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.

Real World Effectiveness of Ledipasvir/Sofosbuvir (LDV/SOF) for 8 weeks in Patients Coinfected with HCV and HIV-1

( Peter Buggisch ),( Ana Moreno ),( Vasily Isakov ),( Lisa Backus ),( Dani Ain ),( Peter Ruane ),( Juan Gonzalez ),( Sooji Lee ),( Sarjita Naik ),( Swarup Mehta ),( Jina Lee ),( Michael Mertens ),( Ma 대한간학회 2017 춘·추계 학술대회 (KASL) Vol.2017 No.1

Aims: The AASLD/IDSA/IAS-USA Guidance and EASL Recommendations on Treatment of Hepatitis C state that HIV/HCV coinfection should be treated the same as HCV monoinfection with careful monitoring of antiretrovirals. Real world cohorts (RWC) have demonstrated excellent efficacy of LDV/SOF for 8weeks in HCV monoinfected patients. The aim of this study was to describe the effectiveness of the STR of LDV/SOF for 8 weeks in HCV GT 1 patients with HIV/HCV coinfection in RWC. Methods: Real world effectiveness data of LDV/SOF for 8weeks in HIV/HCV coinfection is emerging from multiple cohorts. In this descriptive analysis, data from two prospective studies, one investigator- sponsored, 1 registrational trial, and three retrospective RWC of LDV/SOF for 8weeks in HIV/HCV co-infected patients were compared. The prospective trials include data from Ain et al (investigator sponsored) and Isakov et al (registrational trial). The RWC include the Deutsches Hepatitis C-Register, Madrid Coinfection Registry (Madrid-CoRe), and Veterans Affairs HCV Registry. Baseline characteristics and efficacy were analyzed. Results: The majority of the 279 patients included in this descriptive analysis were GT1, treatment naive (TN), noncirrhotic (NC), and had a HCV viral load <6million. The prospective cohorts enrolled 79 patients with the following baseline characteristics: mean age (43 years), male (74%), white (78%), and GT1a (55%). The RWC studies assessed enrolled 200 patients with the following overall baseline characteristics: mean age (53 years) male (79%), white (98%), and GT1a (82%) in those that reported demographics. The overall SVR12 from five diverse real world and post-marketing cohorts was 94% (263/279). The individual study results are presented in Table 1. Conclusions: This analysis of diverse cohorts from the EU and US yielded high SVR rates similar to SVR rates seen in multiple RW moninfected cohorts and supports the use of 8 weeks of LDV/SOF in TN, NC GT 1 HIV/HCV coinfected patients with a baseline HCV viral load <6 million.

Long-term Follow-up of Patients with Chronic HCV Following Treatment with DAAs: Maintenance of SVR, Persistence of Resistance and Clinical Outcomes

( W. Ray Kim ),( Eric J. Lawitz ),( Peter Ruane ),( Catherine Stedman ),( Graham Foster ),( Robert H. Hyland ),( Sarah Coogan ),( Stephanie Moody ),( Hadas Dvory-sobo ),( Steven J. Knox ),( Diana M. B 대한간학회 2016 춘·추계 학술대회 (KASL) Vol.2016 No.1

Aims: Significant advances in the treatment of chronic hepatitis C have been made with direct acting antiviral (DAA) regimens. While SVR rates may now be achieved in the majority of patients, data describing long-term virologic and clinical outcomes with these regimens are needed. Methods: We report interim data from two 3-year registry studies capturing long-term outcomes in patients with chronic hepatitis C treated with DAAs. Subjects are enrolled into two registries according to SVR status; SVR (SVR registry) versus non-SVR (Sequence registry). We determined the durability of SVR, relapse and reinfection rates. The persistence of resistance associated variants (RAVs) in treatment failures is followed. Liver disease progression is assessed by periodic clinical & labroratory evaluations. Results: 5433 patients enrolled in the SVR registry with a median (range) follow-up of 71 (0-156) weeks. 536 patients enrolled in the Sequence registry with a median (range) of follow-up of 44 (0-159) weeks. Demographic and disease characteristics are described below. In the SVR registry, at the time of data analysis, 99.7% (5414/5433) of patients have maintained SVR with 0.3% (19/5433) having emergent virus (6 relapses, 8 new infections, 5 to be confirmed). Viral emergence occurred by Week 96 in all patients. In the Sequence registry of 89 patients who received an NS5A inhibitor and had baseline sequencing data, 91.0% (81/89) had NS5A RAVs at Week 96. HCC was reported in 0.3% (16/5433) and 0.9% (5/536) of patients in the SVR and Sequence registries through Week 96 respectively. There were no significant changes in laboratory evaluations or liver disease assessments. Conclusions: SVR achieved following treatment with DAA regimens is durable. In patients failing NS5A-containing regimens, treatment- emergent NS5A RAVs persist. Rates of clinical disease progression and HCC are low. Ongoing reporting from these registry studies will be required to confirm these findings.

Long-Term Course of Cirrhosis Regression: Lessons from Patients with HCV Cirrhosis Following Successful Sofosbuvir-Based Treatment

( Ira Jacobson ),( Andrew J. Muir ),( Eric Lawitz ),( Edward Gane ),( Brian Conway ),( Peter J. Ruane ),( Ziad Younes ),( Frances Chen ),( Marianne Camargo ),( Anand P. Chokkalingam ),( C. Stephen Dje 대한간학회 2020 춘·추계 학술대회 (KASL) Vol.2020 No.1

Aims: In patients with HCV cirrhosis, a sustained virologic response (SVR) is associated with improved clinical outcomes; however, the temporal course of changes in fibrosis is poorly understood. Our aim was to evaluate changes in noninvasive tests of fibrosis (NITs) in this setting to gain insights into the natural history of cirrhosis regression following removal of the causative exposure. Methods: We studied patients with HCV cirrhosis who achieved SVR with sofosbuvir (SOF)-based regimens (in a trial or clinical practice) in an ongoing, prospective cirrhosis registry (NCT02292706). Patients underwent routine clinical and laboratory assessments, including semi-annual Child-Pugh-Turcotte (CPT) scoring and measurement of the Enhanced Liver Fibrosis (ELF) test, as well as annual liver stiffness measurement by transient elastography (LS by TE). Changes in fibrosis were estimated based on ELF response (defined as ≥0.5 unit reduction), and shifts in estimated fibrosis categories based on ELF (F3, ELF 9.8-11.3; F4, ELF >11.3) and LS by TE (F3, 9.6-12.5 kPa; F4, >12.5 kPa). Logistic regression was used to identify predictors of fibrosis improvement as defined by NITs. Results: 1,574 subjects with HCV cirrhosis (32% female, 39% BMI ≥30 kg/㎡, 7% CPT class B/C) were included in this study; median interval between SVR and registry enrollment was 38 weeks (IQR 27-60). At enrollment, median (IQR) ELF was 14.3 (9.5, 22.1); 586 (37%) and 247 (16%) patients had ELF scores consistent with F3 and F4 fibrosis, respectively. Median LS by TE was 9.9 kPa (9.2, 10.8); 761 (57%) and 227 (17%) patients had LS consistent with F3 and F4 fibrosis, respectively. As of May 2019, median duration of follow-up after registry enrollment was 123 weeks (IQR 96, 168). At week 144, 49% of those with baseline CPT class B/C had improved CPT class, while 98% of those with baseline CPT class A remained in CPT class A. During follow-up, changes in ELF and LS by TE suggested fibrosis improvement in an increasing proportion of patients with both F3 and F4 fibrosis at enrollment (Figure 1). ELF score improved by >0.5 units at week 144 in 27% and 47% of patients with baseline F3 and F4 fibrosis, respectively. Predictors of ELF improvement included higher ELF (P<0.001) and AST (P=0.049), and lower platelets (P=0.02) and BMI (P=0.10) at registry baseline. Conclusions: In patients with cirrhosis in whom HCV has been eradicated by SOF-based therapy, NITs suggest significant fibrosis improvement in 25-50% of patients within 3 years. Associations between reductions in these NITs and improvements in clinical outcomes require evaluation during longer-term follow-up.

Long-Term Follow-Up of Patients with Chronic HCV Infection and Compensated or Decompensated Cirrhosis Following Treatment with Sofosbuvir-Based Regimens

( Alessio Aghemo ),( Alessandra Mangia ),( Eric Lawitz ),( Ed Gane ),( Brian Conway ),( Peter J. Ruane ),( Armando Abergel ),( Sooji Lee ),( Brian McNabb ),( Anu Osinusi ),( Frances Chen ),( Hadas Dvo 대한간학회 2018 춘·추계 학술대회 (KASL) Vol.2018 No.1

Aims: Early results from registries and cohort studies have demonstrated that patients with cirrhosis who achieve SVR with DAA experience improvements in liver-related morbidity, HCC risk, and mortality. However, follow-up time for these studies is generally short. This analysis from the Gilead Cirrhosis Registry evaluates long-term outcomes in patients with cirrhosis who achieved SVR following treatment with a sofosbuvir-(SOF) based regimen. Methods: Patients with cirrhosis who achieved SVR after receiving a SOF-based regimen were eligible for enrollment. Patients enrolled within 60 weeks of completing a treatment study or transfer from another SVR registry study, or within 2 years of achieving SVR following treatment in a clinical practice setting. Patients return for visits every 24 weeks for 5 years for laboratory, clinical, and radiographic assessments of durability of SVR and clinical progression of liver disease. In this abstract we report the HCC incidence, CTP scores, and SVR durability. Results: As of 5 OCT 2017, 1564 patients have been enrolled in the cirrhosis registry. Mean age (range) is 59 (26-86) years, 68% are male, and 84% of patients had pretreatment CTP scores A. Median (range) of registry follow-up time was 53 (<1-144) weeks. Overall, there were 55 observed events of HCC in 3922 person-years (PYs) of follow-up since the start of DAA treatment (34 cases in 3292 PYs of follow-up for CTP-A patients and 21 in 601 PYs of follow-up for CTP B+C patients). Overall, patients with pretreatment CTP-A cirrhosis maintained CTP-A status while patients with pretreatment CTP B or C cirrhosis showed improvement. Conclusions: In this ongoing registry of patients with cirrhosis who achieved SVR after treatment with a SOF-based regimen, HCC was uncommon and occurred more often in patients with decompensated cirrhosis. The majority of patients maintained or improved their CTP category relative to pretreatment through up to week 96.

Sofosbuvir/Velpatasvir (SOF/VEL) for 12 Weeks in Genotype 1, 2, 4, 5, 6 HCV Patients: Results of the ASTRAL-1 Study

( Mark S. Sulkowski ),( Henry Lik Yuen Chan ),( Jordan J. Feld ),( Kosh Agarwal ),( Christophe Hezode ),( Tarik Asselah ),( Peter J. Ruane ),( Norbert Gruener ),( Armand Abergel ),( Alessandra Mangia 대한간학회 2016 춘·추계 학술대회 (KASL) Vol.2016 No.1

Background: Velpatasvir (VEL) is a pangenotypic HCV-NS5A inhibitor. This Phase 3 study evaluated treatment with a fixed dose combination of SOF/VEL for 12 weeks in patients with genotype 1, 2, 4, 5, or 6 HCV infection. Methods: Patients with genotype 1, 2, 4, or 6 chronic HCV infection were randomized 5:1 to received SOF/VEL (400 mg /100 mg daily) or placebo for 12 weeks. Patients with genotype 5 infection were enrolled to the SOF/VEL treatment group and patients with genotype 3 were evaluated in a separate study. Results: 740 patients were enrolled at 81 international sites: 60% male, 79% white, 32% treatment-experienced (TE), and 19% compensated- cirrhosis. Of the 624 patients treated with SOF/VEL, the genotype distribution was 53% GT1, 17% GT2, 19% GT4, 6% GT5 and 7 % GT6. Overall SVR12 for SOF/VEL-treated patients was 99.0% and the study met its primary efficacy endpoint. SVR12 rates by HCV genotype are presented in the table. Two of 328 patients (0.6%) with genotype-1 infection had virologic relapse. No patients with genotype 2, 4, 5, or 6, including 48 with cirrhosis, had virologic failure. Four patients did not achieve SVR12 for non-virologic reasons. AEs and laboratory abnormalities were similar in the SOF/VEL-treated patients compared with the 116 placebo-treated patients. One patient discontinued SOF/VEL treatment due to adverse-events. Conclusions: Treatment with the once daily, all-oral, single tablet regimen of SOF/VEL for 12 weeks is well tolerated and results in high SVR12 rates in treatment-naive and treatment-experienced genotype 1, 2, 4, 5, and 6 HCV-infected patients with and without cirrhosis.