Safety of Sofosbuvir-Based Regimens for the Treatment of Chronic HCV Infection in Patients with Mild or Moderate Renal Impairment

( Sulkowski M ),( Durand F ),( Reddy Kr ),( Lawitz E ),( Bourlière M ),( Cheinquer N ),( Scherbakovsky S ),( Chokkalingam A ),( Ni L ),( Gaggar A ),( Colombo M ),( Kyung Min K ) 대한간학회 2020 춘·추계 학술대회 (KASL) Vol.2020 No.1

Aims: The major metabolite of sofosbuvir (SOF), GS-331007, is cleared renally and tends to accumulate in patients with chronic kidney disease (CKD). However, there are a substantial amount of data showing that this accumulation is not clinically significant, even in patients with end stage renal disease. Methods: This retrospective analysis of 37 Phase 2 and 38 Phase 3 studies presents the safety profile of SOF-based therapies (LDV/SOF, SOF/VEL and SOF/VEL/VOX) in patients with mild to moderate CKD as well as in patients with normal renal function. Results: 8,181 patients were included in this analysis. Mean baseline eGFR was 118.2, 69.3, and 43.6 mL/min/1.73m2 for patients with normal renal function (n=6575), mild (n=1499), or moderate (n=107) renal impairment, respectively. The mean eGFR at post-treatment follow-up week 4 was 114.4, 69.9, and 46.3 mL/min/1.73m2 for patients with normal renal function (n=5519), mild (n=1285), or moderate (n=90) renal impairment, respectively. When comparing baseline levels with those of post-treatment follow-up week 4, there was no clinical difference observed. Baseline characteristics were generally similar across groups, except patients with impaired renal function were older. Table 1 provides a summary of adverse events (AEs). Rates of Grade 3-4 AEs and discontinuations due to AEs were similar across groups. Patients with moderate renal impairment had higher rates of SAEs but most were not treatment-related. Conclusions: Sofosbuvir-based regimens were safe and well-tolerated in patients with mild or moderate renal impairment. Renal function remained stable throughout treatment, and similar rates of AEs were observed across all treatment groups.

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.

Appropriate Application of Direct Acting Antivirals

( Mark Sulkowski ) 대한간학회 2016 춘·추계 학술대회 (KASL) Vol.2016 No.1

Introduction. Five years after the first generation of direct acting antiviral (DAA) regimens gained notoriety for their complexity and treatment-limiting toxicity, multiple oral DAA regimens have been approved by the FDA with the promise of simple, well-tolerated, highly effective therapy. Early observations from large, “real-world” cohorts of patients treated with such regimens indicate that high rates of HCV cure can be achieved in clinical practice. Many observers have concluded that HCV treatment in the modern era is simple and, for many individuals with hepatitis C, this statement is correct. However, there is considerable heterogeneity with respect to the available HCV DAA regimens (> 5 are approved), the virus characteristics (genotypes, subtypes and other polymorphisms conferring resistance to DAAs and patient characteristics (advanced renal and liver disease). In this context, HCV treatment guidelines developed jointly by the American Association for the Study of the Liver (AASLD) and the Infectious Disease Society of America (IDSA) have a crucial role in helping patient and clinician navigate the path toward HCV cure.

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.

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.

Symposium: Current and future issues in hepatitis C treatment : Current and future issues in hepatitis C treatment: Non-responders and relapsers

Mark S. Sulkowski 대한간학회 2009 Clinical and Molecular Hepatology(대한간학회지) Vol.15 No.4(S)

The management of persons non-responsive to peginterferon and RBV therapy requires careful assessment of the liver disease stage and prior treatment course with respect to virologic response and tolerability. Re-treatment with interferon and RBV should be considered in persons with inadequate prior treatment andcorrectable factors as well as those with partial response to prior therapy (>2 log10 at week 12). However, during re-treatment, the milestone measure of treatment effectiveness is the achievement of an undetectable HCV RNA at re-treatment week 12; patients who do not have an undetectable HCV RNA level at this milestone should discontinue therapy. For patients who become undetectable, longer therapy (72 weeks) may increase the likelihood of SVR by reducing the rate of relapse. For patients who remain detectable, long-term interferon therapy is not uniformly recommended but may be considered in persons with baseline portal hypertension based on the findings of the EPIC3study. Persons with treatment failure should be referred to clinical trials of novel therapeutic agents.

Effect of Baseline Resistance-associated Variants on SVR with the 3D Regimen with and without RBV in GT1a and GT1b-infected Patients

( Christoph Sarrazin ),( Mark S. Sulkowski ),( Preethi Krishnan ),( Rakesh Tripathi ),( Gretja Schnell ),( Yan Xie ),( Daniel E. Cohen ),( Roger Trinh ),( Lino Rodrigues-jr. ),( Yan Luo3,Nancy S. Shul 대한간학회 2016 춘·추계 학술대회 (KASL) Vol.2016 No.1

Aims: The 3 direct-acting antiviral (3-DAA) regimen of ombitasvir, ritonavir-boosted paritaprevir and dasabuvir ± RBV is approved in the US and EU for treatment of hepatitis C virus (HCV) genotype (GT) 1 infection. Baseline resistance associated variants (RAVs) in HCV NS3 or NS5A can impact response to other DAA regimens; we assessed the prevalence and impact of RAVs on response to the 3-DAA regimen. Methods: Next-generation sequencing (Illumina MiSeq) assessed baseline samples from treatment-naive (PEARL-IV), -experienced (SAPPHIRE- II), or cirrhotic (TURQUOISE-II) GT1a patients who received 3-DAA + RBV, and treatment-experienced (PEARL-II) or cirrhotic (TURQUOISE-III) GT1b patients who received 3-DAA alone. Thresholds of 1 and 15%, respectively, detected the prevalence and impact of baseline RAVs; impact of RAVs conferring ≥ 5-fold resistance to components of the 3-DAA regimen on response was determined by com- paring SVR rates in patients with or without RAVs. Results: SVR rates were 96% and 100% in patients with GT1a and GT1b, respectively. One or more NS5A RAVs were present in 11% of treatment-experienced or cirrhotic GT1a patients, whereas NS5A RAVs were found in 19% of GT1b patients (15% threshold). Similar SVR rates were seen in GT1a patients with or without NS5A RAVs. All GT1b patients with NS5A RAVs, including at position Y93, achieved SVR. NS3 RAVs were uncommon (≤2%). NS3 RAVs were not seen in any of the 14 virologic failures and an NS5B RAV was seen in 1 virologic failure. The presence of the GT1a NS3 Q80K polymorphism had no impact on SVR. Conclusions: Understanding impact of baseline NS5A RAVs on treatment outcomes is important for relevant HCV therapies. Patients with HCV GT1a-infection treated with the 3-DAA regimen + RBV achieved high SVR rates, regardless of the presence of baseline RAVs. All GT1b patients treated with the 3-DAA regimen alone achieved SVR.

HCV : PE-135 ; Boceprevir plus peginterferon/ribavirin for the treatment of HCV/HIV co-infected patients: End of treatment (WEEK 48) interim results

( J Mallolas ),( S Pol ),( A Rivero ),( H Fainboim ),( C Cooper ),( J Slim ),( S Thompson ),( J Wahl ),( W Greaves ),( M Sulkowski ) 대한간학회 2012 춘·추계 학술대회 (KASL) Vol.2012 No.1

Background: Addition of boceprevir (BOC) to peginterferon (P) and ribavirin (R) significantly increases SVR among HCVmonoinfected patients for whom SVR rates have been low. The objective of this phase 2 trial was to investigate the efficacy and safety of BOC+P/R in HCV/HIV-coinfected patients. Methods: In this multicenter, double-blind, international trial, patients with untreated hepatitis C genotype 1 infections and HIV RNA <50 copies/mL were randomized 2:1 to receive P (PEG 2b 1.5 ug/kg/wk)/R (600-1400 mg/day, by weight) + BOC 800mg TID or P/R+placebo for 44 weeks, after a 4-week lead-in of P/R. NNRTIs, zidovudine, or didanosine were not permitted. Patients were stratified by: cirrhosis/fibrosis (yes vs. no) and baseline HCV-RNA (<800,000 IU/mL vs ≥800,000 IU/mL). The primary efficacy endpoint was SVR, undetectable plasma HCV-RNA 24 weeks after end of treatment (EOT). Secondary endpoints and planned interim analyses included proportion of subjects with undetectable HCV-RNA at treatment week (TW) 4, 8, 12, 24 and 48/EOT. Results: 100 patients were randomized between 11/2009 and 12/2010; 2 patients in the BOC arm did not receive medication; thus, 34 control and 64 experimental patients were treated. The majority were non-cirrhotic (95%), white (82%), male (69%) with median age ~43 years. Most had high baseline HCV-RNA (88%) and HCV genotype 1a (65%). At TW48/EOT, the rate of undetectable HCV-RNA was 63.9% and 29.4% in the BOC and control arms, respectively (Table). 61% of the BOC group and 32% of the control group completed 48 weeks of treatment; 20% and 9%, respectively, discontinued due to adverse events. HCV treatment failure occurred in 9% of the BOC group and 53% of the control group. BOC patients were more likely than controls to have decreased appetite, pyrexia, dysgeusia, vomiting, asthenia, anemia, and neutropenia. By TW48, 2 patients in the BOC group and 3 in the control group had HIV virologic failure. Conclusion: The addition of BOC to P/R was associated with higher rates of undetectable HCV-RNA at all time points, including TW48/EOT. The safety and tolerability profile was consistent with that observed in HCV-monoinfected patients. PE-136 Sustained virologic response (SVR) in prior peginterferon/ribavirin (PR) treatment failures after retreatment with boceprevir (BOC) + PR: The PROVIDE study interim results JP Bronowicki1, M Davis2, S Flamm3, S Gordon4, E Lawitz5, E Yoshida6, J Galati7, V Luketic8, J McCone9, I Jacobson10, P Marcellin11-12, A Muir13, F Poordad14, LD Pedicone15, W Deng15, M Treitel15, J Wahl15, J Vierling16 1University Henri Poincare of Nancy, Vandoeuvre-les-Nancy, France; 2South Florida Center of Gastroenterology, Wellington, FL, USA; 3Northwestern Feinberg School of Medicine, Chicago, IL, USA; 4Henry Ford Hospital, Detroit, MI, USA; 5Alamo Medical Research, San Antonio, TX, USA; 6University of British Columbia and Vancouver General Hospital, Vancouver, BC, Canada; 7Liver Specialists of Texas, Houston, TX, USA; 8Virginia Commonwealth University School of Medicine, Richmond, VA, USA; 9Mt. Vernon Endoscopy Center, Alexandria, VA, USA; 10Weill Cornell Medical College, New

HCV, Alcoholic : PE-135 ; Boceprevir plus peginterferon/ribavirin for the treatment of HCV/HIV co-infected patients: End of treatment (WEEK 48) interim results

( J Mallolas ),( S Pol ),( A Rivero ),( H Fainboim ),( C Cooper ),( J Slim ),( S Thompson ),( J Wahl ),( W Greaves ),( M Sulkowski ) 대한간학회 2012 춘·추계 학술대회 (KASL) Vol.2012 No.-

Background: Addition of boceprevir (BOC) to peginterferon (P) and ribavirin (R) significantly increases SVR among HCV- monoinfected patients for whom SVR rates have been low. The objective of this phase 2 trial was to investigate the efficacy and safety of BOC+P/R in HCV/HIV-coinfected patients. Methods: In this multicenter, double-blind, international trial, patients with untreated hepatitis C genotype 1 infections and HIV RNA <50 copies/mL were randomized 2:1 to receive P (PEG 2b 1.5 ug/kg/wk)/R (600-1400 mg/day, by weight) + BOC 800mg TID or P/R+placebo for 44 weeks, after a 4-week lead-in of P/R. NNRTIs, zidovudine, or didanosine were not permitted. Patients were stratified by: cirrhosis/fibrosis (yes vs. no) and baseline HCV-RNA (<800,000 IU/mL vs ≥800,000 IU/mL). The primary efficacy endpoint was SVR, undetectable plasma HCV-RNA 24 weeks after end of treatment (EOT). Secondary endpoints and planned interim analyses included proportion of subjects with undetectable HCV-RNA at treatment week (TW) 4, 8, 12, 24 and 48/EOT. Results: 100 patients were randomized between 11/2009 and 12/2010; 2 patients in the BOC arm did not receive medication; thus, 34 control and 64 experimental patients were treated. The majority were non-cirrhotic (95%), white (82%), male (69%) with median age ~43 years. Most had high baseline HCV-RNA (88%) and HCV genotype 1a (65%). At TW48/EOT, the rate of undetectable HCV-RNA was 63.9% and 29.4% in the BOC and control arms, respectively (Table). 61% of the BOC group and 32% of the control group completed 48 weeks of treatment; 20% and 9%, respectively, discontinued due to adverse events. HCV treatment failure occurred in 9% of the BOC group and 53% of the control group. BOC patients were more likely than controls to have decreased appetite, pyrexia, dysgeusia, vomiting, asthenia, anemia, and neutropenia. By TW48, 2 patients in the BOC group and 3 in the control group had HIV virologic failure. Conclusion: The addition of BOC to P/R was associated with higher rates of undetectable HCV-RNA at all time points, including TW48/EOT. The safety and tolerability profile was consistent with that observed in HCV-monoinfected patients.