Faculty Bibliography

[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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BACKGROUND:Necrolytic acral erythema (NAE) is a rare dermatological disorder, which is associated with hepatitis C virus (HCV) infection or zinc deficiency. It is characterized by erythematous or violaceous lesions occurring primarily in the lower extremities. The treatment includes systemic steroids and oral zinc supplementation. We report a case of NAE in a 66-year-old human immunodeficiency virus (HIV)/HCV co-infected woman with NAE. NAE is rarely reported in co-infected patients and the exact mechanisms of pathogenesis are still unclear. CASE SUMMARY/METHODS:A 66-year-old HIV/HCV co-infected female patient presented with painless, non-pruritic rash of extremities for one week and underwent extensive work-up for possible rheumatologic disorders including vasculitis and cryoglobulinemia. Punch skin biopsies of right and left thigh revealed thickened parakeratotic stratum corneum most consistent with NAE. Patient was started on prednisone and zinc supplementation with resolution of the lesions and improvement of rash. CONCLUSION/CONCLUSIONS:Clinicians should maintain high clinical suspicion for early recognition of NAE in patients with rash and HCV.

Introduction: TAF is a new prodrug of tenofovir with improved safety profile compared to tenofovir disoproxil fumarate (TDF).
Objective(s): To assess real-world experience with TAF for HBV patients of Asian race in US Clinical Practice. Methodology: This study includes 212 of 1078 TRIO HBV registry patients in care at 10 centers and representing 17 US states. Patients were self-reported Asian race, initiated TAF after Nov 2016, and received >= 6 months TAF with follow up to 18 months.
Result(s): Population characteristics. Country of origin 49% China, 27% South Korea, 7% Viet Nam, 17% from 13 other Asian countries, median age 53 years, BMI 24.0 kg/m2, 58% male, 23% HBeAg positive, 18% osteopenia/osteoporosis, and 6% FIB-4>3.25. 200/212 (94%) TAF patients switched from TDF (182/200, 91%), entecavir (15/200, 8%), or other therapies (3/200, 2%). Median TAF duration was 12 months as of data collection. Paired comparisons. HBV DNA suppression (<2000 IU/ml) increased from 94% patients at baseline to 99% after 6 or 12 months TAF (n = 206, p = 0.006). Mean eGFR increased 4% from baseline 86.5 to 90.1 ml/min after 6 months TAF (n = 179, p<0.001) and 5% from 86.2 to 90.6 ml/min after 12 months TAF (n = 120, p<0.001). Normal ALT (<=29 U/L females, <= 35 U/L males) increased from 73% patients at baseline to 86% after 6 months TAF (n = 185, p = 0.002) and from 70% at baseline to 87% after 12 months TAF (n = 126, p = 0.001).
Conclusion(s): In US, clinical experience with TAF for Asian patients indicates effective HBV suppression and improved renal function and ALT normalization