Fixed-Dose Combination Therapy With Daclatasvir, Asunaprevir, and Beclabuvir for Noncirrhotic Patients With HCV Genotype 1 Infection

Poordad, Fred; Sievert, William; Mollison, Lindsay; Bennett, Michael; Tse, Edmund; Bräu, Norbert; Levin, James; Sepe, Thomas; Lee, Samuel S.; Angus, Peter W; Conway, Brian; Pol, Stanislas; Boyer, Nathalie; Bronowicki, Jean–Pierre; Jacobson, Ira M.; Muir, Andrew J.; Reddy, K. Rajender; Tam, Edward; Ortiz‐Lasanta, Grisell; Lédinghen, Victor de; Sulkowski, Mark S.; Boparai, Navdeep; McPhee, Fiona; Hughes, Eric; Swenson, Eugene S.; Yin, Philip D.

doi:10.1001/jama.2015.3860

Cited by 94 publications

(77 citation statements)

References 19 publications

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“…A proof-of-concept clinical trial of triple-DAA treatment (10) also showed that SOF&DCV&SMV can achieve a high SVR rate, while reducing the treatment period from 12 wk to only 3 wk using a response-guided protocol. Our analysis clearly supports a clinical advantage for triple-DAA-based IFN-free treatments as discussed elsewhere (8,10,(20)(21)(22).…”

Section: Resultssupporting

confidence: 84%

“…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%

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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: Resultssupporting

confidence: 84%

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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“…For example, in patients with baseline NS5A RAVs treated with the NS5A inhibitor daclatasvir combined with asunaprevir (a NS3 protease inhibitor) and beclabuvir (a nonnucleoside NS5B polymerase inhibitor), SVR 12 was achieved in 25 (74%) of the 34 patients with genotype 1a infection versus all 17 (100%) patients with genotype 1b infection (23). There was no evident association between baseline NS3 or NS5B variants and SVR 12 .…”

Section: Discussionmentioning

confidence: 99%

Susceptibilities of Genotype 1a, 1b, and 3 Hepatitis C Virus Variants to the NS5A Inhibitor Elbasvir

Liu

Curry

McMonagle

et al. 2015

Antimicrob Agents Chemother

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Elbasvir is an investigational NS5A inhibitor with in vitro activity against multiple HCV genotypes. Antiviral activity of elbasvir was measured in replicons derived from wild-type or resistant variants of genotypes 1a, 1b, and 3. The barrier to resistance was assessed by the number of resistant colonies selected by exposure to various elbasvir concentrations. In a phase 1b dose-escalating study, virologic responses were determined in 48 noncirrhotic adult men with chronic genotype 1 or 3 infections randomized to placebo or elbasvir from 5 to 50 mg (genotype 1) or 10 to 100 mg (genotype 3) once daily for 5 days. The NS5A gene was sequenced from plasma specimens obtained before, during, and after treatment. Elbasvir suppressed the emergence of resistanceassociated variants (RAVs) in vitro in a dose-dependent manner. Variants selected by exposure to high elbasvir concentrations typically encoded multiple amino acid substitutions (most commonly involving loci 30, 31, and 93), conferring high-level elbasvir resistance. In the monotherapy study, patients with genotype 1b had greater reductions in HCV RNA levels than patients with genotype 1a at all elbasvir doses; responses in patients with genotype 3 were generally less pronounced than for genotype 1, particularly at lower elbasvir doses. M28T, Q30R, L31V, and Y93H in genotype 1a, L31V and Y93H in genotype 1b, and A30K, L31F, and Y93H in genotype 3 were the predominant RAVs selected by elbasvir monotherapy. Virologic findings in patients were consistent with the preclinical observations. NS5A-RAVs emerged most often at amino acid positions 28, 30, 31, and 93 in both the laboratory and clinical trial. (The MK-8742 P002 trial has been registered at ClinicalTrials.gov under identifier NCT01532973.)

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“…peginterferon/ribavirin, suggesting that asunaprevir has no clinically meaningful effect on beclabuvir [39]. Daclatasvir, asunaprevir and beclabuvir are currently in phase 3 development as a fixed-dose combination [40,41].…”

Section: Pharmacokinetics Of Asunaprevir In Combination With Daclatasmentioning

confidence: 99%

Asunaprevir: A Review of Preclinical and Clinical Pharmacokinetics and Drug–Drug Interactions

Eley

Garimella

et al. 2015

Clin Pharmacokinet

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Asunaprevir is a tripeptidic acylsulfonamide inhibitor of the hepatitis C virus (HCV) NS3/4A protease. Asunaprevir undergoes rapid absorption, with a time to reach maximum plasma concentration (T max) of 2-4 h and an elimination half-life (t ½) of ≈15-20 h observed in single-ascending dose studies. Steady state was achieved by day 7 in multiple-ascending dose studies. The large food effect observed with earlier formulations was mitigated by the soft-gel capsule. Asunaprevir demonstrates high apparent oral clearance and minimal renal elimination, and is eliminated primarily via cytochrome P450 (CYP) 3A4-mediated hepatic oxidative metabolism and faecal excretion. Highly preferential distribution of asunaprevir to the liver occurs via organic anion-transporting polypeptide (OATP)-mediated transport and results in low plasma concentrations. The condition of the liver affects disposition, as higher asunaprevir plasma exposures are observed in patients infected with HCV and/or hepatic impairment. Japanese patients also have higher exposure relative to North American/European patients, but comparable safety at the registrational dose. Asunaprevir has a low potential to perpetrate drug-drug interactions via CYP3A4, P-glycoprotein and OATP, but is a moderate CYP2D6 inhibitor; concomitant drugs that are substrates of CYP2D6 or P-glycoprotein and have a narrow therapeutic index should be used with care. Asunaprevir plasma exposure is strongly affected by inhibitors of OATP transport. No clinically significant interactions were observed between asunaprevir and daclatasvir or daclatasvir/beclabuvir. Asunaprevir has a complex pharmacokinetic profile and forms part of potent and well-tolerated all-oral regimens for the treatment of chronic HCV infection.

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Fixed-Dose Combination Therapy With Daclatasvir, Asunaprevir, and Beclabuvir for Noncirrhotic Patients With HCV Genotype 1 Infection

Cited by 94 publications

References 19 publications

Quantifying antiviral activity optimizes drug combinations against hepatitis C virus infection

Quantifying antiviral activity optimizes drug combinations against hepatitis C virus infection

Susceptibilities of Genotype 1a, 1b, and 3 Hepatitis C Virus Variants to the NS5A Inhibitor Elbasvir

Asunaprevir: A Review of Preclinical and Clinical Pharmacokinetics and Drug–Drug Interactions

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