Disclosures Dr. Feld International Liver Congress • Research : Abbott, Abbvie, Gilead, Janssen, Merck • Consulting : Abbvie, Gilead, Merck 2019: Update from Vienna Dr Shah Jordan J. Feld MD MPH • Consulting Fees: Abbvie, Gilead, Merck, Intercept, Lupin Toronto Centre for Liver Disease Sandra Rotman Centre for Global Health University of Toronto Learning Objectives Outline • HCV – Screening & linkage to care 1. Appreciate recent advances in HBV and HCV presented at the – Treatment efficacy International Liver Congress 2019 – Treatment monitoring – HCC post-SVR • HBV 2. Put into context the recent Phase 3 trial results for a new therapy – Current therapies for NASH • Cancer risk • Transmission risk • NASH – Obeticholic acid for NASH – REGENERATE Trial HCV Care Cascade: Diagnosis Gaps by Physician Type HCV Care Cascade: Treatment Gaps by Physician Type HCV Diagnosis HCV Treatment HCV Detection HCV Confirmation by Specialty (%) by Specialty (%) by Specialty (%) by Specialty (%) 95% Generalist* Generalist* Gap: patients with ≥ 2 HCV HCV specialist † HCV specialist † Gap: Ab+ patients seen by RNA tests by physician OB/GYN 46 physician group who did not OB/GYN group but did not receive Other have confirmatory HCV RNA % Other treatment from that Missing specialty 83% testing by that physician Missing specialty physician group group *Includes primary *Includes primary 90% of diagnosed care, family practice, 46% of Ab+ care, family practice, 87% 49 patients received internal medicine. internal medicine. patients received † Includes no HCV therapy % † Includes no hepatologist, hepatologist, gastroenterologist, HCV RNA test gastroenterologist, and ID specialist. 91% and ID specialist. 57 % 91% 54 % Rege. EASL 2019. Abstr PS-066. Rege. EASL 2019. Abstr PS-066. 1
Making Oraquick quicker Real world data on pan-genotypic regimens 20 Mean OraQuick Viremic Non- Predictive Time (minutes) HCV Ab Viremic Values p < 0.001 15 PPV: 86.7% Positive at 5 102 16 95% CI (0.79- 10 min 0.92) NPV: 100.0% 5 Negative at 5 0 15 98% CI (0.73- min 1.00) 0 Sensitivity: 100.0% Specificity: 48.3% Viremic Non-Viremic 98% CI (0.96-1.00) 95% CI (0.32-0.65) If negative at 5 minutes, can tell people they are not viremic Not surprising but very reassuring data – this should apply to most of our patients Once positive, stays positive – no reason to wait to 20’ Smookler, Vanderhoff EASL 2019 Mangia ILC 2019 GS-03, Cornberg M ILC 2019 GS-07 SMART-C: Monitoring During GLE/PIB in SMART-C: Efficacy and Safety Treatment-Naive Patients With GT1-6 HCV Infection Multicenter, randomized, open-label Difference: -3.2% Treatment-Emergent Standard Simplified (95% CI: -8.2 to 1.8) phase IIIb study Wk 8 AEs, n (%) (n = 127) (n = 253) 98 97 98 97 95 100 92 AEs 70 (55) 133 (53) Standard GLE/PIB With Simplified Monitoring Treatment-naive patients with Grade 1/2 80 69 (54) 131 (52) (n = 253) Simplified GT1-6 HCV infection, HCV RNA SVR12 (%) Grade 3 1 (0.8) 2 (0.8) > 10,000 IU/mL, and no GLE/PIB With Standard Monitoring Grade 4 60 0 0 cirrhosis* (n = 127) (N = 380) Common AEs (> 5%) Overall performed very well but did not quite reach noninferiority 40 AEs and adherence assessed by study nurse via phone contact at Wks 4 and 8 in all patients. GLE/PIB dosed orally at 300/120 mg Fatigue 30 (14) 52 (15) QD. Highlights need for good patient selection for this approach Headache 26 (12) 43 (13) 20 *Exclusion criteria: anticipated poor adherence, IDU within past 6 mos, positive urine drug screen. 121/ 233/ 121/ 233/ 121/ 233/ Nausea 25 (12) 17 (5) n/N = Primary endpoint: SVR12 in ITT population 127 253 123 241 123 239 Simplified monitoring: Medication dispensed 0 Serious AEs 0 3 (1.2) PP † (6% noninferiority margin) ITT mITT* at BL; no on-treatment clinic visits Unscheduled visits *Excludes death (n = 1), LTFU (n = 14), or missing HCV RNA (n = 1). Secondary endpoints: SVR12 in mITT and PP † Excludes discontinuation (n = 2) in addition to mITT exclusions. On treatment Standard monitoring: Medication dispensed 3 (2) 11 (4) populations, adherence by Wk 20 pill count, Total 8 (6) 20 (8) at BL and Wk 4; clinic visits with physician, VF: 2 (1.6%) standard vs 6 (2.4%) simplified treatment discontinuation and completion, study nurse, and pathology at Wks 4 and 8 Adherence > 95%: 98% standard vs 96% simplified safety Dore, LB – PS 178 EASL 2019 Dore, LB – PS 178 EASL 2019 Factors associated with HCC risk Risk of HCC after SVR Factors associated with HCC after SVR in patients with F3/F4 Lau EASL 2019 2
Change with treatment does not help Effective for finding low risk patients If validated, could forego surveillance in low risk group Lau EASL 2019 Lau EASL 2019 Therapy for HBV – is 1 nuc better than another? Does U=U for HBV? • Usually we think of Nucs (tenofovir or entecavir) as almost interchangeable Serum from patients with HBV on nuc therapy with HBV DNA detectable but <LLOQ used to infect • Slight differences in resistance profile (less with tenofovir) and renal toxicity (less with entecavir) humanized mice • Recent study from Korea found a higher of liver cancer in those treated with entecavir vs tenofovir Study from Hong Kong – consecutive treated HBV 2008-2018 28,041 ETV with 1,386 HCC vs 1,309 with TDF with 8 HCCs • 9 of 31 established viremia • Unclear if they had taken <LLOD • But highlights transmission of HBV • Importance of vaccination • Importance of disclosure Lower risk of cancer with tenofovir treatment Burdette ILC 2019 PS 150 T CK Yip, G Wong EASL 2019 REGENERATE: Study Design REGENERATE Primary Endpoint: Fibrosis Improvement Study met fibrosis primary endpoint at 18 mos (ITT) International, randomized, double-blind phase III study of FXR agonist obeticholic acid End of Study In PP analysis, OCA 25 mg QD Fibrosis Improvement Stratified by T2DM, treatment with Mo 18 End of Study (Event Driven) thiazolidinediones or vitamin E Interim Analysis (Histology) (Event Driven) by ≥ 1 Stage With No NASH Worsening also associated with fibrosis 100 improvement across subgroups OCA 10 mg QD 80 defined by fibrosis stage, NAS, (n = 312) Patients with biopsy-confirmed Patients (%) T2DM status P = .0002 60 NASH, fibrosis stage 2/3, OCA 25 mg QD NAFLD activity score ≥ 4 P = .04 (n = 308) (target N ~ 2400) 40 Placebo QD 23.1 17.6 20 (n = 311) 11.9 Primary endpoint at interim analysis by paired biopsy: either fibrosis improvement by n = 311 312 308 Primary endpoint at interim analysis by paired biopsy: either fibrosis improvement by 0 ≥ 1 stage without NASH worsening or NASH resolution without fibrosis worsening Placebo OCA 10 mg QD OCA 25 mg QD ≥ 1 stage without NASH worsening or NASH resolution without fibrosis worsening Younossi. EASL 2019. Abstr GS-06. Slide credit: clinicaloptions.com Younossi. EASL 2019. Abstr GS-06. Younossi. EASL 2019. Abstr GS-06. Slide credit: clinicaloptions.com 3
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