3 SAFETY AND EFFICACY OF INTERFERON-FREE REGIMENS OF ABT-450/r, ABT-267, ABT-333 +/− RIBAVIRIN IN PATIENTS WITH CHRONIC HCV GT1 INFECTION: RESULTS FROM THE AVIATOR STUDY

Kowdley, K.V.; Läwitz, E.; Poordad, F.; Cohen, Daniel E.; Nelson, Daniel W.; Zeuzem, Stefan; Everson, Gregory T.; Kwo, Paul Y.; Foster, G.R.; Sulkowski, Mark S.; Xie, Wen-Rui; Larsen, Lis Kjær; Khatri, Arun; Podsadecki, Thomas; Bernstein, Barry

doi:10.1016/s0168-8278(13)60005-7

Cited by 47 publications

(42 citation statements)

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“…Although pegylated interferon may not be a necessary component of future combination regimens, ribavirin appears to remain an essential component of many but not all interferon-free DAA regimens (10)(11)(12)(14)(15)(16)(17).…”

Section: T He Treatment Paradigm For Chronic Hepatitis C Virus (Hcv)mentioning

confidence: 99%

“…Thus, the combination of pegylated alpha interferon plus ribavirin currently remains an essential component of approved protease inhibitor-based combination regimens (1). In order to further improve convenience, safety, and SVR rates in G1-infected patients and to extend the benefits of combination DAA regimens to patients infected with other HCV genotypes, additional classes of DAAs are required, especially to achieve the goal of interferonfree regimens.Novel agents from several DAA classes are in development, and recent data suggest that high SVR rates can be achieved with interferon-free DAA combination regimens (10)(11)(12)(13)(14). Although pegylated interferon may not be a necessary component of future combination regimens, ribavirin appears to remain an essential component of many but not all interferon-free DAA regimens (10)(11)(12)(14)(15)(16)(17).…”

mentioning

confidence: 99%

“…Novel agents from several DAA classes are in development, and recent data suggest that high SVR rates can be achieved with interferon-free DAA combination regimens (10)(11)(12)(13)(14). Although pegylated interferon may not be a necessary component of future combination regimens, ribavirin appears to remain an essential component of many but not all interferon-free DAA regimens (10)(11)(12)(14)(15)(16)(17).…”

mentioning

confidence: 99%

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Intracellular Effects of the Hepatitis C Virus Nucleoside Polymerase Inhibitor RO5855 (Mericitabine Parent) and Ribavirin in Combination

Ma¹,

Pogam

Fletcher

et al. 2014

Antimicrob Agents Chemother

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c Mericitabine (RG7128) is the prodrug of a highly selective cytidine nucleoside analog inhibitor (RO5855) of the hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase. This study evaluated the effects of combining RO5855 and ribavirin on HCV replication in the HCV subgenomic replicon by using two drug-drug interaction models. The effects of RO5855 and ribavirin on the intracellular metabolism of each compound, on interferon-stimulated gene (ISG) expression, and on the viability of hepatocyte-derived cells were also investigated. RO5855 and ribavirin had additive inhibitory activities against HCV subgenomic replicon replication in drugdrug interaction analyses. RO5855 did not affect the uptake or phosphorylation of ribavirin in primary human hepatocytes, human peripheral blood mononuclear cells, or genotype 1b (G1b) replicon cells. Similarly, ribavirin did not affect the concentrations of intracellular species derived from RO5855 in primary human hepatocytes or the formation of the triphosphorylated metabolites of RO5855. Ribavirin at concentrations of >40 M significantly reduced the viability of primary hepatocytes but not of Huh7, the G1b replicon, or interferon-cured Huh7 cells. RO5855 alone or with ribavirin did not significantly alter the viability of Huh7 or G1b replicon cells, and it did not significantly affect the viability of primary hepatocytes when it was administered alone. The viability of primary hepatocytes was reduced when they were incubated with RO5855 and ribavirin, similar to the effects of ribavirin alone. RO5855 alone or with ribavirin had no effect on ISG mRNA levels in any of the cells tested. In conclusion, RO5855 did not show any unfavorable interactions with ribavirin in human hepatocytes or an HCV subgenomic replicon system. T he treatment paradigm for chronic hepatitis C virus (HCV) infection is evolving rapidly (1). The first direct-acting antiviral agents (DAAs) for HCV, i.e., the HCV NS3/4A protease inhibitors boceprevir and telaprevir, were approved in 2011 for patients infected with HCV genotype 1 (G1) virus (1). These agents significantly increase sustained virological response (SVR) rates in patients with G1 infection but must be administered in combination with pegylated alpha interferon plus ribavirin (triple therapy) (2-7). Triple therapy with boceprevir or telaprevir also increases the adverse event burden on patients and is associated with complex drug-drug interactions that are potentially difficult to manage (2-7).When protease inhibitors were evaluated as monotherapy, resistant variants emerged rapidly and control of viral replication was lost within days (8). Moreover, when telaprevir was evaluated in combination with pegylated alpha-2a interferon but without ribavirin, treatment failure rates were unacceptably high (9). Thus, the combination of pegylated alpha interferon plus ribavirin currently remains an essential component of approved protease inhibitor-based combination regimens (1). In order to further improve convenience, safety, and SVR rates in G1-infect...

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Section: T He Treatment Paradigm For Chronic Hepatitis C Virus (Hcv)mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Intracellular Effects of the Hepatitis C Virus Nucleoside Polymerase Inhibitor RO5855 (Mericitabine Parent) and Ribavirin in Combination

Ma¹,

Pogam

Fletcher

et al. 2014

Antimicrob Agents Chemother

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“…An overview of the efficacy and tolerability of DAA combination treatments with or without PEG-IFN is outlined in Table 3 [ Gane et al 2010aFeld et al 2012;Zeuzem et al 2010Zeuzem et al , 2011Zeuzem et al , 2012bZeuzem et al , 2012cJacobson et al 2012;Poordad et al 2012c;Lawitz et al 2012c;Lok et al 2012aLok et al , 2012bChayama et al 2012;Kowdley et al 2013b;Sulkowski et al 2012aSulkowski et al , 2012bEverson et al 2012Everson et al , 2013.…”

Section: Htas and Other Antiviral Treatmentsmentioning

confidence: 99%

An update on the treatment of genotype-1 chronic hepatitis C infection: lessons from recent clinical trials

Wendt

Bourlière

2013

Therapeutic Advances in Infection

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The launch of first-generation protease inhibitors (PIs) was a major step forward in hepatitis C virus (HCV) treatment. However, this major advance is, up to now, restricted to genotype-1 (GT-1) patients. However, the ongoing development of new direct-acting antiviral agents (DAAs) allows new hope for the future. The development of second-wave and second-generation PIs yields higher antiviral potency through plurigenotypic activity, more convenient daily administration, fewer side effects and, for the second-generation PIs, potential activity against resistance-associated variants. NS5B inhibitors (NS5B.I) include nucleoside/nucleotide inhibitors (NIs) and nonnucleotide inhibitors (NNIs). NIs have high efficacy across all genotypes. Sofosbuvir has highly potent antiviral activity across all genotypes in association with pegylated interferon (IFN) and ribavirin (PR), thus allowing shortened treatment duration. NS5A inhibitors (NS5A.I) have highly potent antiviral activity. It has recently been shown for the first time that NS5A.I in combination with PI can cure GT-1b null-responder patients in an IFN-free regimen. In addition, several studies demonstrate that IFN-free regimens with DAA combinations are able to cure a large number of either naïve or treatment-experienced GT-1 patients. Moreover, a quadruple regimen with PR is able to cure almost all GT-1 null-responders. The development of pan-genotypic DAAs (NIs or NS5A.I) allows new combinations with or without PR that increase the rate of sustained virological response (SVR) for all patients, even for those with cirrhosis and independently of the genotype. Therefore, the near future of HCV treatment looks promising. The purpose of this article is to provide an overview of the clinical results recently reported for HCV treatment in GT-1 patients.

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“…Finally, there is a realistic hope for patients with HCV infection, since several IFN-free trials are ongoing with promising early data [8][9][10][11]. We do hope that the majority of patients with HCV infection will become «easy-to-cure», and there will be increase in access to treatment.…”

mentioning

confidence: 99%

Sofosbuvir-based interferon-free therapy for patients with HCV infection

Asselah

2013

Journal of Hepatology

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Background: The standard treatment for hepatitis C virus (HCV) infection is interferon, which is administered subcutaneously and can have troublesome side effects. We evaluated sofosbuvir, an oral nucleotide inhibitor of HCV polymerase, in interferon-sparing and interferon-free regimens for the treatment of HCV infection. Methods: We provided open-label treatment to eight groups of patients. A total of 40 previously untreated patients with HCV genotype 2 or 3 infection were randomly assigned to four groups; all four groups received sofosbuvir (at a dose of 400 mg once daily) plus ribavirin for 12 weeks. Three of these groups also received peginterferon alfa-2a for 4, 8, or 12 weeks. Two additional groups of previously untreated patients with HCV genotype 2 or 3 infection received sofosbuvir monotherapy for 12 weeks or sofosbuvir plus peginterferon alfa-2a and ribavirin for 8 weeks. Two groups of patients with HCV genotype 1 infection received sofosbuvir and ribavirin for 12 weeks: 10 patients with no response to prior treatment and 25 with no previous treatment. We report the rate of sustained virologic response 24 weeks after therapy. Results: Of the 40 patients who underwent randomization, all 10 (100%) who received sofosbuvir plus ribavirin without interferon and all 30 (100%) who received sofosbuvir plus ribavirin for 12 weeks and interferon for 4, 8, or 12 weeks had a sustained virologic response at 24 weeks. For the other patients with HCV genotype 2 or 3 infection, all 10 (100%) who received sofosbuvir plus peginterferon alfa-2a and ribavirin for 8 weeks had a sustained virologic response at 24 weeks, as did 6 of 10 (60%) who received sofosbuvir monotherapy. Among patients with HCV genotype 1 infection, 21 of 25 previously untreated patients (84%) and 1 of 10 with no response to previous therapy (10%) had a sustained virologic response at 24 weeks. The most common adverse events were headache, fatigue, insomnia, nausea, rash, and anemia. Conclusions: Sofosbuvir plus ribavirin for 12 weeks may be effective in previously untreated patients with HCV genotype 1, 2, or 3 infection. (Funded by Pharmasset and Gilead Sciences; ClinicalTrials.gov number, NCT01260350). Ó 2013 European Association for the Study of the Liver. Published by Elsevier B.V.For the treatment of HCV infection, several direct-acting antivirals (DAAs), including NS3 protease inhibitors, nucleoside/ nucleotide analogues and non-nucleoside inhibitors of the RNAdependent RNA polymerase, and NS5A inhibitors, are under development [1]. Among them, sofosbuvir is a potent HCV-specific nucleotide analog (chain terminator). It is given orally, once daily, without food effect. So far, no safety signal in preclinical/ clinical studies has been observed with this compound. Sofosbuvir has a high barrier to resistance with no virologic breakthrough to date. It has a pangenotypic antiviral effect, although it might be less efficient in genotype 3 (G3).The ELECTRON study goal was to evaluate the safety and efficacy of sofosbuvir as a backbone of co...

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3 SAFETY AND EFFICACY OF INTERFERON-FREE REGIMENS OF ABT-450/r, ABT-267, ABT-333 +/− RIBAVIRIN IN PATIENTS WITH CHRONIC HCV GT1 INFECTION: RESULTS FROM THE AVIATOR STUDY

Cited by 47 publications

References 0 publications

Intracellular Effects of the Hepatitis C Virus Nucleoside Polymerase Inhibitor RO5855 (Mericitabine Parent) and Ribavirin in Combination

Intracellular Effects of the Hepatitis C Virus Nucleoside Polymerase Inhibitor RO5855 (Mericitabine Parent) and Ribavirin in Combination

An update on the treatment of genotype-1 chronic hepatitis C infection: lessons from recent clinical trials

Sofosbuvir-based interferon-free therapy for patients with HCV infection

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