg (11 pts >0.5, 4 pts >1.0), >0.8 log for HBcrAg (7 pts >1.0, 3 pts >2.0) and >0.4 log for HBsAg (7 pts >0.5, 3 pts >1.0). When, administered in combination with Nrtl for up to 1 year, 731 has been well-tolerated, with only mild/moderate adverse events and lab abnormalities, and only a single discontinuation due to a Grade 1 rash.
Conclusion(s): ABI-H0731 continues to exhibit a favorable safety and tolerability profile in pts treated for up to 1 yr. The combination of 731+Nrtl results in faster, deeper declines in HBV DNA and RNA than Nrtl alone, as well as subsequent declines in the surrogate markers of cccDNA (pgRNA, HBeAg and HBcrAg) predictive of cccDNA pool depletion, and HBsAg. The emergent data supports the continued development of ABI-H0731. Updated safety and efficacy data will be presented

[Figure Presented] Background and aims: GKT831 is a potent inhibitor of the nicotinamide adenine dinucleotide phosphate oxidases 1 and 4 (NOX1/4). NOX1/4 produce reactive oxygen species and modulate intracellular signaling pathways through oxidation of target proteins. In response to cellular stress including cholestatic injury to cholangiocytes and hepatocytes, NOX1/4 coordinate the activation of multiple inflammatory and fibrogenic pathways. GKT831 has shown marked anti-inflammatory and anti-fibrotic activity in multiple models of advanced cholestatic diseases. We are conducting a 24-week, randomized, double blind, placebo controlled trial to assess the safety and efficacy of GKT831 in patients with primary biliary cholangitis (PBC) and inadequate response to ursodeoxycholic acid (UDCA).
Method(s): PBC patients on a stable dose of UDCA and with alkaline phosphatase (ALP) and gamma glutamyl transpeptidase (GGT) levels >= 1.5 times the upper limit of normal (ULN), and normal bilirubin were randomized to GKT831 400 mg once a day (QD), 400 mg twice a day (BID), or placebo. All subjects continued UDCA treatment during the treatment period. A predefined interim efficacy analysis was conducted when 92 patients completed 6 weeks of treatment.
Result(s): 111 patients with high baseline disease activity were randomized (female = 91%, mean ALp = 312 IU/L, mean GGT = 225 IU/L). Changes in the primary efficacy end point GGT, a marker of liver and bile duct injury, were-7%, -12%, and-23% in the placebo, 400 mg OD and 400 mg BID groups, respectively (p < 0.01 for 400 mg BID vs placebo). GKT831 achieved even greater GGT reductions (29% for GKT831 400 mg BID vs 8% for placebo, p < 0.01) in patients with higher baseline GGT (>= 2.5 x ULN, n = 68), suggesting that GKT831 may also benefit patients with more advanced disease. Changes in ALP were-2%, -8% and -17% in the placebo, 400 mg OD, and 400 mg BID groups, respectively (p < 0.001 for 400 mg BID vs placebo). Although patients had low baseline levels of liver transaminases and high sensitivity C-reactive protein, dose dependent reductions were achieved. Total and conjugated bilirubin remained unchanged.
Conclusion(s): GKT831 achieved rapid, dose and time dependent reductions in markers of cholestatic bile duct and liver injury. These reductions in disease activity were highly significant for both ALP and GGT in the 400 mg BID group at week 6. Quality of life and markers of liver fibrosis will be assessed at week 24.
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Abstract LBO-06 is under embargo until Saturday 13 April 2019, 07:00. This abstract has been selected to be highlighted during official EASL Press Office activities or in official EASL Press Office materials that will be made publicly available on the congress website at 07:00 (CET) on the day of their presentation at the congress. Industry must not issue press releases - even under embargo - covering the data contained in abstracts selected to be highlighted during official EASL Press Office activities or in official EASL Press Office materials until the individual embargo for each data set lifts. Media must not issue coverage of the data contained in abstracts selected to be highlighted during official EASL Press Office activities or in official EASL Press Office materials until the individual embargo for each data set lifts. Journalists, industry, investigators and/or study sponsors must abide by the embargo times set by EASL. Violation of the embargo will be taken seriously. Individuals and/or sponsors who violate EASL's embargo policy may face sanctions relating to current and future abstract submissions, presentations and visibility at EASL Congresses. The EASL Governing Board is at liberty to ban attendance and/or retract data. Copyright for abstracts (both oral and poster) on the website and as made available during The International CongressTM 2019
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Background and aims: TAF provides similar efficacy to tenofovir disoproxil fumarate (TDF) but with an improved safety profile particularly for renal injury. Here, we assess clinical experience with TAF for patients with HBV in US Clinical Practice.
Method(s): The TRIO HBV Registry, consisting of 1078 enrolled patients from 6 academic and 4 community-based centers serving 17 US States, was created to understand real-world HBV treatment. Data presented here are limited to 250 registry patients who initiated TAF between Nov 2016 and Apr 2018, received >= 6 months of TAF therapy, and were followed up to 18 months. Baseline measures were closest to but between -30 to +60 days from regimen start. Measures in other time periods were those with the maximum date while on TAF. Comparisons to baseline were made using paired 2-tailed T-Tests. eGFR was calculated using the CKD-EPI equation.
Result(s): Characteristics of the study population: median age 52 years, BMI 24.3 kg/m2, male (147/250, 59%), Asian ethnicity (220/250, 88%), HBeAg positive (54/250, 22%), osteopenia/osteoporosis (47/250, 19%), and FIB-4 >3.25 (17/250, 7%). Mean and median TAF duration was 13 months as of data collection. 233/250 (93%) of patients receiving TAF switched from TDF (214/233, 92%), entecavir (16/233, 7%), or other therapies (3/233, 1%). At TAF initiation, 17/250 (7%) patients had baseline HBV DNA >= 2000 IU/ml. Of the 17, 16 patients had controlled HBV (< 2000 IU/ml) after 6 or 12 months of TAF therapy. One patient had a 50% viral reduction to 30, 000 IU/ml after 6 months of therapy but did not achieve suppression. 233/250 (93%) patients had baseline HBV DNA<2000 IU/ml; of these, 226 were assessed after 6 or 12 months of therapy and all had maintained HBV suppression (< 2000 IU/ml). 224/250 (90%) patients had baseline eGFR >= 60 ml/min and 26/250 (10%) < 60 ml/min with minimum 28 ml/min. In paired comparisons, mean eGFR increased 5% from baseline 85.7 to 90.1 ml/min (p < 0.001) after 6 months of TAF therapy (n = 213). Of 158 patients with eGFR measures after 12 months of TAF, the mean eGFR increase was 4% from baseline 86.9 to 90.5 ml/min (p = 0.001). For patients with baseline eGFR < 60 ml/min, mean eGFR increased 16% from 48.4 to 56.0 ml/min after 6 months (n = 24, p < 0.001). In the eGFR < 60 ml/min subset with 12+ months of TAF, the change in eGFR was 14% from baseline 54.0 to 61.4 ml/min though this change did not reach significance (n = 11, p = 0.066).
Conclusion(s): In US, clinical practice experience with TAF indicates effective HBV suppression after switching and improved renal function in real-world application. Continued long-term monitoring is critical to assess potential effects of prolonged treatment with lower dose tenofovir. (HBsAg). Currently approved drugs, nucleos (t)ide analogues, effectively reduce HBV DNA but only rarely result in a functional cure (defined as sustained HBsAg loss). Therefore, a critical need arises for novel therapies that reduce HBsAg levels and restore virus-specific immune responsiveness in patients. We have found that two subregions in 3' untranslated region of 2.1/2.4 kb HBV RNAs, here referred as "region X" and "region Y," regulate HBsAg production (unpublished data). Here, focusing on region X and Y, we aimed to screen host proteins to identify novel therapeutic targets reducing HBsAg.
Method(s): Host proteins binding to region X and Y were determined by following two methods. (1) The lysate of HepG2.2.15 hepatoblastoma cells was incubated with in vitro-transcribed RNA corresponding to above two regions, and binding proteins were pulled-down. The proteins pulled-down were identified by SDS-PAGE and LC-MS/MS. (2) Host proteins binding to region X and Y were presented by searching an RNA-binding protein database. siRNAs specific to the proteins determined by above two methods were transfected into HepG2.2.15 cells, and the effects on the HBsAg production were analyzed.
Result(s): Among those proteins either identified by pull-down assays or presented by database search, knockdown of 7 proteins showed potent anti-HBsAg effects, more than 90% reduction in HBsAg, without affecting cell viability. Interestingly, these were all nuclear-localizing proteins. Some of them were reported to regulate RNA splicing, stability or nuclear export of mRNA while the others were functionally unknown. Then, expression levels of 2.1/2.4 kb HBV RNAs were quantified, and silencing of these proteins showed less than 80% reduction in those RNAs, that was slightly milder reduction compared with that in HBsAg protein. These data suggested that the proteins identified here could regulate HBsAg production by affecting RNA processing or dynamics.
Conclusion(s): Host proteins binding to region X and Y in 2.1/2.4 kb HBV RNAs were shown to be attractive therapeutic targets to reduce HBsAg, suggesting novel insights for better understanding of HBV virology.
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