Daclatasvir in Combination With Asunaprevir and Beclabuvir for Hepatitis C Virus Genotype 1 Infection With Compensated Cirrhosis

Muir, Andrew J.; Poordad, Fred; Lalezari, Jacob; Everson, Gregory T.; Dore, Gregory J.; Herring, Robert; Sheikh, Aasim; Kwo, Paul Y.; Hézode, Christophe; Pockros, Paul J.; Tran, Albert; Yozviak, Joseph L; Reau, Nancy; Ramji, Alnoor; Stuart, Katherine; Thompson, Alexander; Vierling, John M.; Freilich, B.; Cooper, James N.; Ghesquière, Wayne; Yang, Rong; McPhee, Fiona; Hughes, Eric; Swenson, Eugene S.; Yin, Philip D.

doi:10.1001/jama.2015.3868

Cited by 119 publications

(119 citation statements)

References 17 publications

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“…Triple-DAA IFNfree combinations are being clinically evaluated to seek more rapid and efficacious elimination of HCV, including NI&N-S5AI&PI and NI&NS5AI&NNI (8,(20)(21)(22). However, it is not yet understood how much advantage triple-DAA treatment can provide over double-DAA treatment, and which triple-DAA combination will give the best treatment outcome (8,(20)(21)(22). Here, we quantified the anti-HCV activity of eight candidate combinations of triple-DAA treatment; SOF with NS5AI (DCV, LDV) plus PI (SMV, ASV) or NNI (VX, DAS) ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Quantifying antiviral activity optimizes drug combinations against hepatitis C virus infection

Koizumi

Nakajim

Ohash

et al. 2016

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With the introduction of direct-acting antivirals (DAAs), treatment against hepatitis C virus (HCV) has significantly improved. To manage and control this worldwide infectious disease better, the "best" multidrug treatment is demanded based on scientific evidence. However, there is no method available that systematically quantifies and compares the antiviral efficacy and drug-resistance profiles of drug combinations. Based on experimental anti-HCV profiles in a cell culture system, we quantified the instantaneous inhibitory potential (IIP), which is the logarithm of the reduction in viral replication events, for both single drugs and multiple-drug combinations. From the calculated IIP of 15 anti-HCV drugs from different classes [telaprevir, danoprevir, asunaprevir, simeprevir, sofosbuvir (SOF), VX-222, dasabuvir, nesbuvir, tegobuvir, daclatasvir, ledipasvir, IFN-α, IFN-λ1, cyclosporin A, and SCY-635], we found that the nucleoside polymerase inhibitor SOF had one of the largest potentials to inhibit viral replication events. We also compared intrinsic antiviral activities of a panel of drug combinations. Our quantification analysis clearly indicated an advantage of triple-DAA treatments over double-DAA treatments, with triple-DAA treatments showing enhanced antiviral activity and a significantly lower probability for drug resistance to emerge at clinically relevant drug concentrations. Our framework provides quantitative information to consider in designing multidrug strategies before costly clinical trials.instantaneous inhibitory potential H epatitis C virus (HCV) affects ∼170 million people worldwide (1-4) and is a major cause of liver cirrhosis and hepatocellular carcinoma. The standard treatment has long been a combination of IFN, IFN-α or pegylated IFN-α (peg-IFN-α), with ribavirin (RBV), with a sustained virological response (SVR) rate of around 50% (5). Improvements in the SVR rate have been made by using anti-HCV agents that inhibit viral-derived factors or cellular factors that are essential for viral replication. Agents inhibiting viral proteins, called direct-acting antivirals (DAAs), typically target HCV nonstructural (NS)3 protease, NS5A, and NS5B polymerase (3). Anti-HCV molecules that target cellular factors, so-called hosttargeting antivirals (HTAs), include those HTAs inhibiting cyclophilins and microRNA-122, which are required for HCV replication (3). These agents have been evaluated in clinical trials. In 2011, the protease inhibitors (PIs) telaprevir (TPV) and boceprevir were approved by the US Food and Drug Administration for use in combination with peg-IFN and RBV. These drug combinations achieved significantly improved clinical outcomes, attaining more than a 70% SVR rate (5).

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Section: Resultsmentioning

confidence: 99%

Quantifying antiviral activity optimizes drug combinations against hepatitis C virus infection

Koizumi

Nakajim

Ohash

et al. 2016

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“…[33][34][35][36] Many of these trials included patients awaiting LT, 31,37 and those with decompensated cirrhosis of liver. 31,38,39 There are several controlled trials with interesting acronyms such as ALLY-1, SOLAR-1, SOLAR-2, SATURN and CORAL-1, which have shown that it is now feasible to treat patients with decompensated cirrhosis (Table 1). In addition, there have been several real world data studies which have given similar conclusions.…”

Section: Feasibility and Effectivenessmentioning

confidence: 99%

Potential Liver Transplant Recipients with Hepatitis C: Should They Be Treated Before or After Transplantation?

Anand

2017

Journal of Clinical and Experimental Hepatology

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“…However, ribavirin could still be useful in pre-treated patients (93% vs 87% SVR with and without ribavirin, respectively) [52] . In G3 cirrhotic patients, preliminary results showed that the association of grazoprevir elbasvir sofosbuvir without ribavirin gave a 91% SVR suggesting that this combination could be an ideal strategy for these difficult to treat population [33] .…”

Section: Multiple Daas Combinations Without Ribavirin In Difficult-tomentioning

confidence: 99%

Ribavirin: Past, present and future

Loustaud‐Ratti¹

2016

WJH

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Before the advent of direct acting antiviral agents (DAAs) ribavirin, associated to pegylated-interferon played a crucial role in the treatment of chronic hepatitis C, preventing relapses and breakthroughs. In the present era of new potent DAAs, a place is still devoted to the drug. Ribavirin associated with sofosbuvir alone is efficient in the treatment of most cases of G2 infected patients. All options currently available for the last difficult-to-treat cirrhotic G3 patients contain ribavirin. Reducing treatment duration to 12 wk in G1 or G4 cirrhotic compensated patients is feasible thanks to ribavirin. Retreating patients with acquired anti NS5A resistance-associated variants using ribavirin-based strategies could be useful. The addition of ribavirin with DAAs combinations however, leads to more frequent but mild adverse events especially in cirrhotic patients. Preliminary data with interferon-free second generation DAAs combinations without ribavirin suggest that future of the drug is jeopardized even in difficult-totreat patients: The optimization of ribavirin dosage according to an early monitoring of blood levels has been suggested to be relevant in double therapy with peginterferon or sofosbuvir but not with very potent combinations of more than two DAAs. Author contributions: Loustaud-Ratti V and Carrier P wrote the manuscript; Debette-Gratien M, Jacques J, Alain S, Marquet P, Sautereau D and Rousseau A read the manuscript and conducted a critical analysis. Conflict-of-interest statement:The authors have no conflict of interest concerning this work.Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/ licenses/by-nc/4.0/ INTRODUCTIONBefore the advent of direct acting antiviral agents (DAAs) ribavirin played a crucial role in the treatment of chronic hepatitis C associated to pegylated interferon [1] . This combination is still relevant in many parts of the world which do not have access to new therapies because of cost issues [2] . Although the role of ribavirin in the era of DAAs will probably decrease in the future with the arrival of second generation drugs, it remains essential in strategies decreasing treatment duration or in some difficult situations. The goal of this review is to briefly recall the recent past of ribavirin and consider its present and potential future. RIbavIRIN: meChaNIsms Of aCTIONSo far, multiple mechanisms of action of ribavirin have been described. The antiviral mechanism is probably the best documented, the erroneous incorporation of ribavirin triphosphate into replicating RNA strands inhibiting chain elongation [3] ...

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Daclatasvir in Combination With Asunaprevir and Beclabuvir for Hepatitis C Virus Genotype 1 Infection With Compensated Cirrhosis

Cited by 119 publications

References 17 publications

Quantifying antiviral activity optimizes drug combinations against hepatitis C virus infection

Quantifying antiviral activity optimizes drug combinations against hepatitis C virus infection

Potential Liver Transplant Recipients with Hepatitis C: Should They Be Treated Before or After Transplantation?

Ribavirin: Past, present and future

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