Safety and Efficacy of Elbasvir/Grazoprevir in Asian Participants with Hepatitis C Virus Genotypes 1 and 4 Infection

( Wei Lai ),( Hiromitsu Kumada ),( Ponni Perumalswami ),( Tawesak Tanwandee ),( Wendy Cheng ),( Jeong Heo ),( Pin Nan Cheng ),( Peggy Hwang ),( Sheng Mei Mu ),( Xu Min Zhao ),( Michael Robertson ),( B 대한간학회 2018 춘·추계 학술대회 (KASL) Vol.2018 No.1

Aims: Clinical experience with direct-acting antiviral treatments for hepatitis C virus (HCV) infection is emerging in the Asia-Pacific region. We conducted an integrated analysis of the safety and efficacy of elbasvir (EBR)/grazoprevir (GZR) in self-identified Asian participants who were enrolled in 11 EBR/GZR phase 2/3 studies. Methods: All participants received EBR/GZR 50 mg/100 mg alone for 12 weeks or in combination with ribavirin (RBV) for 16 weeks. The primary endpoint of all studies was sustained virologic response (HCV RNA < 15 IU/mL) 12 weeks after end of therapy (SVR12). Results: A total of 780 Asian participants with HCV GT1 or 4 infection were included (GT1b, n=715; GT1non-b, n=63; GT4, n=2). Most participants were enrolled from Japan (n=366, 46.9%), mainland China (n=146, 18.7%), Taiwan (n=109, 14.0%) and South Korea (n=90, 11.5%). Overall, 12.4% of participants had cirrhosis, and 20.4% were treatment-experienced. SVR12 was achieved by 756/780 (96.9%, 95% CI 95.5-98.0) of all Asian participants, including 748/772 (96.9%, 95% CI 95.4- 98.0) who received EBR/GZR for 12 weeks and 8/8 (100%, 95% CI 63.1-100.0) who received EBR/GZR + RBV for 16 weeks. The frequency of safety events among Asian participants was: any adverse event (AE), 58.1% (453/780), drug-related AEs, 23.6% (184/780), serious AEs, 2.6% (20/780), and discontinuation due to an AE, 0.9% (7/780). Fifteen participants (1.9%) had elevated ALT/AST levels that met the criteria for an event of clinical interest (ALT/AST >3× baseline and >100 U/L), 3 of whom discontinued treatment. The efficacy and safety profile of EBR/GZR was comparable to that observed among non-Asians. Conclusions: The combination of EBR/GZR was safe and highly effective in this large population of Asian participants with primarily HCV GT1b infection. Late transaminase elevations were reported in approximately 2% of participants, which is consistent with the safety profile of EBR/GZR in non-Asians.

Treatment of hepatitis C with direct-acting antiviral agents: Japanese experience

( Fumitaka Suzuki ),( Hiromitsu Kumada ) 대한간학회 2012 춘·추계 학술대회 (KASL) Vol.2012 No.1

In Japan, an estimated 100-150 million people are persistently infected with hepatitis C virus (HCV). The present standard-of-care (SOC) therapy for patients infected with HCV of genotype 1b, the most prevalent genotype in Japan, is peginterferon (PEG-IFN) combined with ribavirin (RBV) for 48 weeks. However, sustained virological response (SVR), judged by the loss of detectable HCV RNA from serum 24 weeks after the completion of therapy, can be achieved in only 42?52% of the patients. To cope with this grim situation, a number of direct acting antivirals (DAAs) have been designed and developed, represented by NS3/4A protease inhibitors and NS5B polymerase or NS5A inhibitors. Among them, telaprevir (TVR) has shown promising results, when combined with PEG-IFN and RBV, in the phase 2 and 3 clinical trials, by improving SVR to ~70% in patients infected with HCV-1. Moreover, the triple therapy with TVR, PEG-IFN, and RBV for 12 weeks, followed by PEG-IFN and RBV for an additional 12 weeks (T12PR24) were reimbursed since November 2011 in Japan. In Japanese clinical studies (phase III, T12PR24), the SVR rates of naive, relapse and non-responder were 73% (92/126), 88% (96/109) and 35% (11/32). We investigate the predictive factors of SVR to a 12-week or 24-week regimen of triple therapy in 81 Japanese patients infected with HCV genotype 1. SVR was achieved by 45% and 67% in the 12- and 24 week regimens, respectively. Multivariate analysis identified rs8099917 near the IL28B gene (genotype TT) and substitution at aa 70 (Arg70) as significant determinants of SVR. Prediction of response to therapy based on a combination of these factors had high sensitivity, specificity, and positive and negative predictive values. The efficacy of triple therapy was high in the patients with genotype TT, who accomplished SVR (85%), irrespective of substitution of core aa 70. In the patients having genotype non-TT, those of Arg70 gained high SVR (57%), and SVR (17%) was the worst in patients who possessed both genotype non-TT and Gln70 (His70). Important adverse events were anemia and shin disorder (mainly rash, drug eruptions, and erythema). Next, dual oral therapy with the NS5A inhibitor (daclatasvir) and NS3 protease inhibitor (asunaprevir) in HCV genotype 1b-infected null responders or patients ineligible or intolerant to peginterferon/ribavirin were done (phase II) in Japan. This study (AI447-017) enrolled two populations infected with HCV genotype 1, including null responders and patients intolerant or medically ineligible to PEG-IFN and RBV. The overall SVR rate was 77%. A higher SVR rate was observed in the null responders (91%) compared to the ineligible and intolerant patients (64%). The overall response to therapy was not influenced by IL28B genotype. Potential association between virologic failure and pre-existing NS5A polymorphisms and low plasma concentrations of asunaprevir and daclatasvir requires further study.

Treatment of hepatitis C with direct-acting antiviral agents: Japanese experience

( Fumitaka Suzuki ),( Hiromitsu Kumada ) 대한간학회 2012 춘·추계 학술대회 (KASL) Vol.2012 No.-

In Japan, an estimated 100-150 million people are persistently infected with hepatitis C virus (HCV). The present standard-of-care (SOC) therapy for patients infected with HCV of genotype 1b, the most prevalent genotype in Japan, is peginterferon (PEG-IFN) combined with ribavirin (RBV) for 48 weeks. However, sustained virological response (SVR), judged by the loss of detectable HCV RNA from serum 24 weeks after the completion of therapy, can be achieved in only 42-52% of the patients. To cope with this grim situation, a number of direct acting antivirals (DAAs) have been designed and developed, represented by NS3/4A protease inhibitors and NS5B polymerase or NS5A inhibitors. Among them, telaprevir (TVR) has shown promising results, when combined with PEG-IFN and RBV, in the phase 2 and 3 clinical trials, by improving SVR to ~70% in patients infected with HCV-1. Moreover, the triple therapy with TVR, PEG-IFN, and RBV for 12 weeks, followed by PEG-IFN and RBV for an additional 12 weeks (T12PR24) were reimbursed since November 2011 in Japan. In Japanese clinical studies (phase III, T12PR24), the SVR rates of naive, relapse and non-responder were 73% (92/126), 88% (96/109) and 35% (11/32). We investigate the predictive factors of SVR to a 12-week or 24-week regimen of triple therapy in 81 Japanese patients infected with HCV genotype 1. SVR was achieved by 45% and 67% in the 12- and 24-week regimens, respectively. Multivariate analysis identified rs8099917 near the IL28B gene (genotype TT) and substitution at aa 70 (Arg70) as significant determinants of SVR. Prediction of response to therapy based on a combination of these factors had high sensitivity, specificity, and positive and negative predictive values. The efficacy of triple therapy was high in the patients with genotype TT, who accomplished SVR (85%), irrespective of substitution of core aa 70. In the patients having genotype non-TT, those of Arg70 gained high SVR (57%), and SVR (17%) was the worst in patients who possessed both genotype non-TT and Gln70 (His70). Important adverse events were anemia and shin disorder (mainly rash, drug eruptions, and erythema). Next, dual oral therapy with the NS5A inhibitor (daclatasvir) and NS3 protease inhibitor (asunaprevir) in HCV genotype 1b-infected null responders or patients ineligible or intolerant to peginterferon/ribavirin were done (phase II) in Japan. This study (AI447-017) enrolled two populations infected with HCV genotype 1, including null responders and patients intolerant or medically ineligible to PEG-IFN and RBV. The overall SVR rate was 77%. A higher SVR rate was observed in the null responders (91%) compared to the ineligible and intolerant patients (64%). The overall response to therapy was not influenced by IL28B genotype. Potential association between virologic failure and pre-existing NS5A polymorphisms and low plasma concentrations of asunaprevir and daclatasvir requires further study.

High Efficacy in Patients with Chronic Hepatitis C Virus (HCV) Genotype (GT)1b Infection Treatment with Elbasvir/Grazo-previr for 12 Weeks: An Integrated Analysis

( Do Young Kim ),( Won Young Tak ),( Stefan Zeuzem ),( Lawrence Serfaty ),( John M. Vierling ),( Wendy Cheng ),( Jacob George ),( Jan Sperl ),( Simone I. Strasser ),( Hiromitsu Kumada ),( Peggy Hwang 대한간학회 2017 춘·추계 학술대회 (KASL) Vol.2017 No.1

Aims: GT1b is the most common HCV genotype globally, accounting for the largest proportion of infections in Europe, Latin America, Russia, Turkey, and East Asia. We report the efficacy of 12 weeks of once-daily elbasvir/grazoprevir (50 mg/100 mg) (NS5A inhibitor/ NS3/4 protease inhibitor) in HCV GT1b-infected patients enrolled in the clinical development program. Methods: This analysis of treatment-naïve and treatment-experienced GT1b-infected patients used data pooled from 11 trials involving 30 countries and included 1070 patients with/without cirrhosis, chronic kidney disease (CKD), and HIV co-infection. Cirrhosis (F4, compensated) was confirmed by either liver biopsy or noninvasive tests. Patients with Stage 4 or Stage 5 CKD on hemodialysis were included. HIV/HCV co-infected patients were required to be on a stable antiretroviral regimen (ARV) (tenofovir or abacavir, emtricitabine or lamivudine, and either raltegrevir, dolutegravir, or rilpivirine) with CD4 >200/μL and HIV viral load undetectable, or if not on ARVs, have CD4 >500/μL and viral load < 50,000 IU/mL. The primary endpoint was the proportion of patients with HCV RNA below the lower limit of quantitation 12 weeks after treatment (SVR12). Efficacy data are presented for the full analysis set (FAS), which includes all patients who received at least one dose of study medication, and for the per-protocol (PP) population, which excludes nonvirologic failures. Results: A total of 1,070 patients were included in the analysis. Mean patient age was 53.7 years (range, 19-80); 50% were male; 47% were white, 43% were Asian, and 9% were black or African American; 20% were treatment-experienced; 39% had a baseline viral load >2,000,000 IU/mL; and 18% had evidence of cirrhosis. SVR12 was 97% (1040/1070) in the FAS; 15 patients (1.4%) were categorized as virologic failures and 15 (1.4%) were categorized as nonvirologic failures (lost-to-follow-up or withdrawal). Excluding the nonvirologic failures, SVR12 was 99% (1040/1055) in the PP analysis. There were no notable differences in subgroup analyses: SVR12 was 97% in both treatment-naïve and treatment-experienced patients; 99% in cirrhotics and 97% in noncirrhotics; 98% in patients with a baseline viral load < 2,000,000 IU/mL and 97% in patients with a baseline viral >2,000,000 IU/mL; 94% in HIV/HCV co-infected patients; and 100% and 95% in patients with Stage 4 or 5 CKD, respectively. Conclusions: High efficacy was achieved in the GT1b-infected population treated with elbasvir/grazoprevir for 12 weeks, with comparable efficacy across subgroups, including those with cirrhosis, high baseline viral load, and prior treatment failures.