Safety and Efficacy of Once-Daily Ledipasvir/Sofosbuvir (90/400 mg) for 12 Weeks in Genotype 1 HCV-Infected Patients with Severe Renal Impairment

( Eric Lawitz ),( Charles S. Landis ),( Benedict J. Maliakkal ),( Maurizio Bonacini ),( Grisell Ortiz-lasanta ),( Jin Youn ),( Jie Zhang ),( Erik Mogalian ),( Shampa De-oertel ),( Anu O. Osinusi ),( D 대한간학회 2018 춘·추계 학술대회 (KASL) Vol.2018 No.1

Aims: Despite higher concentrations of sofosbuvir (SOF) metabolite, GS-331007, in patients with severe renal impairment (RI), retrospective case series and claims database analyses have suggested substantial use of ledipasvir (LDV)/SOF in this population with no untoward effects described. The current study evaluated the safety, efficacy, and pharmacokinetics (PK) of LDV/SOF (90/400 mg) once-daily for 12 weeks in patients with genotype (GT) 1 HCV-infection and severe RI. Methods: Treatment naïve or experienced patients with or without compensated cirrhosis and creatinine clearance (CLcr) = 30 mL/min (Cockcroft-Gault equation), not on dialysis, received open-label treatment with LDV/SOF once daily for 12 weeks. Virologic response, pharmacokinetics (PK), and safety, including echocardiograms, were assessed. Results: Of the 18 patients enrolled and treated, mean (range) CLcr at baseline was 24.9 (9.0-39.6) mL/min. All had GT1 HCV infection (14 GT1a and 4 GT1b), 14 (78%) were treatment naïve, and 2 (11%) had cirrhosis. All patients completed 12 weeks of LDV/SOF treatment. There were no early discontinuations nor any on-treatment virologic failures. The SVR12 rate is 100% (18/18). Plasma concentrations of the terminal SOF metabolite GS-3310007 were approximately 6 fold higher than in the LDV/SOF Phase 3 trials. SOF and LDV concentrations were similar to those observed in patients with normal, mild or moderate RI. The most common adverse events (AEs) were fatigue (22%), headache (22%), and hyperkalemia (17%). Six serious AEs were reported among 4 patients (22%), including 2 renal events; no SAEs were considered related to study drugs. There were no treatment-related cardiac AEs, including bradycardia, and no meaningful changes in QTc intervals or other parameters. Conclusions: Treatment with LDV/SOF (90/400 mg) for 12 weeks in genotype 1 patients with and without cirrhosis and severe renal impairment resulted in 100% SVR12 rate. The regimen was safe and well-tolerated with no treatment discontinuations and no treatment-related SAEs.

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.

Noninvasive Tests of Fibrosis as Markers of Disease Progression in Patients with Non-Alcoholic Steatohepatitis (NASH)

( Jin-woo Lee ),( George Boon Bee Goh ),( Quentin M. Anstee ),( Mi-chael Trauner ),( Eric J. Lawitz ),( Natalie Bzowej ),( Raj Vuppalan-chi ),( Ziad Younes ),( Dora Ding ),( Georgia Li ),( Kathryn Ker 대한간학회 2020 춘·추계 학술대회 (KASL) Vol.2020 No.1

Aims: Surrogate endpoints that predict complications are necessary for approval of new therapies for NASH. We assessed associations between histologic and noninvasive fibrosis markers with disease progression in NASH. Methods: Patients with advanced fibrosis (Ishak stages 3-6) due to NASH (NAS ≥3) were enrolled in Phase 3, placebo-controlled trials of selonsertib. Treatment groups were combined for this analysis. Liver fibrosis at baseline[BL] and W48 were staged according to the Ishak classification. Hepatic collagen and a-SMA expression were quantified by morphometry. Noninvasive tests of fibrosis such as LS by TE, ELF and NAFLD Fibrosis Score (NFS) were calculated. Cox regression determined associations between these parameters with disease progression (i.e. progression to cirrhosis in patients with bridging fibrosis and adjudicated clinical events [e.g. decompensation, transplantation, death] in those with cirrhosis), and discrimination was assessed using c-statistics. Results: 1679 subjects with bridging fibrosis(n=802) or cirrhosis( n=877) were randomized (median age 59 yrs, 60% female, 74% diabetes). During a median follow-up(FU) of 14.3 mos, 16% of subjects (117/748 with W48 biopsies) with bridging fibrosis progressed to cirrhosis. Risk of histological progression was greater with higher BL Ishak stage, hepatic collagen, a-SMA expression, ELF, NFS, and LS, as well as greater increases in these markers over time(Table). BL ELF(c-statistic, 0.68) and LS(0.70) more accurately discriminated progression to cirrhosis than BL Ishak stage(0.58) and hepatic collagen(0.56; all P<0.05). During a median FU of 14.3 mos, 26(3%) cirrhotic subjects had clinical events. BL factors associated with clinical events included higher Ishak stage, hepatic collagen, a-SMA, ELF, NFS, and LS(Table). After adjustment for BL, increases in hepatic collagen, a-SMA, NFS, and LS were associated with an increased risk of events. Prediction of future clinical events was greatest for BL ELF (c-statistic, 0.84 vs. 0.66 for Ishak stage and 0.62 for hepatic collagen; both P<0.05). Conclusions: Clinical disease progression in patients with advanced fibrosis due to NASH is associated with greater fibrosis burden at baseline and larger increases over time, measured histologically or with noninvasive markers. These data support the utility of noninvasive fibrosis markers as endpoints in NASH clinical trials.

Race Does Not Affect the Performance of Noninvasive Tests for the Discrimination of Advanced Fibrosis due to Non-Alcoholic Steatohepatitis(NASH)

( Won Young Tak ),( Vincent Wai-sun Wong ),( George Boon Bee Goh ),( Pin-nan Cheng ),( Eric J. Lawitz ),( Zobair M. Younossi ),( Raj Vuppalanchi ),( Natalie H. Bzowej ),( Ziad Younes ),( Naim Alkhouri 대한간학회 2020 춘·추계 학술대회 (KASL) Vol.2020 No.1

Background: Routinely available noninvasive tests of fibrosis (NITs) can be used to identify patients with advanced fibrosis due to NASH, but their performance may vary by race. Our aim was to evaluate the effect of patient race on the diagnostic performance of NITs using data from the global phase 3 STELLAR studies of selonsertib. Methods: The STELLAR studies (NCT03053050 and NCT03053063) enrolled patients with bridging fibrosis (F3) or compensated cirrhosis (F4) due to NASH (NAFLD Activity Score [NAS] ≥3). Baseline liver biopsies were centrally read using the NASH Clinical Research Network classification and NITs, including the NAFLD fibrosis score (NFS), Fibrosis-4 (FIB-4) index, Enhanced Liver Fibrosis (ELF) test, and liver stiffness by transient elastography (LS by TE) were measured. The performance of these tests to discriminate advanced (F3-F4) fibrosis by self-reported patient race was evaluated using areas under the receiver operating characteristics curves (AUROCs) with 5-fold cross-validation repeated 100x. Results for White and Asian patients are presented; data for other races (5% of patients screened) are excluded. Results: Among 3202 patients screened for the STELLAR studies with evaluable liver histology, 24% were Asian and 71% were White. The median age was 58 years in both groups; 47% of Asians and 57% of Whites were female (p<0.0001). The prevalence of F3-F4 fibrosis was 67% in Asians and 72% in Whites (p=0.01). AUROCs for each of the NITS for the discrimination of advanced fibrosis were similar between Asian and White patients (Table). In general, literature-based thresholds for the NITs had similar sensitivity and specificity among the specific racial subgroups. Conclusion: In these large, global phase 3 trials, the diagnostic performance of routinely available NITs for the discrimination of advanced fibrosis due to NASH was acceptable and similar between Asian and White patients.