Ledipasvir/Sofosbuvir for 8 Weeks in Genotype 1 Treatment- naive Non-cirrhotic Patients with HCV RNA < 6 Million IU/mL: Phase-3 and Real World

( Peter Buggisch ),( Jorg Peterson ),( Stefan Mauss ),( Kris Kowdley ),( Micheal Curry ),( Peter Ruane ),( Dani Ain ),( Naoky Tsai ),( Yoori Lee ),( Edward Eggleton ),( Macky Natha ),( Bruce Kreter ) 대한간학회 2016 춘·추계 학술대회 (KASL) Vol.2016 No.1

Aims: The optimal duration of therapy to achieve SVR depends on multiple factors. In a post-hoc analysis of the Phase 3 ION-3 (treatment-naive (TN), non-cirrhotic (NC) patients) 8 week of LDV/SOF data, a viral load (VL) <6M was shown to be the best predictor of SVR. Real world effectiveness (RWE) is often different from Phase III trials and there is a need to understand real-world 8 week regimens in a broader spectrum of patients. Methods: RWE 8 week LDV/SOF data is emerging from multiple single- center and multicenter retrospective and prospective cohorts. In this analysis, the phase-3 ION-3 data is compared with data from several diverse real world populations and one post-marketing investigator sponsored HIV/HCV trial. Patient demographics, characteristics, SVR12 and discontinuation data has been compared. Results: The ION-3 post-hoc analysis reported 123 patients who were TN, NC and VL<6M and treated with 8 weeks of LDV/SOF. Mean age was 52, 22% black, 72% GT1a; the SVR12 was 97% (119/123). The overall SVR12 rate from six diverse real world and post marketing cohorts was also 97% (638/658). There was no significant impact of HCV genotypes or subtypes (GT1a, 1b versus GT4), prior treatment history, presence or absence of cirrhosis, high viral load (HCV VL>6M), or HIV/HCV co-infection. All response rates are detailed in Figure1. Conclusions: LDV/SOF for 8 weeks yielded high SVR rates in ION-3. Analysis of RWE data from several diverse and heterogeneous cohorts from the US & EU show SVR outcomes that were consistent with the ION-3 results and supports the use of 8 weeks LDV/SOF in treatment- naive, non-cirrhotic GT1 patients with a baseline HCV VL <6M and possibly in other populations including HIV/HCV co-infected patients. Discontinuation rates were low despite diverse patients and clinical settings. Data from the TARGET and TRIO cohorts also suggests that the 8-week regimen is underutilized.

No Impact of RASs on the Efficacy of SOF/VEL/VOX for 12 weeks in DAA-Experienced Patients: Integrated Analysis of the POLARIS-1/POLARIS-4 Studies

( Christoph Sarrazin ),( Curtis L. Cooper ),( Michael P. Manns ),( Rajender Reddy ),( Kris Kowdley ),( Sooji Lee ),( Hadas Dvory-Sobol ),( Evguenia Svarovskia ),( Ross Martin ),( Gregory Camus ),( Bri 대한간학회 2017 춘·추계 학술대회 (KASL) Vol.2017 No.1

Aims: The pangenotypic combination of sofosbuvir (SOF) /velpatasvir (VEL)/voxilaprevir(VOX), inhibit distinct HCV targets, the NS5B polymerase, the NS5A protein, and NS3/4A protease, respectively. In Phase 3 studies, SOF/VEL/VOX administered for 12weeks demonstrated a 96% SVR12 rate in NS5A inhibitor-experienced patients in POLARIS-1, and a 97% SVR12 rate in DAA-experienced patient who had not previously received an NS5A inhibitor in POLARIS-4. Here, we evaluate the effect of baseline resistance associated substitutions (RASs) on treatment outcome and the emergence of RASs in patients who experienced virologic failure. Methods: NS3, NS5A, and NS5B deep sequencing was performed at baseline for all patients and at the time of virologic failure. NS3 and NS5A class RASs as well as VOX or VEL-specific RASs that confer >2.5-fold changes in EC50 were evaluated. Results: In POLARIS-1, 79% of NS5A inhibitor-experienced patients (205/260) had baseline NS3 and/or NS5A class RASs. Of these, 75% (196/260) had baseline NS5A RASs, the most common RASs. The SVR12 rates were similar in subjects with or without NS3 and/or NS5A class RASs, and with or without VOX or VEL-specific RASs(Table 1). RASs at NS5A position Y93 were present in 25% of patients, of whom 63(95%) achieved SVR12; all patients with ≥2 NS5A RASs achieved SVR12 (n=77). 95%(18/19) of patients with NS5B nucleoside inhibitor(NI) RASs achieved SVR12; 2 patients had S282T at baseline and achieved SVR12. In POLARIS-4, the overall prevalence of baseline NS3 and/or NS5A class RASs was 47%(83/178) and all achieved SVR12. All patients with. Conclusions: Baseline RASs had no impact on response in DAA-experienced patients following treatment with SOF/VEL/VOX for 12 weeks. Viral relapse was not associated with emergence of viral resistance.

Impact of Treatment Duration and Addition of Ribavirin on Real-World Effectiveness of Elbasvir/Grazoprevir: Retrospective Analyses from the Trio Network

( Eungeol Sim ),( Chizoba Nwankwo ),( Bruce Bacon ),( Michael P. Curry ),( Douglas T. Dieterich ),( Steven L. Flamm ),( Kris V. Kowdley ),( Scott Milligan ),( Naoky C. Tsai ),( Zobair M. Younossi ),( 대한간학회 2018 춘·추계 학술대회 (KASL) Vol.2018 No.1

Aims: Lengthening treatment with elbasvir/grazoprevir (EBR/ GZR) to 16 weeks and/or adding ribavirin (RBV) is recommended for select patients with HCV GT1 infection. However, realworld data (J Hepatol 2017;66:S295) suggest that utilization of this regimen is low. This study examined the use of 12- and 16- week EBR/GZR ±RBV regimens in different patient subgroups. Methods: Data were collected from providers and specialty pharmacies through Trio Health’s disease management program. Patients (n=442) with HCV GT1 infection who initiated EBR/GZR therapy between Jan 28, 2016 (FDA approval) to Dec 31, 2016 were included. Results: 401 (91%) patients received EBR/GZR for 12 weeks, 12 (3%) received EBR/GZR+RBV for 12 weeks, 11 (2%) received EBR/GZR for 16 weeks, and 18 (4%) received EBR/GZR+RBV for 16 weeks. Possible baseline NS5A resistance was identified in 13/285 patients with GT1a infection: 3 (23%) received EBR/ GZR for 12 weeks, 1 (8%) received EBR/GZR+RBV for 12 weeks, 2 (15%) received EBR/GZR for 16 weeks, and 7 (54%) received EBR/GZR+RBV for 16 weeks. Across all patients, the +RBV subgroup had a higher proportion of treatment-experienced patients (43%, 13/30) than the -RBV group (17%, 69/412); and the 16-week subgroup had a higher proportion of GT1A subtype (93%, 27/29) than the 12-week group (62%, 258/413). Other characteristics including gender, age, baseline viral load, and cirrhosis were similar between regimens and between groups defined by RBV addition or therapy duration. SVR12 results at time of abstract submission were available for 262/442 patients. Overall per protocol (PP) SVR12 was 97% (253/262). Across GT1 subgroups (defined by subtype, prior treatment experience, and fibrosis) that received EBR/GZR for 12 weeks without RBV, the PP SVR12 was ≥94% (TABLE). Conclusions: In real-world practice, EBR/GZR was highly effective, with the majority of patients treated for 12 weeks without RBV. Full SVR12 data will be presented at the conference.

Validation of the Performance of MRE for the Detection of Advanced Fibrosis due to NASH across Multiple Clinical Trials

( Rohit Loomba ),( Naim Alkhouri ),( Mazen Noureddin ),( Jie Zhang ),( Bryan J. Mccolgan ),( C. Stephen Djedjos ),( Robert P. Myers ),( Michael Middleton ),( Zachary Goodman ),( Kris Kowdley ),( Atsus 대한간학회 2020 춘·추계 학술대회 (KASL) Vol.2020 No.1

Aims: Magnetic resonance elastography(MRE) is a quantitative imaging biomarker for the detection of advanced fibrosis due to NASH. Our aim was to validate the performance of MRE for detection of advanced fibrosis using data from multiple clinical trials. Methods: Baseline data were pooled on 296 subjects with NASH from seven randomized, phase 2 and 3 trials including ATLAS and STELLAR-3/-4 trials. All subjects underwent 2D MRE and liver biopsy with staging of fibrosis according to NASH CRN classification. Associations between MRE-stiffness, fibrosis stage, noninvasive tests (NITs) of fibrosis (ELF, FibroTest, FIB-4, NAFLD Fibrosis Score [NFS]), and NASH activity (NAFLD Activity Score ≥5 vs <5) were determined. The discrimination of MRE for advanced fibrosis (F3-F4 vs F0-F2) and cirrhosis (F4 vs F0- F3) was evaluated using areas under receiver operating characteristic (AUROC) curves, and cutoffs from literature-based MRE thresholds (3.64 and 4.67 kPa, respectively) and optimal thresholds(defined by the maximal sum of sensitivity and specificity) were determined. Results: Among 296 subjects, fibrosis stages were F0-1(6%), F2(11%), F3(44%), and F4(40%); median MRE-stiffness was 4.71 kPa(IQR 3.52, 6.35). MRE-stiffness was correlated with fibrosis stage(Spearman ρ=0.60), and other NITs of fibrosis(ρ =0.47-0.52; all P<0.05). The AUROCs(95% CI) of MRE-stiffness for detecting advanced fibrosis and cirrhosis were 0.85(0.80, 0.90) and 0.81(0.76, 0.86), respectively. In general, cutoffs from the literature and optimal cutoffs derived from this dataset had similar performance for classification of fibrosis by 2D MRE. Among subjects with F0-F2 fibrosis on biopsy, those with MRE-stiffness ≥3.64 kPa (potential misclassification) had higher ELF and FibroSure than those with MRE-stiffness <3.64 kPa (both P<0.05). Conversely, among subjects with F3-F4 fibrosis on biopsy, those with MRE-stiffness <3.64 kPa had lower ELF, FibroSure, FIB-4, and NFS compared with those with MRE-stiffness ≥3.64 kPa(all P<0.05). Conclusions: This multi-center, multi-study validation demonstrates the clinical utility of 2D MRE for the detection of advanced fibrosis due to NASH.