Dataset Information

Daclatasvir plus asunaprevir for chronic HCV genotype 1b infection.

ABSTRACT: All-oral combinations of direct-acting antivirals may improve efficacy and safety outcomes for patients with hepatitis C virus (HCV) infection, particularly those who are poor candidates for current interferon/ribavirin-based regimens. In this open-label, phase 3 study, 135 interferon-ineligible/intolerant and 87 nonresponder patients with chronic HCV genotype 1b infection were enrolled at 24 centers in Japan. Patients received daclatasvir 60 mg once daily plus asunaprevir 100 mg twice daily for 24 weeks. The primary endpoint was sustained virologic response 24 weeks after treatment (SVR24 ). This study is registered with ClinicalTrials.gov (NCT01497834). SVR24 was achieved by 87.4% of interferon-ineligible/intolerant patients and 80.5% of nonresponder (null and partial) patients; rates were similar in cirrhosis (90.9%) and noncirrhosis (84.0%) patients, and in patients with IL28B CC (84.5%) or non-CC (84.8%) genotypes. Fourteen patients in each group (12.6%) discontinued dual therapy, mainly due to adverse events or lack of efficacy. Nine nonresponder patients received additional treatment with peginterferon/ribavirin per protocol-defined criteria. The rate of serious adverse events was low (5.9%) and varied among patients. The most common adverse events were nasopharyngitis, increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST), headache, diarrhea, and pyrexia.Interferon-free, ribavirin-free all-oral therapy with daclatasvir and asunaprevir for 24 weeks is well tolerated and can achieve a high rate of SVR in patients with HCV genotype 1b who were ineligible, intolerant, or had not responded to prior interferon-based therapy. (Hepatology 2014;59:2083-2091).

SUBMITTER: Kumada H

PROVIDER: S-EPMC4315868 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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Daclatasvir plus asunaprevir for chronic HCV genotype 1b infection.

Kumada Hiromitsu H Suzuki Yoshiyuki Y Ikeda Kenji K Toyota Joji J Karino Yoshiyasu Y Chayama Kazuaki K Kawakami Yoshiiku Y Ido Akio A Yamamoto Kazuhide K Takaguchi Koichi K Izumi Namiki N Koike Kazuhiko K Takehara Tetsuo T Kawada Norifumi N Sata Michio M Miyagoshi Hidetaka H Eley Timothy T McPhee Fiona F Damokosh Andrew A Ishikawa Hiroki H Hughes Eric E

Hepatology (Baltimore, Md.) 20140401 6

<h4>Unlabelled</h4>All-oral combinations of direct-acting antivirals may improve efficacy and safety outcomes for patients with hepatitis C virus (HCV) infection, particularly those who are poor candidates for current interferon/ribavirin-based regimens. In this open-label, phase 3 study, 135 interferon-ineligible/intolerant and 87 nonresponder patients with chronic HCV genotype 1b infection were enrolled at 24 centers in Japan. Patients received daclatasvir 60 mg once daily plus asunaprevir 100 ...[more]

PMID: 24604476

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Project description:AimTo assess daclatasvir plus asunaprevir (DUAL) in treatment-naïve patients from mainland China, Russia and South Korea with hepatitis C virus (HCV) genotype 1b infection.MethodsPatients were randomly assigned (3:1) to receive 24 wk of treatment with DUAL (daclatasvir 60 mg once daily and asunaprevir 100 mg twice daily) beginning on day 1 of the treatment period (immediate treatment arm) or following 12 wk of matching placebo (placebo-deferred treatment arm). The primary endpoint was a comparison of sustained virologic response at posttreatment week 12 (SVR12) compared with the historical SVR rate for peg-interferon plus ribavirin (70%) among patients in the immediate treatment arm. The first 12 wk of the study were blinded. Safety was assessed in DUAL-treated patients compared with placebo patients during the first 12 wk (double-blind phase), and during 24 wk of DUAL in both arms combined.ResultsIn total, 207 patients were randomly assigned to immediate (n = 155) or placebo-deferred (n = 52) treatment. Most patients were Asian (86%), female (59%) and aged < 65 years (90%). Among them, 13% had cirrhosis, 32% had IL28B non-CC genotypes and 53% had baseline HCV RNA levels of ≥ 6 million IU/mL. Among patients in the immediate treatment arm, SVR12 was achieved by 92% (95% confidence interval: 87.2-96.0), which was significantly higher than the historical comparator rate (70%). SVR12 was largely unaffected by cirrhosis (89%), age ≥ 65 years (92%), male sex (90%), baseline HCV RNA ≥ 6 million (89%) or IL28B non-CC genotypes (96%), although SVR12 was higher among patients without (96%) than among those with (53%) baseline NS5A resistance-associated polymorphisms (at L31 or Y93H). During the double-blind phase, aminotransferase elevations were more common among placebo recipients than among patients receiving DUAL. During 24 wk of DUAL therapy (combined arms), the most common adverse events (≥ 10%) were elevated alanine aminotransferase and upper respiratory tract infection; emergent grade 3-4 laboratory abnormalities were infrequently observed, and all grade 3-4 aminotransferase abnormalities (alanine aminotransferase, n = 9; aspartate transaminase, n = 6) reversed within 8-11 d. Two patients discontinued DUAL treatment; one due to aminotransferase elevations, nausea, and jaundice and the other due to a fatal adverse event unrelated to treatment. There were no treatment-related deaths.ConclusionDUAL was well-tolerated during this phase 3 study, and SVR12 with DUAL treatment (92%) exceeded the historical SVR rate for peg-interferon plus ribavirin of 70%.

Project description:IntroductionOral daclatasvir (DCV; pangenotypic NS5A inhibitor) plus asunaprevir (ASV; NS3 protease inhibitor) is approved in Japan and Korea for treatment of chronic hepatitis C virus (HCV) genotype 1. Response to DCV + ASV is affected by DCV resistance-associated polymorphisms (RAPs) in HCV NS5A. The prevalence and influence of these RAPs on 12-week sustained virologic response (SVR12) to DCV + ASV was evaluated in Asian and non-Asian patients.MethodsData were pooled from 5 national and international studies of patients with HCV genotype 1b (GT-1b) receiving DCV + ASV at their recommended doses. Baseline NS5A RAPs and their effect on SVR12 were assessed overall, in older (≥65 years) patients, patients with cirrhosis, and in patients stratified by baseline HCV RNA or prior treatment experience with interferon-based therapy.ResultsBaseline NS5A sequences were available from 988 patients (374 Japanese; 125 Korean/Taiwanese; 489 from non-Asian countries), 979 of whom were assessed for SVR12. Pretreatment NS5A-L31F/I/M/V and/or NS5A-Y93H polymorphisms were present in 18% of Japanese and 12-13% of non-Japanese patients; these RAPs reduced SVR12 by 54.9% overall (93.9% [787/838] SVR12 when absent, 39.0% [55/141] SVR12 when present), with comparable reductions observed in Asians and non-Asians and across all categories of treatment experience, age, and cirrhosis. RAP-associated SVR12 rates declined with increasing baseline HCV RNA (SVR12 with RAPs: 64.7% [11/17] at 5-6 log10 IU/mL, 29.8% [14/47] at 7-8 log10). Without baseline RAPs, very high SVR12 rates (92-100%) were observed in older patients and patients with cirrhosis irrespective of national origin, with similarly high rates observed among treatment-naïve and interferon-experienced patients and those with high baseline HCV RNA.ConclusionsFollowing DCV + ASV treatment, the SVR12 rates in GT-1b patients without baseline NS5A-L31F/I/M/V and/or NS5A-Y93H polymorphisms were very high (approximately 90-100%), irrespective of age, cirrhosis, prior interferon treatment, or baseline HCV RNA.FundingBristol-Myers Squibb.

Project description:BACKGROUND:Abnormal serum lipid profiles have been noted in patients with chronic hepatitis C virus (HCV) infection. Moreover, many reports suggest that serum lipoprotein profiles are more profoundly distorted in patients with HCV G1b infection who have an unfavorable response to pegylated interferon (peg-IFN) plus ribavirin (RBV) combination therapy. However, after the discovery of single nucleotide polymorphisms near the IL28B gene (rs8099917 and rs12979860) as potent predictive factors affecting the response to peg-IFN plus RBV, lipid factors are thought to be confounding factors. OBJECTIVES:To re-examine the significance of lipoprotein profiles on virological response to peg-IFN plus RBV combination therapy in patients with chronic HCV G1b infection, we examined cholesterol and triglyceride concentrations in each lipoprotein fraction separated by high performance liquid chromatography. PATIENTS AND METHODS:Lipoprotein profiles were examined using fasting sera from 108 patients infected with HCV G1b who had chronic hepatitis, as determined by liver biopsy. Results of lipoprotein profiles and clinical data, including IL28B genotype and amino acid substitution at aa70 of HCV G1b, were compared between patients with a sustained virological response (SVR) and non-SVR or a non-virological response (NVR) and virological responses other than NVR (non-NVR). In addition, significant predictive factors independently associated with virological response to peg-IFN?-2b plus RBV were determined by logistic regression analysis. RESULTS:An increased ratio of cholesterol/triglyceride in very low-density lipoprotein (odds ratio (OR) 3.03; 95% confidence interval (CI) 1.01-9.44) along with a major genotype of rs8099917 (OR 9.09; 95% CI 2.94-33.33), were independent predictive factors for SVR. In contrast, lipid factors were not elucidated as independent predictive factors for NVR. CONCLUSIONS:Examination of the fasting lipid profile has clinical importance in predicting the efficacy of peg-IFN-?-2b plus RBV combination therapy for patients with HCV G1b even after the discovery of the IL28 genotype as a potent predictive factor.

Dataset Information

Daclatasvir plus asunaprevir for chronic HCV genotype 1b infection.

Publications

Daclatasvir plus asunaprevir for chronic HCV genotype 1b infection.

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