O165 Simeprevir Plus Sofosbuvir With/Without Ribavirin in HCV Genotype 1 Prior Null-Responder/Treatment-Naive Patients (Cosmos Study): Primary Endpoint (Svr12) Results in Patients With Metavir F3–4 (Cohort 2)

Läwitz, E.; Ghalib, Reem; Rodrı́guez-Torres, Maribel; Younossi, Zobair M.; Corregidor, Ana; Sulkowski, Mark S.; DeJesus, Edwin; Pearlman, Brian L.; Rabinovitz, Mordechai; Gitlin, Norman; Lim, J.K.; Pockros, Paul J.; Fevery, Bart; Lambrecht, Tom; Ouwerkerk‐Mahadevan, Sivi; Callewaert, Katleen; Symonds, William T.; Picchio, Gastón; Lindsay, Karen L.; Beumont–Mauviel, Maria; Jacobson, Ira M.

doi:10.1016/s0168-8278(14)61460-4

Cited by 22 publications

(21 citation statements)

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“…Two phase Ⅲ trials of SMV/SOF without RBV are ongoing (OPTIMIST-1 and -2) [89] . These studies provide us much bigger data about SOF/SIM regimen, and investigate the efficacy and safety of SMV 150 mg in combination with sofosbuvir 400 mg in HCV genotype 1 infected naïve or experienced patients, with and without cirrhosis.…”

Section: Second-generation Pismentioning

confidence: 99%

“…SVR12 rates were not different between 12 or 24 wk of treatment, with or without RBV, and comparing naive patients to experienced (95% vs 91%) [87,88] . In this small study, the regimen SOF plus SMV with or without RBV was well tolerated; the most common side effects were headache, fatigue, and nausea, and only four (2%) patients discontinued treatment due to these events.Although the results of this study are encouraging, due to the small number of patients and the future availability of other oral regimes with better antiviral efficacy and fewer side effects, this regimen should be considered as a second-line option.Two phase Ⅲ trials of SMV/SOF without RBV are ongoing (OPTIMIST-1 and -2) [89] . These studies provide us much bigger data about SOF/SIM regimen, and investigate the efficacy and safety of SMV 150 mg in combination with sofosbuvir 400 mg in HCV genotype 1 infected naïve or experienced patients, with and without cirrhosis.…”

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confidence: 99%

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Chronic hepatitis C: This and the new era of treatment

Bertino

Ardiri

Proiti

et al. 2016

WJH

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Over the last years it has started a real revolution in the treatment of chronic hepatitis C. This occurred for the availability of direct-acting antiviral agents that allow to reach sustained virologic response in approximately 90% of cases. In the near future further progress will be achieved with the use of pan-genotypic drugs with high efficacy but without side effects. Core tip: This review analyzes the current therapies for chronic hepatitis C and the future challenges of the research. So it tries to give an update on the research of hepatitis C virus (HCV) infection, providing a critical view of the emerging therapies and their impact on the future management of HCV infection. Since novel TOPIC HIGHLIGHT Chronic hepatitis C: This and the new era of treatment2016 Hepatitis C Virus: Global view treatments for HCV infection are highly efficacious but costly, priority should be given to patients with advanced hepatic fibrosis, which is a disease that cannot be deferred. INTRODUCTIONThe hepatitis C virus (HCV), identified in the 70s but cloned in 1989, is a single-stranded RNA virus belonging to the family Flaviviridae.HCV is the main cause of progressive liver diseases and a public health problem worldwide. It is estimated that approximately 150-180 million people in the world are living with chronic hepatitis [1,2] , 350 million of whom die each year from liver damage associated with the infection [3] . About 80% of people infected with HCV develop chronic hepatitis, of which 20%-40% will develop liver cirrhosis or hepatocellular carcinoma (HCC) 20-30 years after infection.As a consequence, chronic HCV infection is the major reason of liver transplantation in developed countries [4][5][6][7] . According to the Global Burden Disease Study in Europe, the death rate for viral hepatitis is significantly higher than that for human immunodeficiency virus (HIV) and acquired immune deficiency syndrome; in particular in 2010, the number of deaths from viral hepatitis have been ten times bigger than that attributed to HIV. It is reasonable to think that this difference is due to the lack of effective therapies for HCV until a few years ago [8] .HCV is also one of the main causes of death [9] . The virus causes both liver damage and extra-hepatic manifestations, many of these syndromes are associated with the ability of HCV to replicate in peripheral blood mononuclear cells (PBMCs); an example is the mixed cryoglobulinemia, which is by far the most common extrahepatic disease closely connected with the infection.Recently it was shown that antiviral treatment is associated with improved renal and cardiovascular outcomes in patients with cryoglobulinemia [4,6,10,11] . Newly approved oral anti-HCV drugs are very safe and effective, but unfortunately their cost will force to choose a priority of treatment. The intent should therefore be to identify and treat patients with a higher risk of morbidity and mortality due to HCV.The availability of these new oral treatments can definitely heal patients and ...

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Section: Second-generation Pismentioning

confidence: 99%

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confidence: 99%

Chronic hepatitis C: This and the new era of treatment

Bertino

Ardiri

Proiti

et al. 2016

WJH

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“…In cohort two, SVR12 was seen in 93% and 93% of patients who received 12 weeks of sofosbuvir plus simeprevir plus ribavirin and simeprevir plus sofosbuvir, respectively. In the same cohort, SVR12 was seen in 93% and 100% of patients who received 24 weeks of sofosbuvir plus simeprevir plus ribavirin and simeprevir plus sofosbuvir, respectively [28]. It can be concluded from this trial that the combination of sofosbuvir and simeprevir, with or without ribavirin, is highly effective in treatment‐naïve patients and previous null responders with genotype 1 HCV infection, regardless of treatment duration, METAVIR score or the addition of ribavirin.…”

Section: Drug–drug Interactionsmentioning

confidence: 68%

Sofosbuvir, a novel nucleotide analogue inhibitor used for the treatment of hepatitis C virus

Summers

Beavers

Klibanov

2014

Journal of Pharmacy and Pharmacology

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Objective To provide an overview of a novel anti-hepatitis C agent, sofosbuvir. Key findings Sofosbuvir is a novel nucleotide analogue inhibitor of hepatitis C virus (HCV) NS5B polymerase that has recently been approved by the Federal Drug Administration for the treatment of HCV genotypes 1, 2, 3 or 4 in a variety of patients. The emergence of such a novel treatment provides benefit to previously untreated genotypes and patient populations, with little chance of promoting significant viral resistance. Excellent sustained virologic response rates 12 weeks after the end of treatment (SVR12) were seen in phase II and III clinical trials when sofosbuvir was used with ribavirin. Even more promising are the results from phase II and III clinical trials that evaluated sofosbuvir in combination with other oral direct acting antivirals (DAAs). Data with sofosbuvir in the hepatitis C virus (HCV)/HIV coinfected and in the pre-and posttransplantation populations are still emerging. The drug was very well tolerated in clinical studies, with the most common adverse events of headache, nausea and fatigue. Summary Overall, sofosbuvir presents a new and effective treatment option for HCV-infected patients.

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“…This finding might have important implications for the potential retreatment of patients with failure to direct antiviral therapies with direct antiviral agents binding to the same target, like the currently used protease inhibitor-based regimens involving simeprevir or ABT-450 (24)(25)(26)(27)(28)(29).…”

Section: Discussionmentioning

confidence: 95%

Evolution of Hepatitis C Virus Quasispecies during Repeated Treatment with the NS3/4A Protease Inhibitor Telaprevir

Susser

Flinders

Reesink

et al. 2015

Antimicrob Agents Chemother

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In treating hepatitis B virus (HBV) and human immunodeficiency virus (HIV) infections, the rapid reselection of resistanceassociated variants (RAVs) is well known in patients with repeated exposure to the same class of antiviral agents. For chronic hepatitis C patients who have experienced virologic failure with direct-acting antiviral drugs, the potential for the reselection of persistent RAVs is unknown. Nine patients who received 14 days of telaprevir monotherapy were retreated with telaprevir-based triple therapy 4.3 to 5.7 years later. In four patients with virologic failure with both telaprevir-containing regimens, populationbased and deep sequencing (454 GS-FLX) of the NS3 protease gene were performed before and at treatment failure (median coverage, 4,651 reads). Using deep sequencing, with a threshold of 1.0% for variant calling, no isolates were found harboring RAVs at the baseline time points. While population-based sequencing uncovered similar resistance patterns (V36M plus R155K for subtype 1a and V36A for subtype 1b) in all four patients after the first and second telaprevir treatments, deep sequencing analysis revealed a median of 7 (range, 4 to 23) nucleotide substitutions on the NS3 backbone of the resistant strains, together with large phylogenetic differences between viral quasispecies, making the survival of resistant isolates highly unlikely. In contrast, in a comparison of the two baseline time points, the median number of nucleotide exchanges in the wild-type isolates was only 3 (range, 2 to 8), reflecting the natural evolution of the NS3 gene. In patients with repeated direct antiviral treatment, a continuous evolution of HCV quasispecies was observed, with no clear evidence of persistence and reselection but strong signs of independent de novo generation of resistance. Antiviral therapy for chronic viral infections, like HIV, hepatitis B virus (HBV), or hepatitis C virus (HCV), faces several challenges. These viruses have evolved survival strategies and proliferate by escaping the host's immune system. The development of direct-acting antiviral agents is an important achievement in fighting these infections. Viral variants conferring resistance to direct antiviral drugs lead to treatment failure. For HIV/HBV, it is well known that viral variants associated with treatment failure will be archived and reselected rapidly during retreatment with the same drug/class of drugs. We explored the mechanisms and rules of how resistant variants are selected and potentially reselected during repeated direct antiviral therapies in chronically HCV-infected patients. Interestingly, in contrast to HIV and HBV, we could not prove long-term persistence and reselection of resistant variants in HCV patients who failed protease inhibitor-based therapy. This may have important implications for the potential to reuse direct-acting antivirals in patients who failed the initial direct antiviral treatment. (The phase IIIb study described in this paper is registered at ClinicalTrials.gov under registration number N...

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O165 Simeprevir Plus Sofosbuvir With/Without Ribavirin in HCV Genotype 1 Prior Null-Responder/Treatment-Naive Patients (Cosmos Study): Primary Endpoint (Svr12) Results in Patients With Metavir F3–4 (Cohort 2)

Cited by 22 publications

References 0 publications

Chronic hepatitis C: This and the new era of treatment

Chronic hepatitis C: This and the new era of treatment

Sofosbuvir, a novel nucleotide analogue inhibitor used for the treatment of hepatitis C virus

Evolution of Hepatitis C Virus Quasispecies during Repeated Treatment with the NS3/4A Protease Inhibitor Telaprevir

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