1406 Alisporivir (Alv) Plus Peg-Interferon/Ribavirin (Pr) in HCV G1 Treatment-Experienced Patients Achieves Primary Endpoint With Superior Efficacy at Treatment Week 12 Compared to Retreatment With Pr

Alberti, Antonio; Chuang, Wan‐Long; Flisiak, Robert; Mazzella, Giuseppe; Horban, Andrzéj; Goeser, Tobias; Calistru, Petre Iacob; Buti, María; Gl, Davis; Gong, Yuan; Avila, Claudio; Kao, Jia‐Horng

doi:10.1016/s0168-8278(12)61417-2

Cited by 12 publications

(12 citation statements)

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“…The VITAL-1 study evaluated the effect of Alisporivir administered either as monotherapy, as a 2-drug combination with ribavirin, or with the delayed addition of pegylated interferon and ribavirin to patients with chronic genotype 2 or 3 infection who were naïve to any form of prior treatment [56]. The FUNDAMENTAL study evaluated the effect of adding Alisporivir to background therapy comprised of pegylated interferon and ribavirin in patients with genotype 1 infection and documented evidence of prior nonresponse to interferon-based therapy [57]. Additional phase II and III clinical studies were recently initiated.…”

Section: Resultsmentioning

confidence: 99%

Cyclophilin Inhibitors: An Emerging Class of Therapeutics for the Treatment of Chronic Hepatitis C Infection

Hopkins

Gallay

2012

Viruses

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The advent of the replicon system together with advances in cell culture have contributed significantly to our understanding of the function of virally-encoded structural and nonstructural proteins in the replication cycle of the hepatitis C virus. In addition, in vitro systems have been used to identify several host proteins whose expression is critical for supporting such diverse activities as viral entry, RNA replication, particle assembly, and the release of infectious virions. Among all known host proteins that participate in the HCV replication cycle, cyclophilins are unique because they constitute the only host target that has formed the basis of pharmaceutical drug discovery and drug development programs. The introduction of the nonimmunosuppressive cyclophilin inhibitors into clinical testing has confirmed the clinical utility of CsA-based inhibitors for the treatment of individuals with chronic hepatitis C infection and has yielded new insights into their mechanism(s) of action. This review describes the biochemical evidence for the potential roles played by cyclophilins in supporting HCV RNA replication and summarizes clinical trial results obtained with the first generation of nonimmunosuppressive cyclophilin inhibitors.

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Section: Resultsmentioning

confidence: 99%

Cyclophilin Inhibitors: An Emerging Class of Therapeutics for the Treatment of Chronic Hepatitis C Infection

Hopkins

Gallay

2012

Viruses

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“…In another Phase II study known as FUNDAMENTAL, pegIFN null-responder genotype 1 HCV-infected patients were treated for 24 weeks with either ALV 400 mg BID with pegIFN and RBV or pegIFN and RBV alone. Remarkably, 75.4% of patients on ALV triple therapy attained SVR 12 compared to 8.9% in the control group (Alberti et al, 2012). …”

Section: Hcv Host-targeting Antiviralsmentioning

confidence: 97%

Host-targeting agents in the treatment of hepatitis C: A beginning and an end?

2013

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The development of two distinct classes of hepatitis C antiviral agents, direct-acting antivirals (DAAs) and host-targeting antivirals (HTAs), have distinctly impacted the hepatitis C virus (HCV) field by generating higher sustained virological response (SVR) rates within infected patients, via reductions in both adverse side effects and duration of treatment when compared to the old standard of care. Today DAAs are actively incorporated into the standard of care and continue to receive the most advanced clinical trial analysis. With a multitude of innovative and potent second-generation DAA compounds currently being tested in clinical trials, it is clear that the future of DAAs looks very bright. In comparison to the other class of compounds, HTAs have been slightly less impactful, despite the fact that primary treatment regimens for HCV began with the use of an HTA - interferon alpha (IFNα). The compound was advantageous in that it provided a broad-reaching antiviral response; however deleterious side effects and viral/patient resistance has since made the compound outdated. HTA research has since moved onward to target a number of cellular host factors that are required for HCV viral entry and replication such as scavenger receptor-BI (SR-BI), 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCoA reductase), cyclophilin A (CypA), fatty acid synthase (FASN) and miRNA-122. The rationale behind pursuing these HTAs is based upon the extremely low mutational rate that occurs within eukaryotic cells, thereby creating a high genetic barrier to drug resistance for anti-HCV compounds, as well as pan-genotypic coverage to all HCV genotypes and serotypes. As the end appears near for HCV, it becomes important to ask if the development of novel HTAs should also be analyzed in combination with other DAAs, in order to address potential hard-to-treat HCV patient populations. Since the treatment regimens for HCV began with the use of a global HTA, could one end the field as well?

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“…Phase II studies show increased SVR rates compared with PR for naïve GT-1 patients receiving a combination of ALV and PR for at least 24 weeks. For GT-1 treatment-experienced patients, ALV þ PR demonstrated higher cEVR compared to PR in relapsers, partial responders and null-responders [Alberti et al 2012]. Moreover, for GT-2/3 naïve patients, the possibility of an IFN-free regimen has been studied and the results demonstrate the ability of such a regimen to cure almost one-quarter of GT-2/3 naïve patients [Pawlostky et al 2012].…”

Section: Htas and Other Antiviral Treatmentsmentioning

confidence: 98%

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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1406 Alisporivir (Alv) Plus Peg-Interferon/Ribavirin (Pr) in HCV G1 Treatment-Experienced Patients Achieves Primary Endpoint With Superior Efficacy at Treatment Week 12 Compared to Retreatment With Pr

Cited by 12 publications

References 0 publications

Cyclophilin Inhibitors: An Emerging Class of Therapeutics for the Treatment of Chronic Hepatitis C Infection

Cyclophilin Inhibitors: An Emerging Class of Therapeutics for the Treatment of Chronic Hepatitis C Infection

Host-targeting agents in the treatment of hepatitis C: A beginning and an end?

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

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