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.

Ledipasvir/Sofosbuvir for 12 or 24 Weeks Is Safe and Effective in Kidney-transplant Recipients with Genotype 1 or 4 HCV Infection

( Massimo Colombo ),( Alessio Aghemo ),( Lin Liu ),( Robert H. Hyland ),( Chohee Yun ),( Diana M. Brainard ),( John G. Mchutchison ),( Sunjin Hwang ),( Marc Bourliere ),( Markus Peck-radosavljevic ),( 대한간학회 2016 춘·추계 학술대회 (KASL) Vol.2016 No.1

Methods: Kidney transplant recipients with chronic GT1 or GT4 HCV infection, treatment-naive and treatment-experienced, with or without compensated cirrhosis were randomized 1:1 at 5 sites in Europe to receive LDV/SOF (90 mg/400 mg) for 12 or 24 weeks. Randomization was stratified by HCV genotype, treatment history and presence or absence of cirrhosis. Cirrhosis was determined by liver biopsy (Metavir score = 4 or Ishak score ≥5), Fibroscan® >12.5 kPa, or Fibrotest® >0.75 and APRI >2. A pretreatment creatinine clearance <40 mL/min was an exclusionary criterion. The primary endpoint was SVR12. Results: 114 patients were randomized and treated; median age was 53, 58% were male, 94% were white, 72% carried the non-CC IL28B allele, 91% had GT 1 infection, 69% were treatment-naive, and 15% had compensated cirrhosis. The median eGFR was 56ml/min (range 35-135ml/min). All 92 patients with SVR4 data available achieved SVR4 including a patient discontinuing treatment at Week 4 due to an AE. SAEs were reported in 12 (11%) patients; 3 were assessed as treatment related: syncope, pulmonary embolism, and blood creatinine increased. The most frequent AEs were headache (19%), asthenia (13%), and fatigue (10%). Conclusions: Administration of LDV/SOF for 12 or 24 weeks in patients with chronic HCV genotype 1 or 4 patients who have undergone kidney transplant was safe and highly effective with an SVR4 rate of 100%. Treatment was well-tolerated. SVR12 data for all patients will be presented.

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.

Resistance Analyses for Ledipasvir/Sofosbuvir Containing Regimens in HCV-infected Patients Who Have Advanced Liver Disease or Are Post Liver Transplant

( Michael Charlton ),( Michael Manns ),( Hadas Dvory-sobol ),( Evguenia Svarovskaia ),( Brian Doehle ),( Sarah Arterburn ),( Chohee Yun ),( Diana M. Brainard ),( John G. Mchutchison ),( Michael Miller 대한간학회 2016 춘·추계 학술대회 (KASL) Vol.2016 No.1

Aims: Ledipasvir/sofosbuvir (LDV/SOF) with ribavirin (RBV) demonstrated high SVR rates in patients with chronic hepatitis C (HCV) genotype (GT) 1 or 4 infection who have decompensated cirrhosis or who have undergone liver transplantation. Here we evaluated the effect of baseline HCV NS5A and NS5B resistance-associated variants (RAVs) on treatment outcome and characterized the viral resistance in all virologic failures. Methods: Deep sequencing with a 1% assay cut-off was performed for NS5A and NS5B at baseline for all the patients and at the time of virologic failure for those who relapsed. Results: Out of 625, 622, and 619 samples were analyzed for baseline NS5A and NS5B respectively. Table 1 summarizes SVR12 rates by treatment duration and the presence or absence of baseline NS5A RAVs. NS5B RAVs at baseline were uncommon, occurring in 4.8% (28/586) GT1 patients and 3.2% (1/31) GT 4 patients. Of these 29 patients, only one GT1 patient with CPT C cirrhosis who had L159F at baseline and was treated for 24 weeks with LDV/SOF+RBV did not achieve SVR12. NS5A RAVs at positions 24, 28, 30, 31, 58, and 93 were enriched or emerged in 20/22 (91%) GT1 and 1/3 GT4 infected patients with virologic failure. The NS5B NI RAV E237G emerged in 3 GT1a patients and 1 GT4d patient at the time of relapse (4/23, 17%). Conclusions: The presence of baseline NS5A or NS5B RAVs did not impact the treatment outcome to 12 or 24 weeks of LDV/SOF+RBV in GT1 or GT4 HCV patients with liver ransplantation without decompensated liver disease, or 24 weeks of LDV/SOF+RBV in patients with decompensated cirrhosis. Lower SVR rates were observed among the limited number of patients with decompensated cirrhosis and baseline NS5A RAVs who received 12 weeks of LDV/SOF+RBV treatment.

The Accuracy of Transient Elastography and Comparison of Non-invasive Markers for Assessing Fibrosis in Korean Patients with Nonalcoholic Fatty Liver Disease

( Mark Sulkowski ),( Kwang-hyub Han ),( Jia-horng Kao ),( Jenny C. Yang ),( Bing Gao ),( Diana M. Brainard ),( Wan-long Chuang ),( Edward J. Gane ) 대한간학회 2016 춘·추계 학술대회 (KASL) Vol.2016 No.1

Aims: HBV reactivation during HCV treatment with direct-acting antiviralregimens has been reported in HCV infected patients who areHB surface antigen (HBsAg) negative, HB core antibody (HBcAb) positive,and HBV DNA undetectable. To evaluate the risk of HBV reactivationin these HCV infected patients, we analyzed samples froma Phase 3b study, GS-US-337-0131, of ledipasvir/sofosbuvir (LDV/SOF)for 12 weeks conducted in Korea and Taiwan where HBV is endemic.All enrolled subjects were HBsAg negative at screening per protocol.The SVR12 rate was 98% in this trial.Methods: A serum sample per patient, collected during post-treatmentfollow up was analyzed for HBcAb. Samples positive for HBcAb wereanalyzed for HBV DNA and retested for HBsAg if HBV DNA wasdetectable.Results: 173 of 178 patients had one post-treatment sample withinthe 1 year stability limit. Of the 173 patients, 60% (n=103) wereHBcAb positive and HBsAg negative; no subject was HBsAg positive.Two of 103 patients had HBV DNA <20 IU/mL, detected and theremaining patients were <20 IU/mL, target not detected. MedianALT during treatment and post-treatment follow-up were similar betweenHBcAb positive and negative patients; all patients had ALTdeclined from baseline. No patients had clinical signs of HBV reactivationduring treatment or post-treatment follow up. No differencesin overall adverse events or laboratory abnormality observedin patients who were HBcAb positive or negative.Conclusions: Among 103 HCV-infected patients with reactive HB coreantibody and absent HB surface antigen, there was no evidence ofHBV reactivation following successful HCV treatment with LDV/SOF.These data suggest HBV reactivation in patients with HCV and reactiveHB core antibody is uncommon. A Phase 3b study evaluating 12weeks of LDV/SOF in patients with chronic HCV and overt HBV (HBsAgpositive) co-infection is ongoing in Taiwan and can provide furthersafety information.

Absence of HBV Reactivation among HCV Infected Patients with Reactive Hepatitis B Core Antibody Treated withLedipasvir/Sofosbuvir for 12 Weeks

( Mark Sulkowski ),( Kwang-hyub Han ),( Jia-horng Kao ),( Jenny C. Yang ),( Bing Gao ),( Diana M. Brainard ),( Wan-long Chuang ),( Edward J. Gane ) 대한간학회 2016 춘·추계 학술대회 (KASL) Vol.2016 No.1

Aims: HBV reactivation during HCV treatment with direct-acting antiviralregimens has been reported in HCV infected patients who areHB surface antigen (HBsAg) negative, HB core antibody (HBcAb) positive,and HBV DNA undetectable. To evaluate the risk of HBV reactivationin these HCV infected patients, we analyzed samples froma Phase 3b study, GS-US-337-0131, of ledipasvir/sofosbuvir (LDV/SOF)for 12 weeks conducted in Korea and Taiwan where HBV is endemic.All enrolled subjects were HBsAg negative at screening per protocol.The SVR12 rate was 98% in this trial.Methods: A serum sample per patient, collected during post-treatmentfollow up was analyzed for HBcAb. Samples positive for HBcAb wereanalyzed for HBV DNA and retested for HBsAg if HBV DNA wasdetectable.Results: 173 of 178 patients had one post-treatment sample withinthe 1 year stability limit. Of the 173 patients, 60% (n=103) wereHBcAb positive and HBsAg negative; no subject was HBsAg positive.Two of 103 patients had HBV DNA <20 IU/mL, detected and theremaining patients were <20 IU/mL, target not detected. MedianALT during treatment and post-treatment follow-up were similar betweenHBcAb positive and negative patients; all patients had ALTdeclined from baseline. No patients had clinical signs of HBV reactivationduring treatment or post-treatment follow up. No differencesin overall adverse events or laboratory abnormality observedin patients who were HBcAb positive or negative.Conclusions: Among 103 HCV-infected patients with reactive HB coreantibody and absent HB surface antigen, there was no evidence ofHBV reactivation following successful HCV treatment with LDV/SOF.These data suggest HBV reactivation in patients with HCV and reactiveHB core antibody is uncommon. A Phase 3b study evaluating 12weeks of LDV/SOF in patients with chronic HCV and overt HBV (HBsAgpositive) co-infection is ongoing in Taiwan and can provide furthersafety information.

Use of Ledipasvir/Sofosbuvir (LDV/SOF) in Patients with Advanced Chronic Kidney Disease (eGFR ≤30ml/min): A Case Series

( Meghan E. Sise ),( Naim Alkhouri ),( Brian Borg ),( Sooji Lee ),( Thomas Mcquaid ),( Joseph Llewellyn ),( Macky Natha ),( Shampa De-oertel ),( Diana M. Brainard ),( Marc Carp ),( Michael Fuchs ),( H 대한간학회 2017 춘·추계 학술대회 (KASL) Vol.2017 No.1

Aims: Little is known about the safety and efficacy of LDV/SOF in patients with advanced chronic kidney disease (CKD) with eGFR ≤ 30 ml/min or on hemodialysis. Yet, off-label use of LDV/SOF in this population occurs. Methods: Providers proactively reporting such off-label use to Gilead Sciences were asked to submit de-identified case reports. Demographics, clinical characteristics at baseline, during, and after LDV/SOF treatment, and adverse events were collected. Summary statistics and paired sample t-tests are presented. Results: Twenty-one case summaries were submitted. Median Age was 59 (range 26-71). Eleven patients (52%) were black, 20 had genotype 1 (13-1a, 4-1b) and one patient had genotype 3. Median pretreatment viral load was 1,680,000 IU (range 133,000-37,200,000 IU). Twelve patients (56%) were on hemodialysis and 9 had CKD Stage 4 (eGFR 15-29 ml/min), 13 (62%) had cirrhosis, 11 (50%) had diabetes, 5 had history of organ transplantation (4 kidney, 1 liver). All patients received full dose LDV/SOF for 12 weeks with one patient also receiving 200 mg Ribavirin every other day in combination. Eight adverse events were reported; 2 patients (10%) with anemia, 1 case of insomnia, nausea/vomiting, headache, and chest pain (5%) each. Of the 9 patients with CKD stage 4, 2 experienced an increase in eGFR and 5 a decrease in eGFR post treatment. All 21 patients achieved SVR 12 (100%). No patient discontinued treatment due to an adverse event. Conclusions: In this small case series describing the use of ledipasvir/sofosbuvir in Patients with Advanced Chronic Kidney Disease: 62% had cirrhosis, 52% had diabetes mellitus, and 57% were on hemodialysis. All 21 patients achieved SVR12 including 12 patients on hemodialysis. LDV/SOF was relatively well tolerated and there were no treatment discontinuations. Most patients had stable renal function before and after treatment with LDV/SOF.

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.

High Rates of SVR12 in Adolescents Treated with the Combination of Ledipasvir/Sofosbuvir

( Kathleen Schwarz ),( Karen F. Murray ),( Philip Rosenthal ),( Sanjay Bansal ),( Chuan-hao Lin ),( Sooji Lee ),( Liyun Ni ),( Bittoo Kanwar ),( Jenna Fraser ),( Polina German ),( Diana M. Brainard ) 대한간학회 2018 춘·추계 학술대회 (KASL) Vol.2018 No.1

Aims: Although direct acting antivirals have transformed HCV treatment of adults, the standard of care for adolescents and younger children with GT1 HCV is still limited to treatment with pegylated interferon+ribavirin for 48 weeks. The aim of this study was to evaluate the safety, efficacy and pharmacokinetics of the fixed dose single tablet regimen, ledipasvir/sofosbuvir (LDV/SOF), administered for 12weeks in GT1 HCV-infected adolescent patients. Methods: Treatment-naive and treatment-experienced adolescent patients aged 12 to less than 18 years old with chronic GT1 HCV were enrolled into this open-label ongoing study to receive 12 weeks of treatment with LDV/SOF 90mg/400 mg once daily. The primary efficacy endpoint is SVR12 (HCV RNA<lower limit of quantitation). Safety is assessed by clinical evaluation and laboratory monitoring. Intensive pharmacokinetic (PK) sampling was done on Day 10 in the first 10 patients (PK lead-in) to confirm the appropriateness of the adult dose in the adolescent population. Results: 100 GT1 patients have been enrolled and treated. The majority are GT1a (81%), female (63%), white (90%), treatment-naive (80%), and vertically infected (84%). The mean age is 15 (range 12-17) years. In the PK lead-in, administration of 1 tablet daily of LDV/SOF provided comparable plasma exposures of LDV, SOF, and GS-331007 (SOF primary metabolite) to those observed in adults. SVR12 rate was 97% (97/100). 3 patients were lost to follow-up. No serious adverse events (AEs) have been reported. AEs are generally mild in severity and grade 3/4 laboratory abnormalities have been infrequent and transient. Conclusions: The 12-week regimen of LDV/SOF 90mg/400 mg has resulted in high SVR rates and is well-tolerated. This regimen provides a safe and effective therapy for adolescents with GT1 HCV infection. Further evaluation is ongoing in children aged 3-11 years old.