Daclatasvir for previously untreated chronic hepatitis C genotype-1 infection: a randomised, parallel-group, double-blind, placebo-controlled, dose-finding, phase 2a trial
ABSTRACT Several direct-acting antivirals for chronic hepatitis C virus (HCV) infection are available, but they are limited by tolerability and dosing schedules. Once-daily daclatasvir, a potent NS5A replication complex inhibitor, was generally well tolerated in phase 1 studies. We assessed daclatasvir in combination with pegylated interferon (peginterferon) and ribavirin for chronic HCV.
In this double-blind, parallel-group, dose-finding, phase 2a study, treatment-naive patients with HCV genotype-1 infection (without cirrhosis) from 14 centres in the USA and France were randomly assigned (1:1:1:1) to receive peginterferon alfa-2a (180 μg per week) and ribavirin (1000-1200 mg daily) plus placebo or 3 mg, 10 mg, or 60 mg of daclatasvir taken once daily, for 48 weeks. The primary efficacy endpoint was undetectable HCV RNA at 4 weeks and 12 weeks after start of treatment (extended rapid virological response, eRVR). Analysis was of all participants who received one dose of study drug. We used descriptive analyses to compare results. This study is registered with ClinicalTrials.gov, number NCT00874770.
48 patients were randomly assigned (12 per group); all received at least one dose of study drug. 15 patients discontinued treatment before week 48. Five of 12 patients (42%, 80% CI 22-64%) who received 3 mg daclatasvir achieved eRVR, compared with ten of 12 (83%, 61-96%) who received 10 mg daclatasvir, nine of 12 (75%, 53-90%) who received 60 mg daclatasvir, and one of 12 (8%, 1-29%) who received placebo. Adverse events and discontinuations as a result of adverse events occurred with similar frequency across groups.
Daclatasvir seems to be a potent NS5A replication complex inhibitor that increases the antiviral potency of peginterferon and ribavirin. Our findings support the further development of regimens containing 60 mg daclatasvir for the treatment of chronic genotype-1 HCV infection.
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ABSTRACT: Staging of liver fibrosis is an integral part of the management of HCV. Liver biopsy is hampered by its invasiveness and possibility of sampling error. Current noninvasive methods are disadvantaged by their cost and complexity. In this study, we aimed at developing a noninvasive method for the staging of liver fibrosis based only on routine laboratory tests and clinical data. Basic clinical and laboratory data and liver biopsies were collected from 994 patients presenting for the evaluation of HCV. Logistic regression was used to create a model predictive of fibrosis stages. A sequential test was then developed by combining our new model with APRI. In the training set (497) a model was created by logistic regression for the prediction of significant fibrosis (≥F2), it included platelets, AST and age (PLASA). The areas under the curve (AUC), sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were 0.753, 66.8, 71.4, 69.8, 68.4, respectively, while in the validation set (497), they were 0.777, 66.7, 72.8, 68.6 and 71, respectively. These were the best performance indicators when compared to APRI, FIB-4, King's score, platelets, fibrosis index, age-platelet index and Lok index in the same set of patients. A sequential test was then developed including APRI followed by PLASA [Cairo University Fibrosis Assessment (CUFA) algorithm], this allowed saving 20% and 34% of liver biopsies for patients being tested for significant fibrosis and cirrhosis, respectively. In conclusion, the CUFA algorithms at no cost allow saving a significant proportion of patients from performing a liver biopsy or a more complex costly test. These algorithms could be used as the first step in the assessment of liver fibrosis before embarking on the more costly advanced serum markers, Fibroscan or liver biopsy.Journal of Viral Hepatitis 07/2014; 21(12). DOI:10.1111/jvh.12270 · 3.31 Impact Factor
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ABSTRACT: The treatment of hepatitis C virus (HCV) infection with pegylated interferon alpha and ribavirin leads to a sustained virologic response in around 50% of patients with HCV genotype 1, 65% with HCV genotype 4, 75% with HCV genotype 3 and around 80% with HCV genotype 2. A better understanding of the HCV lifecycle has resulted in the development of several potential direct-acting antiviral drugs (DAAs) targeting viral proteins [NS3/4A protease inhibitors, NS5B nucleos(t)idic and non-nucleos(t)idic polymerase inhibitors, NS5A replication complex inhibitors]. This review summarizes the main clinical data for the combinations of oral DAAs. DAAs, either in combination with pegylated interferon alpha or in interferon-free regimens, have demonstrated a high level of antiviral efficacy and a generally well-tolerated safety profile in treatment-naïve patients and in prior nonresponders to pegylated interferon alpha/ribavirin. Oral combination of new DAAs is likely to become the standard of care for chronic HCV in treatment-naïve or treatment-experienced patients. However, most studies so far have included small numbers of ‘easy-to-treat’ patients with short post-treatment periods for defining the sustained virologic response. Extension of the number of treated patients (including ‘difficult-to-treat’ patients, i.e. patients infected with genotype 3, who failed to respond to first-generation protease inhibitors or with cirrhosis as well as immunocompromised patients) and of the post-treatment follow up in a real-life setting could significantly worsen the rate of recovery. In these ‘difficult-to-treat’ patients, the rate of virologic cure with new DAAs could be lower than expected and consequently interferons may be still necessary in combination with the new drugs.06/2013; 1(3):107-116. DOI:10.1177/2049936113488359
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ABSTRACT: Recent data have clearly shown that a sustained virologic response can be achieved in different HCV infected patient populations with various interferon-free treatment regimens. Despite the successful implementation of telaprevir- and boceprevir-based triple therapies, all-oral regimens will certainly become a first choice for a number of HCV-infected patients in the very near future, as triple therapy approaches are burdened with significant side-effects and limited success in patients with advanced liver fibrosis and prior null-response to pegylated interferon-α (pegIFN-α) / ribavirin therapy. However, available data from phase I and II clinical trials evaluating interferon-free regimes have not yet revealed a clearly outstanding all-oral combination, and numerous challenges remain to be addressed by intensive ongoing and future research. In particular, thus far evaluated all-oral regimens did not cure a satisfactory percentage of patients with unfavorable baseline characteristics, namely patients infected with HCV genotype 1a, previous null-response to pegIFN-α / ribavirin, or liver cirrhosis. In this review, we summarize available data of interferon-free regimens for the treatment of chronic hepatitis C and assess implications for perspectives and challenges in the further development of all-oral therapies.Journal of Hepatology 10/2012; 58(3). DOI:10.1016/j.jhep.2012.10.019 · 10.40 Impact Factor