R1626 plus peginterferon Alfa-2a provides potent suppression of hepatitis C virus RNA and significant antiviral synergy in combination with ribavirin

Division of Gastroenterology and Hepatology, Scripps Clinic, La Jolla, CA 92037, USA.
Hepatology (Impact Factor: 11.06). 08/2008; 48(2):385-97. DOI: 10.1002/hep.22357
Source: PubMed


R1626, a prodrug of the hepatitis C virus (HCV) RNA polymerase inhibitor R1479, showed time-dependent and dose-dependent reduction of HCV RNA levels in a previous study. The present study evaluated the efficacy and safety of R1626 administered for 4 weeks in combination with peginterferon alfa-2a +/- ribavirin in HCV genotype 1-infected treatment-naive patients. Patients were randomized to: DUAL 1500 (1500 mg R1626 twice daily [bid] + peginterferon alfa-2a; n = 21); DUAL 3000 (3000 mg R1626 bid + peginterferon alfa-2a; n = 32); TRIPLE 1500 (1500 mg R1626 bid + peginterferon alfa-2a + ribavirin; n = 31); or standard of care (SOC) (peginterferon alfa-2a + ribavirin; n = 20). At 4 weeks HCV RNA was undetectable (<15 IU/mL) in 29%, 69%, and 74% of patients in the DUAL 1500, DUAL 3000, and TRIPLE 1500 arms, respectively, compared with 5% of patients receiving SOC, with respective mean reductions in HCV RNA from baseline to week 4 of 3.6, 4.5, 5.2, and 2.4 log(10) IU/mL. Synergy was observed between R1626 and peginterferon alfa-2a and between R1626 and ribavirin. There was no evidence of development of viral resistance. Adverse events (AEs) were mainly mild or moderate; seven patients had nine serious AEs (including one patient with one serious AE in SOC). The incidence of Grade 4 neutropenia was 48%, 78%, 39%, and 10% in DUAL 1500, DUAL 3000, TRIPLE 1500, and SOC, respectively, and was the main reason for dose reductions. Conclusion: A synergistic antiviral effect was observed when R1626 was combined with peginterferon alfa-2a +/- ribavirin; up to 74% of patients had undetectable HCV RNA at week 4. Dosing of R1626 was limited by neutropenia; a study of different dosages of R1626 in combination with peginterferon alfa-2a and ribavirin is underway.

Download full-text


Available from: Maribel Rodríguez-Torres, Oct 01, 2014
  • Source
    • "re 3. 6 , 4 . 5 , 5 . 2 , and 2 . 4 log 10 IU / ml . A synergistic effect was observed between the three drugs , and there was no evidence of viral resistance development . The incidence of grade 4 neutropenia was 48% , 78% , 39% , and 10% in 1 500 BID , 3 000 BID , 1 500 TID , and SOC , respectively , and was the main reason for dose reductions ( Pockros et al . , 2008b ) . The highest rates of relapse were observed in the combination arm of 1 500 mg BID R1626 with weekly PEG - IFN -  ( 1 500 BID arm ; 55% , 6 of 11 ) and in the 1 500 TID arm ( 28% , 7 of 25 ) . In five of the seven subjects in the 1 500 TID arm who experienced relapse , HCV RNA breakthrough occurred during the early stages of treatme"
    [Show abstract] [Hide abstract]
    ABSTRACT: Infection with hepatitis C virus (HCV) affects approximately 170 million people worldwide. However, no vaccine or immunoglobulin is currently available for the prevention of HCV infection. The standard of care (SOC) involving pegylated interferon-α (PEG-IFN α) plus ribavirin (RBV) for 48 weeks results in a sustained virologic response in less than 50% of patients with chronic hepatitis C genotype 1, the most prevalent type of HCV in North America and Europe. Recently, reliable in vitro culture systems have been developed for accelerating antiviral therapy research, and many new specifically targeted antiviral therapies for hepatitis C (STAT-C) and treatment strategies are being evaluated in clinical trials. These new antiviral agents are expected to improve present treatment significantly and may potentially shorten treatment duration. The aim of this review is to summarize the current developments in new anti-HCV drugs.
    Full-text · Article · Jan 2012 · Journal of Zhejiang University SCIENCE B
  • Source
    • "NS3 protease and NS5B polymerase enzymes, essential for HCV replication, are primary targets. Results for inhibitors targeting these enzymes (combined with pegIFN + RBV) are positive in clinical trials [11, 96, 97] and preclinical studies [98–100]. The most promising of these are the protease inhibitors telaprevir and boceprevir, which are expected to be approved this year [101, 102]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: World-wide, hepatitis C virus (HCV) accounts for approximately 130 million chronic infections, with an overall 3% prevalence. Four to 5 million persons are co-infected with HIV. It is well established that HIV has a negative impact on the natural history of HCV, including a higher rate of viral persistence, increased viral load, and more rapid progression to fibrosis, end-stage liver disease, and death. Whether HCV has a negative impact on HIV disease progression continues to be debated. However, following the introduction of effective combination antiretroviral therapy, the survival of coinfected individuals has significantly improved and HCV-associated diseases have emerged as the most important co-morbidities. In this review, we summarize the newest studies regarding the pathogenesis of HIV/HCV coinfection, including effects of coinfection on HIV disease progression, HCV-associated liver disease, the immune system, kidney and cardiovascular disease, and neurologic status; and effectiveness of current anti-HIV and HCV therapies and proposed new treatment strategies.
    Full-text · Article · Mar 2011 · Current HIV/AIDS Reports
  • Source
    • "The prodrug of 4′-azidocytidine (R1626) was tested in genotype 1 infected, treatment naïve patients in combination with IFN-α and/or ribavirin. −3.1log10 to −4.6log10 reductions of HCV RNA were seen in the different treatment arms with triple combination therapy giving the greatest reduction [63]. No selection of resistance mutations was noted during treatment, indicating that, as with other NIs, there is a high barrier to the development of resistance. "
    [Show abstract] [Hide abstract]
    ABSTRACT: More than 20 years after the identification of the hepatitis C virus (HCV) as a novel human pathogen, the only approved treatment remains a combination of pegylated interferon-α and ribavirin. This rather non-specific therapy is associated with severe side effects and by far not everyone benefits from treatment. Recently, progress has been made in the development of specifically targeted antiviral therapy for HCV (STAT-C). A major target for such direct acting antivirals (DAAs) is the HCV RNA-dependent RNA polymerase or non-structural protein 5B (NS5B), which is essential for viral replication. This review will examine the current state of development of inhibitors targeting the polymerase and issues such as the emergence of antiviral resistance during treatment, as well as strategies to address this problem.
    Full-text · Article · Oct 2010 · Viruses
Show more