Survival Benefits of Direct-Acting Antiviral Therapy in Patients with Decompensated Hepatitis C Cirrhosis

( W. Ray Kim ),( Anu Osinusi ),( Ajitha Mannalithara ),( Bo Hyun Kim ),( Raul Aguilar Schall ),( Diana Brainard ) 대한간학회 2018 춘·추계 학술대회 (KASL) Vol.2018 No.1

Aims: Current direct-acting antiviral (DAA) therapy for hepatitis C virus (HCV) infection leads to sustained virological response (SVR) in the vast majority of patients, even in those with decompensated cirrhosis. SVR in patients with decompensated cirrhosis has been associated with improvement in liver function; however, the extent to which DAA impacts on mortality remains to be determined. We analyze mortality in patients who participated in clinical trials evaluating sofosbuvir-based regimens in patients with decompensated HCV cirrhosis (GS-US-334-0125, SOLAR and ASTRAL studies), in comparison with mortality predicted by a survival model derived in untreated HCV patients. Methods: Current direct-acting antiviral (DAA) therapy for hepatitis C virus (HCV) infection leads to sustained virological response (SVR) in the vast majority of patients, even in those with decompensated cirrhosis. SVR in patients with decompensated cirrhosis has been associated with improvement in liver function; however, the extent to which DAA impacts on mortality remains to be determined. We analyze mortality in patients who participated in clinical trials evaluating sofosbuvir-based regimens in patients with decompensated HCV cirrhosis (GS-US-334-0125, SOLAR and ASTRAL studies), in comparison with mortality predicted by a survival model derived in untreated HCV patients. Results: There was a total of 492 patients, whose median age was 58 years, MELD 12, sodium 137mEq/l and albumin 2.9 g/ dl. Ascites and HE were common (79% and 63%, respectively). Altogether, 411/479 (86%) patients achieved SVR12. During the follow up, there were 25 deaths within one year of DAA therapy start, including 15 in the SOLAR and 10 in the ASTRAL data; no deaths occurred in GS-US-334-0125. The number of observed deaths in the clinical trials closely followed the expected/predicted numbers early in the treatment course (Figure). Starting at 100 days after initiation of DAA, however, the observed number of deaths was statistically significantly smaller than expected (SMR=0.54, 95% confidence interval [CI]=0.30- 0.98). All subsequent deaths occurred at a lower frequency than expected. The last (25th) death during the study period occurred on day 339, when the SMR had decreased to 0.44 (95% CI=0.30-0.65), which remained unchanged at the end of the analysis (day 365). Conclusions: DAA therapy in patients with decompensated HCV cirrhosis leads to significantly decreased mortality, which may be apparent as early as 100 days after the initiation of therapy with the risk of mortality decreasing to 44% of the expected by the end of the first year.

Risk of Cardiovascular and Cerebrovascular Events in Hepatitis C Patients Following Completion of Direct-Acting Antiviral Therapy: A Retrospective Cohort Study

( Sooji Lee ),( Amanda W. Singer ),( Anu Osinusi ),( Diana M. Brainard ),( Anand P. Chokkalingam ) 대한간학회 2017 춘·추계 학술대회 (KASL) Vol.2017 No.1

Aims: Chronic hepatitis C virus (HCV) infection has been associated with adverse cardiovascular and cerebrovascular outcomes. Viral eradication with direct-acting antiviral (DAA) therapy may decrease the risk of these events among HCV patients. We aimed to characterize the risk of cardiovascular and cerebrovascular events among HCV patients treated with DAA regimens compared to untreated patients in US claims data. Methods: 322,276 adults with chronic HCV were enrolled in the database between January 2006 and September 2015. We identified 8,342 HCV patients dispensed at least 12 weeks of DAA therapy (excluding boceprevir and telaprevir) and, for comparison, 76,423 untreated HCV patients who had follow-up time in the DAA era. Events were identified by diagnostic claims for acute and chronic ischemic heart disease, angina pectoris, cardiomyopathy, heart failure, subarachnoid hemorrhage, occlusion and stenosis of precerebral or cerebral arteries, cerebrovascular disease, cerebral atherosclerosis, intracerebral hemorrhage, and transient cerebral ischemia. Hazard ratios (HRs) estimating risk of incident cardiovascular and cerebrovascular events associated with completion of DAA therapy were calculated with adjustment for covariates using Cox proportional hazards methods. Results: HCV patients dispensed a full course of DAA therapy were more likely to be male, over 55 years-old, with baseline diagnoses of cirrhosis, diabetes, or hypertension, and on cardiovascular medications. After adjustment for covariates, there was a reduced risk of total cardiovascular and cerebrovascular events in patients completing DAA therapy compared to untreated patients (HR=0.86, 95% confidence interval [CI]: 0.74-0.99). Adjusted HRs were similar for cardiovascular disease (HR=0.90, 95%CI: 0.76-1.05) and cerebrovascular disease (HR=0.89, 95%CI: 0.74-1.08). Conclusions: In this real-world cohort, DAA therapy appeared to reduce the risk of cardiovascular and cerebrovascular events in HCV patients even within a short period following therapy. The benefits of curative DAA therapy in reducing extrahepatic complications of HCV may be even greater with longer follow-up.

Sustained Viral Response Following Treatment with Direct Acting Antiviral Agents for Chronic Hepatitis C and the Risk of Hepatocellular Carcinoma

( K Rajender Reddy ),( Marc Bourliere ),( Kosh Agarwal ),( Eric Lawitz ),( Leia Kim ),( Anu Osinusi ),( Kathryn Kersey ),( Gerald Crans ),( Stephanie Moody ),( Liyun Ni ),( Diana M. Brainard ),( John 대한간학회 2017 춘·추계 학술대회 (KASL) Vol.2017 No.1

Aims: Sustained virologic response (SVR) after interferon (IFN)-based treatment for HCV infection is associated with reduced risk of hepatocellular cancer (HCC), although the risk is not eliminated. Less is known regarding the risk of de novo HCC following SVR with IFN-free direct acting antiviral (DAA) therapy. In this analysis, a review of incident HCC in patients treated with SOF-containing regimens was performed. Methods: Data from Gilead HCV clinical trials (from treatment start to 24 weeks post-treatment) and registry studies (3 to 5 year follow-up observation) were analyzed to evaluate the incidence of de novo HCC. The clinical database was searched to identify adverse events of liver tumors; the occurrence of HCC is recorded at each visit in the registry studies. Incidence rates and exposure-adjusted incidence rates, time to development, and risk factors for development of HCC were assessed in patients with and without cirrhosis (compensated and decompensated) who received IFN- containing (Peg- IFN+RBV±SOF) vs IFN-free treatment (SOF, ledipasvir/SOF, SOF/velpatasvir ± RBV), and SVR vs no SVR. Results: In the clinical trial database, 0.3% (36 of 13,525) patients had AEs of HCC or suspected HCC while in the registry study database, 0.5% (33 of 6675) were reported to have HCC. The rate was similar in non-cirrhotic patients who achieved SVR with an IFN-containing vs IFN-free regimen (0.09 vs 0.03 per 100 patient years of follow-up, respectively); few patients with compensated cirrhosis and none with decompensated cirrhosis received IFN-containing regimens. Among subjects treated with IFN-free regimens, higher rates were observed with advanced liver disease and non SVR (see table). Conclusions: Data from the Gilead clinical trial and registry study databases show incidence of HCC in subjects treated with IFN-free regimens is similar to that reported in the IFN-era in similar populations. While SVR significantly reduces the risk of HCC, the risk is not completely eliminated, particularly among patients with decompensated cirrhosis.

No Increased Risk of HCC Recurrence for Patients Following Interferon-Free, DAA Treatment for HCV: A Large Population- Based Analysis

( Laura E. Telep Raj Reddy ),( Joonwoo Bahn ),( David Muramoto ),( Anu Osinusi ),( Diana M. Brainard ),( Anand P. Chokkalingam ) 대한간학회 2017 춘·추계 학술대회 (KASL) Vol.2017 No.1

Aims: Hepatocellular carcinoma (HCC) is a common secondary liver disease of chronic hepatitis C virus (HCV) infection. The advent of interferon(IFN)-free, direct actinga ntiviral (DAA) regimens for HCV infection has enabled access to curative treatment for previously untreated patients. However, the effect of IFN-free DAA regimens on recurrence of HCC is poorly understood and hasn’t been studied in a large, population. This study aims to examine risk of HCC recurrence among HCV patients treated wit IFN-free DAA treatments versus regimens containing IFN. Methods: Using United States administrative claims data from 01/01/2006 to 09/30/2015, we identified 4,887 patients who were ever treated for HCC. HCV treatment regimens were stratified by presence or absence of concomitant IFN. Patients were observed from HCV treatment start until the first of: claim for HCC treatment, initiation of a different HCV regimen, enrollment end, or September 30, 2015. Hazard ratios (HRs) estimating risk of HCC recurrence associated with completion of IFN-free vs. IFN- containing therapy were calculated after adjusting for baseline confounders. Results: Patients completing IFN-free treatment (vs. IFN-containing) were more likely to be ≥ 55 years (82.7% vs. 45.1%) and have cirrhosis (95.7% vs. 88.2%), liver necrosis (34.8% vs. 9.8%), and portal hypertension (58.0% vs. 35.3%) at baseline. Median follow-up time was shorter in IFN-free regimens (182 daysvs. 349 days). After adjusting for age, sex, and significant baseline covariates, there was no difference in risk of HCC recurrence through the end of follow-up with IFN-free treatment regimens when compared to regimens containing IFN(adjusted HR: 0.97(95% CI: 0.49 - 1.92) Similar results were observed at 3, 6, and 12 months of follow-up. Conclusions: The results indicate that after adjusting for covariates, there is no difference in risk of HCC recurrence associated with IFN-free DAA-based HCV treatment regimens when compared to regimens containing IFN.

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.

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.

Twelve Weeks of Ledipasvir/Sofosbuvir for Patients with Chronic Hepatitis C Genotype 2 Infection: Integrated Analysis of Three Clinical Studies

( Chung-feng Huang ),( Yasuhiro Asahina ),( Chun-jen Liu ),( Edward Gane ),( Yoshito Itoh ),( Norifumi Kawada ),( Yoshiyuki Ueno ),( Jin Youn ),( Chen-yu Wang ),( Joe Llewellyn ),( Anu Osinusi ),( Jen 대한간학회 2018 춘·추계 학술대회 (KASL) Vol.2018 No.1

Aims: HCV genotype (GT) 2 is the second most common genotype in several Asian countries including Taiwan and Korea. Treatment options for GT2 remain limited in these countries. The once-daily fixed-dose combination of ledipasvir/sofosbuvir (LDV/SOF) was evaluated for the treatment of GT 2, in patients with or without compensated cirrhosis, in three phase 2 and 3 studies. Methods: This was a retrospective analysis of subjects treated with LDV/SOF for 12 weeks in the GS-US-337-1655 (Taiwan), GS-US-337-1903 (Japan) and GS-US-1468 (New Zealand) studies. Subjects analyzed in this integrated analysis were either mono-infected with HCV GT2, or co-infected with HCV GT2 and HBV. The data was pooled and safety and efficacy were analyzed. Results: Overall 200 subjects were treated and analyzed; 88% of subjects were Asian, 46% male, 31% had prior treatment failure, 15% were cirrhotic, 25% were IL28B non-CC, 34% were 65 years or older and 22% (n=43) were co-infected with HBV. The overall SVR rate was 97% (194/200), and was 93% (27/29) among patients with cirrhosis and 97% (59/61) in patients who had failed previous therapy. Of the 197 patients with available testing; NS5A resistance-associated substitutions (RASs) were present in 86% (169/197) at baseline. SVR12 rate was 98% (165/169) in patients with baseline NS5A RASs compared with 100% (28/28) in patients without NS5A RASs. No new RASs emerged in patients with virologic failure. Treatment with LDV/SOF for 12 weeks was well tolerated. Overall the most common adverse events AEs were headache and nasopharyngitis. Few subjects experienced serious AEs, none of which were assessed as treatment related. One patient discontinued treatment due to AE. Conclusions: Treatment with LDV/SOF for 12 weeks is highly effective and well tolerated in patients with GT2 HCV infection, including patients who are treatment experienced and/or have compensated cirrhosis, baseline NS5A RASs and with HBV/HCV coinfection.