Sofosbuvir/Velpatasvir/Voxilaprevir for 12 Weeks is a Safe and Effective Salvage Regimen in NS5A Inhibitor-Experienced Patients with Genotype1-6 Infection: The POLARIS-1 Study

( Edward J. Gane ),( Marc Bourliere ),( Stuart C. Gordon ),( Alnoor Ramji ),( Natarajan Ravendhran ),( Tram T. Tran ),( Rob H. Hyland ),( Jie Zhang ),( Hadas Dvory-sobol ),( Luisa M. Stamm ),( Diana M 대한간학회 2017 춘·추계 학술대회 (KASL) Vol.2017 No.1

Aims: NS5A inhibitors are potent DAAs which are key components of HCV treatment regimens. In combination with other DAAs, NS5A inhibitors provide cure to over 90% of patients. For patients who have failed a regimen with an NS5A inhibitor, there is concern about long-lasting NS5A RASs and currently no approved retreatment option. Sofosbuvir (SOF) and velpatasvir (VEL) are pangenotypic inhibitors of the NS5B and NS5A proteins, respectively, and voxilaprevir (VOX) is a pangenotypic NS3/4A protease inhibitor. This study evaluates treatment with a SOF/VEL/VOX for 12 weeks in patients who previously received an NS5A inhibitor. Methods: Eligible patients received at least 4 weeks of a prior NS5A inhibitor-containing. Those with HCV GT1 were randomized 1:1 to receive SOF/VEL/VOX (400mg/100 mg/100 mg) or matching placebo daily for 12 weeks, stratified by the presence or absence of cirrhosis. Patients of all other GTs were assigned to receive SOF/VEL/VOX for 12 weeks. Those patients assigned to receive placebo were offered deferred treatment with SOF/VEL/VOX for 12 weeks. The primary endpoint evaluated the superiority of SVR12 to a performance goal of 85%. Results: Of 415 patients enrolled and treated with SOF/VEL/VOX, 76% were male, 80% were white, 46% had compensated cirrhosis, and 57% had GT 1infection. The majority of patients had DAA experience with an NS5A inhibitor given in combination with an NS5B inhibitor, and the most common prior NS5A inhibitor was ledipasvir (50%). Treatment with SOF/VEL/VOX was well tolerated. No serious adverse events attributed to study medication were reported. Overall, 253/263 (96%) of patients treated with SOF/VEL/VOX achieved SVR12, which was superior to the prespecified goal of 85% (p<0.001). High SVR12 was achieved across HCV GTs and regardless of selected baseline factors such as cirrhosisand RASs at any position. Conclusions: SOF/VEL/VOX for 12 weeks is a safe, well-tolerated and effective treatment for patients previously failed an NS5A inhibitor-containing DAA regimen, a group that currently has no retreatment option.

An Integrated Analysis of the Efficacy of Glecaparevir/ Pibrentasvir by Geographical Region

( Edward Gane ),( Kazuaki Chayama ),( Mudra Kapoor ),( Stuart K Roberts ),( Jeong Heo ),( Jia-horng Kao ),( Thomas Berg ),( Philippe J Zamor ),( Brian Conway ),( James Park ),( Sandra S Lovell ),( Rak 대한간학회 2018 춘·추계 학술대회 (KASL) Vol.2018 No.1

Aims: The pangenotypic direct-acting antiviral (DAA) regimen glecaprevir (developed by AbbVie and Enanta) coformulated with pibrentasvir (G/P) is approved in the US, EU, and Japan to treat chronic HCV genotype (GT) 1-6 infection. In the US and EU, G/P is indicated for treatment-naïve, HCV genotype (GT) 1-6-infected patients without and with compensated cirrhosis for 8-week and 12-week treatment durations, respectively, and achieved SVR12 rates ≥95% across all six major GTs. In clinical studies, G/P exposures were similar across ethnicities; an integrated analysis of the efficacy of G/P by geographical region was conducted to assess the impact of geography and ethnicity on SVR12. Methods: Data were pooled from 9 phase 2 and 3 clinical studies; data from 2 additional phase 3 clinical studies conducted in Japan were pooled separately. Patients had HCV GT1-6 infection with or without compensated cirrhosis and were either HCV treatment-naïve or experienced with interferon (IFN) or pegIFN with or without ribavirin (RBV), sofosbuvir and RBV with or without pegIFN, or NS5A- and/or protease inhibitor-containing regimens. G/P (300 mg/120 mg) was orally dosed once-daily for 8, 12, or 16 weeks. The primary efficacy endpoint in all studies was SVR12. Safety and tolerability were assessed in all patients. Data from all 11 studies will be pooled for presentation. Results: In total, 2369 patients were included in the integrated analysis: 964 (41%) were enrolled in North America, 891 (38%) in Europe, and 514 (22%) enrolled and pooled from Taiwan, Korea, Australia, New Zealand, Chile, Israel, and South Africa; 332 additional patients were enrolled in Japan. The SVR12 results by region were 97% (935/964; 95% CI 95.9-98.1), 98% (876/891; 95% CI 97.5-99.1), and 96% (496/514; 95% CI 94.9-98.1) for patients enrolled in North America, Europe, and the other pooled countries, respectively. Patients enrolled in Japan achieved a 98% (325/332; 95% CI 95.7-99.0) SVR12 rate. Less than 1% of all patients had virologic failure. G/P was well-tolerated with a favorable safety profile; treatment discontinuations due to adverse events and cases of drug-induced liver injury were rare (<1%). Conclusions: G/P efficacy, safety and tolerability were consistently favorable regardless of baseline characteristics, suggesting that recently updated HCV treatment guidelines for the use of G/P in clinical practice can be applied to all ethnicities and geographical regions, without need for modification.

The Safety and Tolerability of SOF/VEL/VOX for 8/12 Weeks in >1,000 Patients Treated in the POLARIS Studies: An Integrated Analysis

( Michael Manns ),( Edward J. Gane ),( Bernard E. Willems ),( Stuart K. Roberts ),( Steven Flamm ),( Marc Bourlière ),( Tarik Asselah ),( Laurent Alric ),( Sunjin Hwang ),( Robert H. Hyland ),( Luisa 대한간학회 2017 춘·추계 학술대회 (KASL) Vol.2017 No.1

Aims: The once-daily fixed-dose combination tablet of sofosbuvir/ velpatasvir/voxilaprevir (SOF/VEL/VOX) was evaluated for the treatment of genotype 1-6 HCV patients with and without compensated cirrhosis. Treatment was for 12 weeks for DAA-experienced patients (POLARIS-1 and POLARIS-4) and for 8 weeks for DAA-naive patients (POLARIS-2 and POLARIS-3). This analysis describes the safety of these 4 Phase 3 studies. Methods: Treatment-emergent adverse events (AEs) and laboratory abnormalities were assessed in patients who received SOF/VEL/VOX or placebo for 12 weeks(POLARIS-1), SOF/VEL/VOX or SOF/VEL for 12 weeks(POLARIS-4), or SOF/VEL/VOX for 8 weeks or SOF/VEL for 12 weeks(POLARIS-2 and POLARIS-3). SAEs and deaths were followed until post-treatment Week 24. Results: 1056 patients were treated with SOF/VEL/VOX for 8 (n=611) or 12 (n=445) weeks, 700 received SOF/VEL for 12 weeks, and 152 received placebo. 38% had compensated cirrhosis, 28% had a BMI ≥30 kg/m2, 36% were female, and 12% were ≥65 years old. Two deaths were reported, one illicit drug overdose and one attributed to hypertension, neither were related to treatment. SAEs and discontinuations were more frequent in the placebo group and occurred with similar frequency in the other groups; none were related to study treatment. Headache, fatigue, nausea, and diarrhea were the most common AEs. Mild diarrhea and nausea occurred more frequently in the SOF/VEL/VOX groups. Overall, 5.1 - 6.6% of patients who received SOF/VEL/VOX or SOF/VEL had Grade 3 or 4 laboratory abnormalities. Among patients receiving VOX, one patient each had a Grade 3 elevation in ALT and bilirubin. Conclusions: SOF/VEL/VOX for 8 or 12 weeks in the POLARIS studies was well tolerated with a low frequency of Grade 3 or 4 AEs, SAEs, and AEs leading to discontinuation. The frequency of AEs in the SOF/VEL/VOX groups was similar to SOF/VEL and placebo groups, with higher rates of mild diarrhea and nausea compared to SOF/VEL.

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.

Switching from Tenofovir Disoproxil Fumarate (TDF) to Tenofovir Alafenamide (TAF) in Virally Suppressed Chronic Hepatitis B (CHB) Patients with Moderate or Severe Renal Impairment, or in End-Stage Renal Disease (ESRD) Patients on Hemodialysis (HD): Week 2

( Jeong Heo ),( Harry L.A. Janssen ),( Young-suk Lim ),( Edward J. Gane ),( Claire Fournier ),( Sang Hoon Ahn ),( Owen Tsang ),( Wan-long Chuang ),( Aric Josun Hui ),( Magdy Elkhashab ),( Chi-yi Chen 대한간학회 2020 춘·추계 학술대회 (KASL) Vol.2020 No.1

Aims: TAF, a novel tenofovir prodrug, has demonstrated noninferior efficacy to TDF with superior bone and renal safety in virally suppressed CHB patients with eGFR (by Cockcroft-Gault; eGFR_CG) ³50 mL/min when switched from TDF. The efficacy and safety of virally suppressed patients on TDF with renal impairment who were switched to TAF were evaluated in this Phase 2 study. Methods: CHB patients with renal impairment taking TDF for ³48 weeks and virally suppressed for ³6 months with HBV DNA <20 IU/mL at screening were enrolled into 2 cohorts: 1) moderate-severe renal impairment (eGFR_CG 15 to <60mL/min) and 2) ESRD (eGFR_CG <15 mL/min) patients on chronic HD. All patients were switched to TAF 25 mg QD for 96 weeks. Co-primary endpoints were proportion with HBV DNA <20 IU/mL and graded adverse events (AEs)/lab abnormalities at Week 24. Results: 93 patients (Mod-severe impairment 78; ESRD 15) were enrolled from 26 sites in 8 countries. Median age was 65 years, 74% male, 77% Asian, 83% HBeAg-negative, up to 60% had low BMD at hip and/or spine, and 60% and 24% had a history of HTN and/or diabetes, respectively. Key efficacy/safety results at Week 24 are summarized in the Table. All patients on treatment at Week 24 maintained HBV DNA <20 IU/mL and a high proportion had normal ALT levels. Relative to baseline levels, switching to TAF from TDF resulted in increases in hip/spine BMD, decreases in bone turnover markers, as well as increases in eGFR_CG and decreases in renal tubular markers. TAF was well tolerated with few having Grade 3 or 4 AEs (8%) and no discontinuations due to AEs. Conclusions: In renally-impaired CHB patients, including ESRD patients on HD, viral suppression was well maintained and the bone and renal safety were improved 24 weeks after switching from TDF to TAF.

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.

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.

Viral Kinetics in Women of Child Bearing Potential with Chronic HBV Following Treatment with Tenofovir Alafenamide or Tenofovir Disoproxil Fumarate

( Brunetto ),( Carla Coffin ),( Audrey Lau ),( Shuyuan Mo ),( John F. Flaherty ),( Anuj Gaggar ),( G Mani Subramanian ),( Mindie H. Nguyen ),( Selim Gurel ),( Alexander Thompson ),( Edward J. Gane ) 대한간학회 2017 춘·추계 학술대회 (KASL) Vol.2017 No.1

Aims: Suppression of the HBV in women of childbearing potential (WOCBP) has important implications in preventing transmission of HBV from mother to infant. Antiviral therapy that reduces HBV DNA to < 2x105 IU/mL at delivery in mothers can substantially reduce the risk of perinatal transmission. We evaluated the viral kinetics of TAF and TDF in WOCBP. Methods: : In two Phase 3 studies (HBeAg positive and negative patients), 1301 patients (37% female) were randomized (2:1) to receive TAF 25 mg QD or TDF 300 mg QD. All patients were required to have HBV DNA >2x104 IU/mL at screening and serum ALT >2 times AASLD criteria.WOCBP were defined as nonmenopausal females 18 years or older without history of hysterectomy, bilateral oophorectomy, or ovarian failure. For this subanalysis, patients were stratified by baseline HBV DNA levelsand the endpoints were virologic suppression to HBV DNA <29 IU/mL or < 2x105 IU/mL. Results: 365(76%) female were identified as WOCBP with 118 (32%) having HBV DNA >1x108 IU/mL at baseline. Suppression rates were generally similar between TAF and TDF groups and within viral load strata for HBeAg positive and negative patients. After 12 weeks of treatment with TAF or TDF, 77% of WOCBP with baseline HBV DNA <2x105 IU/mL had full suppression to <29 IU/mL compared to 1% of those at the highest baseline viral load (Figure A). By Week 24, 54% of all WOCBP had achieved complete viral suppression. Of WOCBP with baseline viral load ≥2x105 IU/mL (n=305), 76%, 89%, and 93% achieved viral load reduction to <2x105 IU/mL by Weeks 4, 8, and 12, respectively (Figure B). Conclusions: After 12 weeks of treatment the majority of WOCBP had HBV DNA to <2x105 IU/mL. In women with higher baseline viral loads, longer treatment duration may be necessary to achieve viral suppression below recommended thresholds.