Dual oral therapy with daclatasvir and asunaprevir for patients with HCV genotype 1b infection and limited treatment options

Suzuki, Yoshiyuki; Ikeda, Kenji; Suzuki, Fumitaka; Toyota, Joji; Karino, Yoshiyasu; Chayama, Kazuaki; Kawakami, Yoshiiku; Ishikawa, Hiroki; Watanabe, Hideaki; Hu, Wenhua; Eley, Timothy; McPhee, Fiona; Hughes, Eric; Kumada, Hiromitsu

doi:10.1016/j.jhep.2012.09.037

Cited by 224 publications

(200 citation statements)

References 21 publications

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“…40,41 Response rates in prior null responders, as reported in one of the trials, were 100%; in the other trial, response rates of 63.6% and 90.5% were reported in PegIFN intolerant/ineligible (n ¼ 22) and null-responder (n ¼ 10) patients, respectively. 40,41 Of note, in these Japanese phase 2 trials asunaprevir dose was adjusted from 600 mg twice daily to 200 mg twice daily due to observed hepatotoxicity at higher doses. 43 The U.S. study investigated different dosing regimens of asunaprevir (200 mg twice daily vs. 200 mg once daily) in HCV genotype1b null-responders without cirrhosis: SVR rates ranged from 65 to 78%.…”

Section: Clinical Trials Investigating the Combination Of A Ns3/4a Prmentioning

confidence: 92%

“…Therapeutic efficacy of this dual DAA regimen administered for 24 weeks was further investigated in several phase 2 trials conducted in Japan and in the United States. [40][41][42] Two Japanese studies enrolled HCV genotype 1b patients without cirrhosis who were intolerant/ineligible and/or nullresponder patients. 40,41 Response rates in prior null responders, as reported in one of the trials, were 100%; in the other trial, response rates of 63.6% and 90.5% were reported in PegIFN intolerant/ineligible (n ¼ 22) and null-responder (n ¼ 10) patients, respectively.…”

Section: Clinical Trials Investigating the Combination Of A Ns3/4a Prmentioning

confidence: 99%

“…[40][41][42] Two Japanese studies enrolled HCV genotype 1b patients without cirrhosis who were intolerant/ineligible and/or nullresponder patients. 40,41 Response rates in prior null responders, as reported in one of the trials, were 100%; in the other trial, response rates of 63.6% and 90.5% were reported in PegIFN intolerant/ineligible (n ¼ 22) and null-responder (n ¼ 10) patients, respectively. 40,41 Of note, in these Japanese phase 2 trials asunaprevir dose was adjusted from 600 mg twice daily to 200 mg twice daily due to observed hepatotoxicity at higher doses.…”

Section: Clinical Trials Investigating the Combination Of A Ns3/4a Prmentioning

confidence: 99%

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Interferon-Free Strategies without a Nucleoside/Nucleotide Analogue

Welzel

Zeuzem

2014

Semin Liver Dis

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The establishment of a robust hepatitis C virus (HCV) cell culture system and subsequent detailed characterization of the HCV life cycle was a key step toward the identification of putative antiviral targets and respective antiviral drugs. 1,2 These include direct-acting antiviral agents (DAAs) such as NS3/4A protease inhibitors, NS5A inhibitors, nucleos(t)ide and non-nucleoside polymerase inhibitors, as well as hosttargeting agents (HTAs) directed against cellular factors involved in viral entry or replication. 3 Trials investigating different drug classes with and without pegylated interferon (PegIFN) and/or ribavirin have rapidly evolved, yielding highly promising sustained virologic response (SVR) rates. 4,5 In regard to the enormous public health impact of HCV infection with an estimated 184 million anti-HCV positive persons worldwide, the recent advances in HCV drug development, together with implementation of improved HCV screening programs, have the potential to substantially reduce the burden of HCV-associated advanced liver disease including hepatocellular carcinoma. 6-9The first-in-class NS3/4A inhibitors telaprevir and boceprevir were approved in 2011. Addition of these drugs to the PegIFN/ribavirin backbone has considerably improved response rates in HCV therapy naïve and experienced patients compared with PegIFN/ribavirin alone. [10][11][12][13] The poor side-effect profile of these IFN-based therapies, however, limits the wide clinical applicability. Proof of the principle that viral clearance can be achieved with an IFN-free DAA combination has fast-tracked design and the conduct of clinical trials investigating IFN-free DAA combinations. 14 Different HCV genotypes and multiple subtypes result in a genotype and subtype-dependent efficacy of many available DAAs. 15,16 Furthermore, viral clearance is challenged by the presence and selection of resistance-associated variants (RAVs). 17,18 Thus, essential prerequisites for DAAs in clinical development comprise a high antiviral efficacy, a broad and at best pan-genotypic activity, as well as a high barrier to resistance. In this respect, nucleos(t)ide polymerase inhibitors display very favorable characteristics. [19][20][21] In addition to a high antiviral efficacy, binding to the highly conserved active site of the RNA-dependent RNA-polymerase (RdRp) and incorporation as active triphosphates into the growing HCV RNA chain terminating its elongation, confers a pan-genotypic activity. Also, the low replication fitness of emergent Keywords ► interferon-free HCV treatment ► direct-acting antiviral agents ► NS3/4A protease inhibitors ► NS5A inhibitors ► non-nucleoside polymerase inhibitors ► host-targeting agents AbstractThe identification of viral and host factors involved in hepatitis C virus (HCV) replication was a key prerequisite for the discovery and further exploration of antiviral drug targets. As of today, numerous direct-acting antiviral agents (DAAs), as well as host-targeting agents (HTAs), have been developed and entered clinical testing. The...

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Section: Clinical Trials Investigating the Combination Of A Ns3/4a Prmentioning

confidence: 92%

Section: Clinical Trials Investigating the Combination Of A Ns3/4a Prmentioning

confidence: 99%

Section: Clinical Trials Investigating the Combination Of A Ns3/4a Prmentioning

confidence: 99%

See 1 more Smart Citation

Interferon-Free Strategies without a Nucleoside/Nucleotide Analogue

Welzel

Zeuzem

2014

Semin Liver Dis

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“…Other host factors that contribute to the antiviral non-response include age, sex, race, alcohol use, obesity, insulin resistance, hepatic steatosis, and vitamin D and vitamin B12 deficiencies [16]. The CC genotype may increase early viral suppression by enhancing responsiveness to endogenous IFNs that are released as a result of the rapid antiviral activity of DAA therapy [17].…”

Section: Host Factorsmentioning

confidence: 99%

Mechanisms of Virologic Failure in Hepatitis C and Strategies for Treatment Failure

Kishida¹

2016

MOJI

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“…However, all these combination or triple therapies often cause frequent and severe adverse events (AEs) and increase the complexity of these treatments (9)(10)(11). Recently, several all-oral combination trials (12)(13)(14)(15)(16) with different direct-acting antiviral agents (DAAs) have shown high SVR rates, excellent tolerability, and shortened treatment duration in the US, EU and other developed countries, but PegIFN-based treatment is still widely used in most developing countries (17).…”

Section: Introductionmentioning

confidence: 99%

Efficacy and safety of simeprevir in combination with peginterferon and ribavirin for patients with hepatitis C genotype 1 infection: A meta-analysis of randomized trials

2015

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Background and aim: A simeprevir (SMV)-based regimen has shown promising results in treating chronic hepatitis C virus (HCV) infection. This meta-analysis aimed to assess the efficacy and safety of simeprevir for treating HCV genotype 1 infection.Methods: MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were searched, along with the reference lists of retrieved articles. The meta-analysis only included randomized controlled trials (RCTs) that compared the efficacy and safety of addition of SMV to peginterferon (PegIFN) and ribavirin (RBV) (triple regimen) with PegIFN/RBV alone (dual regimen) in treating chronic HCV genotype 1 infection.Results: A total of seven RCTs involving 2,301 patients were included. The triple regimen had a higher pooled sustained virologic response (SVR) rate [odds ratio (OR) = 4.57; 95% confidence interval (CI): 3.34-6.27; p < 0.001)] and lower pooled relapse rate [relative risk (RR) = 0.41; 95% CI: 0.33-0.50; p < 0.001] than the dual regimen had. The pooled incidence of adverse events (AEs) was comparable between the two regimens (RR = 1.01; 95% CI: 0.99-1.03; p = 0.339), whereas the incidence of serious AEs in the triple regimen was lower (RR = 0.7; 95% CI: 0.50-0.98; p < 0.05). Conclusions:The meta-analysis demonstrates that the addition of SMV to pegIFN and RBV is effective and well-tolerated in treating chronic HCV genotype 1 infection, with a low incidence of AEs.

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Dual oral therapy with daclatasvir and asunaprevir for patients with HCV genotype 1b infection and limited treatment options

Cited by 224 publications

References 21 publications

Interferon-Free Strategies without a Nucleoside/Nucleotide Analogue

Interferon-Free Strategies without a Nucleoside/Nucleotide Analogue

Mechanisms of Virologic Failure in Hepatitis C and Strategies for Treatment Failure

Efficacy and safety of simeprevir in combination with peginterferon and ribavirin for patients with hepatitis C genotype 1 infection: A meta-analysis of randomized trials

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