Journal articles: 'Daclatasvir, NS5A inhibitor'

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Gottwein, Judith M., Sanne B. Jensen, Yi-Ping Li, Lubna Ghanem, Troels K. H. Scheel, Stéphanie B. N. Serre, Lotte Mikkelsen, and Jens Bukh. "Combination Treatment with Hepatitis C Virus Protease and NS5A Inhibitors Is Effective against Recombinant Genotype 1a, 2a, and 3a Viruses." Antimicrobial Agents and Chemotherapy 57, no. 3 (December 28, 2012): 1291–303. http://dx.doi.org/10.1128/aac.02164-12.

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ABSTRACTWith the development of directly acting antivirals, hepatitis C virus (HCV) therapy entered a new era. However, rapid selection of resistance mutations necessitates combination therapy. To study combination therapy in infectious culture systems, we aimed at developing HCV semi-full-length (semi-FL) recombinants relying only on the JFH1 NS3 helicase, NS5B, and the 3′ untranslated region. With identified adaptive mutations, semi-FL recombinants of genotypes(isolates) 1a(TN) and 3a(S52) produced supernatant infectivity titers of ∼4 log10focus-forming units/ml in Huh7.5 cells. Genotype 1a(TN) adaptive mutations allowed generation of 1a(H77) semi-FL virus. Concentration-response profiles revealed the higher efficacy of the NS3 protease inhibitor asunaprevir (BMS-650032) and the NS5A inhibitor daclatasvir (BMS-790052) against 1a(TN and H77) than 3a(S52) viruses. Asunaprevir had intermediate efficacy against previously developed 2a recombinants J6/JFH1 and J6cc. Daclatasvir had intermediate efficacy against J6/JFH1, while low sensitivity was confirmed against J6cc. Using a cross-titration scheme, infected cultures were treated until viral escape or on-treatment virologic suppression occurred. Compared to single-drug treatment, combination treatment with relatively low concentrations of asunaprevir and daclatasvir suppressed infection with all five recombinants. Escaped viruses primarily had substitutions at amino acids in the NS3 protease and NS5A domain I reported to be genotype 1 resistance mutations. Inhibitors showed synergism at drug concentrations reportedin vivo. In summary, semi-FL HCV recombinants, including the most advanced reported genotype 3a infectious culture system, permitted genotype-specific analysis of combination treatment in the context of the complete viral life cycle. Despite differential sensitivity to lead compound NS3 protease and NS5A inhibitors, genotype 1a, 2a, and 3a viruses were suppressed by combination treatment with relatively low concentrations.

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Pelosi, Lenore A., Stacey Voss, Mengping Liu, Min Gao, and Julie A. Lemm. "Effect on Hepatitis C Virus Replication of Combinations of Direct-Acting Antivirals, Including NS5A Inhibitor Daclatasvir." Antimicrobial Agents and Chemotherapy 56, no. 10 (July 30, 2012): 5230–39. http://dx.doi.org/10.1128/aac.01209-12.

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ABSTRACTThree hepatitis C virus (HCV) inhibitors, asunaprevir (ASV; BMS-650032), daclatasvir (DCV; BMS-790052), and BMS-791325, each targeting a different nonstructural protein of the virus (NS3, NS5A, and NS5B, respectively), have independently demonstrated encouraging preclinical profiles and are currently undergoing clinical evaluation. Since drug-resistant variants have rapidly developed in response to monotherapy with almost all direct-acting antiviral agents (DAAs) for HCV, the need for combination therapies to effectively eradicate the virus from infected patients is clear. These studies demonstrated the additive-synergistic effects on replicon inhibition and clearance of combining NS3 protease or NS5B RNA polymerase inhibitors with the first-in-class, NS5A replication complex inhibitor daclatasvir (DCV) and reveal new resistance pathways for combinations of two small-molecule inhibitors that differ from those that develop during monotherapy. The results suggest that under a specific selective pressure, a balance must be reached in the fitness costs of substitutions in one target gene when substitutions are also present in another target gene. Further synergies and additional novel resistance substitutions were observed during triple-combination treatment relative to dual-drug therapy, indicating that, in combination, HCV inhibitors can exert cross-target influences on resistance development. Enhanced synergies in replicon inhibition and a reduced frequency of resistance together lend strong support to the utility of combinations of DAAs for the treatment of HCV, and the identification of altered resistance profiles during combination treatment provides useful information for monitoring resistance in the clinic.

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Wang, Chunfu, Lourdes Valera, Lingling Jia, Melissa J. Kirk, Min Gao, and Robert A. Fridell. "In VitroActivity of Daclatasvir on Hepatitis C Virus Genotype 3 NS5A." Antimicrobial Agents and Chemotherapy 57, no. 1 (October 22, 2012): 611–13. http://dx.doi.org/10.1128/aac.01874-12.

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ABSTRACTThe NS5A replication complex inhibitor daclatasvir (DCV; BMS-790052) inhibits hybrid replicons containing hepatitis C virus (HCV) genotype 3a (HCV3a) NS5A genes with 50% effective concentrations (EC50s) ranging from 120 to 870 pM. Selection studies with a hybrid HCV3a replicon identified NS5A residues 31 and 93 as sites for DCV-selected resistance. Our results support the potential use of DCV as a component in combination therapies for HCV3a chronic infection.

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Liu, Dandan, Juan Ji, Tanya P. Ndongwe, Eleftherios Michailidis, Charles M. Rice, Robert Ralston, and Stefan G. Sarafianos. "Fast Hepatitis C Virus RNA Elimination and NS5A Redistribution by NS5A Inhibitors Studied by a Multiplex Assay Approach." Antimicrobial Agents and Chemotherapy 59, no. 6 (April 6, 2015): 3482–92. http://dx.doi.org/10.1128/aac.00223-15.

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ABSTRACTWhile earlier therapeutic strategies for the treatment of hepatitis C virus (HCV) infection relied exclusively on interferon (IFN) and ribavirin (RBV), four direct-acting antiviral agents (DAAs) have now been approved, aiming for an interferon-free strategy with a short treatment duration and fewer side effects. To facilitate studies on the mechanism of action (MOA) and efficacy of DAAs, we established a multiplex assay approach, which employs flow cytometry, aGaussialuciferase reporter system, Western blot analysis, reverse transcription-quantitative PCR (RT-qPCR), a limited dilution assay (50% tissue culture infectious dose [TCID50]), and an image profiling assay that follows the NS5A redistribution in response to drug treatment. We used this approach to compare the relative potency of various DAAs and the kinetics of their antiviral effects as a potential preclinical measure of their potential clinical utility. We evaluated the NS5A inhibitors ledipasvir (LDV) and daclatasvir (DCV), the NS3/4A inhibitor danoprevir (DNV), and the NS5B inhibitor sofosbuvir (SOF). In terms of kinetics, our data demonstrate that the NS5A inhibitor LDV, followed closely by DCV, has the fastest effect on suppression of viral proteins and RNA and on redistribution of NS5A. In terms of MOA, LDV has a more pronounced effect than DCV on the viral replication, assembly, and infectivity of released virus. Our approach can be used to facilitate the study of the biological processes involved in HCV replication and help identify optimal drug combinations.

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Hikita, Hayato, and Tetsuo Takehara. "NS5A-P32 Deletion in Hepatitis C Genotype 1b Infection is the Most Refractory Treatment-Mediated Amino Acid Change Exhibiting Resistance to all NS5A Inhibitors." Seminars in Liver Disease 40, no. 02 (December 13, 2019): 143–53. http://dx.doi.org/10.1055/s-0039-3402001.

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AbstractNS5A-P32 deletion (P32del) is a resistance-associated amino acid change that has recently gained popularity in direct-acting antiviral treatment for chronic hepatitis C. Although not yet detected in naive patients, it appears in 5 to 10% of hepatitis C genotype 1b patients who fail to respond to daclatasvir/asunaprevir and sofosbuvir/ledipasvir treatments. In contrast to signature resistance-associated substitutions, such as substitutions at the NS5A-L31 and NS5A-Y93 positions, it shows complete resistance to all NS5A inhibitors in replicon and cell culture. Studies of humanized liver mice suggest that P32del retains good replication fitness and requires two classes of antivirals, except NS5A inhibitors, to be suppressed effectively. Patients with the P32del virus do not respond to glecaprevir/pibrentasvir but do respond to sofosbuvir/velpatasvir/voxilaprevir, presumably to sofosbuvir + glecaprevir/pibrentasvir, and at least partially to sofosbuvir/velpatasvir + ribavirin. Attention should be given to P32del in patients who experience failure with any NS5A inhibitor, especially those with genotype 1b infection.

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O'Boyle, Donald R., Peter T. Nower, Min Gao, Robert Fridell, Chunfu Wang, Piyasena Hewawasam, Omar Lopez, et al. "Synergistic Activity of Combined NS5A Inhibitors." Antimicrobial Agents and Chemotherapy 60, no. 3 (December 28, 2015): 1573–83. http://dx.doi.org/10.1128/aac.02639-15.

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Daclatasvir (DCV) is a first-in-class hepatitis C virus (HCV) nonstructural 5A replication complex inhibitor (NS5A RCI) that is clinically effective in interferon-free combinations with direct-acting antivirals (DAAs) targeting alternate HCV proteins. Recently, we reported NS5A RCI combinations that enhance HCV inhibitory potentialin vitro, defining a new class of HCV inhibitors termed NS5A synergists (J. Sun, D. R. O’Boyle II, R. A. Fridell, D. R. Langley, C. Wang, S. Roberts, P. Nower, B. M. Johnson F. Moulin, M. J. Nophsker, Y. Wang, M. Liu, K. Rigat, Y. Tu, P. Hewawasam, J. Kadow, N. A. Meanwell, M. Cockett, J. A. Lemm, M. Kramer, M. Belema, and M. Gao, Nature 527:245–248, 2015, doi:10.1038/nature15711). To extend the characterization of NS5A synergists, we tested new combinations of DCV and NS5A synergists against genotype (gt) 1 to 6 replicons and gt 1a, 2a, and 3a viruses. The kinetics of inhibition in HCV-infected cells treated with DCV, an NS5A synergist (NS5A-Syn), or a combination of DCV and NS5A-Syn were distinctive. Similar to activity observed clinically, DCV caused a multilog drop in HCV, followed by rebound due to the emergence of resistance. DCV–NS5A-Syn combinations were highly efficient at clearing cells of viruses, in line with the trend seen in replicon studies. The retreatment of resistant viruses that emerged using DCV monotherapy with DCV–NS5A-Syn resulted in a multilog drop and rebound in HCV similar to the initial decline and rebound observed with DCV alone on wild-type (WT) virus. A triple combination of DCV, NS5A-Syn, and a DAA targeting the NS3 or NS5B protein cleared the cells of viruses that are highly resistant to DCV. Our data support the observation that the cooperative interaction of DCV and NS5A-Syn potentiates both the genotype coverage and resistance barrier of DCV, offering an additional DAA option for combination therapy and tools for explorations of NS5A function.

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Yau, Alan Hoi Lun, and Eric M. Yoshida. "Hepatitis C Drugs: The End of the Pegylated Interferon Era and the Emergence of All-Oral, Interferon-Free Antiviral Regimens: A Concise Review." Canadian Journal of Gastroenterology and Hepatology 28, no. 8 (2014): 445–51. http://dx.doi.org/10.1155/2014/549624.

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Between 2001 and 2011, the standard of care for chronic hepatitis C virus (HCV) infection was a combination of pegylated interferon (PEGIFN) and ribavirin (RBV). In May 2011, boceprevir and telaprevir, two first-generation NS3/4A protease inhibitors, were approved in combination with PEG-IFN and RBV for 24 to 48 weeks in hepatitis C virus genotype 1 infections. In December 2013, simeprevir, a second-generation NS3/4A protease inhibitor, was approved for use with PEG-IFN and RBV for 12 weeks in genotype 1, while sofosbuvir, a NS5B nucleotide polymerase inhibitor, was approved for use with PEG-IFN and RBV for 12 weeks in genotypes 1 and 4, as well as with RBV alone for 12 weeks in genotype 2 and for 24 weeks in genotype 3. Sofosbuvir combined with simeprevir or an NS5A replication complex inhibitor (ledipasvir or daclatasvir) with or without RBV for 12 weeks in genotype 1 resulted in a sustained virological response >90%, irrespective of previous treatment history or presence of cirrhosis. Similarly impressive sustained virological response rates have been shown with ABT-450/r (ritonavir-boosted NS3/4A protease inhibitor)-based regimens in combination with other direct-acting antiviral agent(s) with or without RBV for 12 weeks in genotype 1. The optimal all-oral interferon-free antiviral regimen likely entails a combination of an NS5B nucleotide polymerase inhibitor with either a second-generation NS3/4A protease inhibitor or an NS5A replication complex inhibitor with or without RBV. Further research is needed to determine the role of resistance testing, clarify the optimal follow-up duration post-treatment, and evaluate the antiviral efficacy and safety in difficult-to-cure patient populations.

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Friborg, Jacques, Steven Levine, Chaoqun Chen, Amy K. Sheaffer, Susan Chaniewski, Stacey Voss, Julie A. Lemm, and Fiona McPhee. "Combinations of Lambda Interferon with Direct-Acting Antiviral Agents Are Highly Efficient in Suppressing Hepatitis C Virus Replication." Antimicrobial Agents and Chemotherapy 57, no. 3 (December 28, 2012): 1312–22. http://dx.doi.org/10.1128/aac.02239-12.

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ABSTRACTThe clinical efficacy of a pegylated form of human lambda 1 interferon (IFN-λ1; also referred to herein as lambda) has been demonstrated in patients chronically infected with hepatitis C virus (HCV) representing genotypes 1 through 4. In these proof-of-concept studies, lambda showed an improved safety profile compared to the pegylated form of alfa interferon (referred to herein as alfa). In the study described in this report, an assessment of thein vitroantiviral activity of type III IFNs toward different HCV replicons revealed that the unpegylated recombinant form of IFN-λ1 (rIFN-λ1) exerted the most robust effect, while rIFN-λ3 exhibited greater activity than rIFN-λ2. More importantly, cross-resistance to rIFN-λ1 was not observed in replicon cell lines known to have reduced susceptibility to investigational direct-acting antiviral (DAA) agents targeting the essential HCV nonstructural protein NS3, NS5A, or NS5B. When combined with either rIFN-α, the NS3 protease inhibitor (NS3 PI) asunaprevir (ASV), the NS5A replication complex inhibitor (NS5A RCI) daclatasvir (DCV), or the NS5B polymerase site I inhibitor (NS5B I) BMS-791325, rIFN-λ1 displayed a mixture of additive and synergistic effects. In three-drug combination studies, inclusion of lambda with ASV and DCV also yielded additive to synergistic effects. In line with these observations, it was demonstrated that a regimen that used a combination of rIFN-λ1 with one or two DAAs was superior to an IFN-free regimen in clearing HCV RNA in genotype 1a cell lines representing wild-type and NS3 protease inhibitor-resistant sequences. Overall, these data support further clinical development of lambda as part of alternative combination treatments with DAAs for patients chronically infected with HCV.

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McPhee, Fiona, Amy K. Sheaffer, Jacques Friborg, Dennis Hernandez, Paul Falk, Guangzhi Zhai, Steven Levine, et al. "Preclinical Profile and Characterization of the Hepatitis C Virus NS3 Protease Inhibitor Asunaprevir (BMS-650032)." Antimicrobial Agents and Chemotherapy 56, no. 10 (August 6, 2012): 5387–96. http://dx.doi.org/10.1128/aac.01186-12.

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ABSTRACTAsunaprevir (ASV; BMS-650032) is a hepatitis C virus (HCV) NS3 protease inhibitor that has demonstrated efficacy in patients chronically infected with HCV genotype 1 when combined with alfa interferon and/or the NS5A replication complex inhibitor daclatasvir. ASV competitively binds to the NS3/4A protease complex, withKivalues of 0.4 and 0.24 nM against recombinant enzymes representing genotypes 1a (H77) and 1b (J4L6S), respectively. Selectivity was demonstrated by the absence of any significant activity against the closely related GB virus-B NS3 protease and a panel of human serine or cysteine proteases. In cell culture, ASV inhibited replication of HCV replicons representing genotypes 1 and 4, with 50% effective concentrations (EC50s) ranging from 1 to 4 nM, and had weaker activity against genotypes 2 and 3 (EC50, 67 to 1,162 nM). Selectivity was again demonstrated by the absence of activity (EC50, >12 μM) against a panel of other RNA viruses. ASV exhibited additive or synergistic activity in combination studies with alfa interferon, ribavirin, and/or inhibitors specifically targeting NS5A or NS5B. Plasma and tissue exposuresin vivoin several animal species indicated that ASV displayed a hepatotropic disposition (liver-to-plasma ratios ranging from 40- to 359-fold across species). Twenty-four hours postdose, liver exposures across all species tested were ≥110-fold above the inhibitor EC50s observed with HCV genotype-1 replicons. Based on these virologic and exposure properties, ASV holds promise for future utility in a combination with other anti-HCV agents in the treatment of HCV-infected patients.

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Plaza, Zulema, Vincent Soriano, Eugenia Vispo, Maria del Mar Gonzalez, Pablo Barreiro, Eduardo Seclén, and Eva Poveda. "Prevalence of natural polymorphisms at the HCV NS5A gene associated with resistance to daclatasvir, an NS5A inhibitor." Antiviral Therapy 17, no. 5 (2012): 921–26. http://dx.doi.org/10.3851/imp2091.

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Herbst, D. Alan, and K. Rajender Reddy. "NS5A inhibitor, daclatasvir, for the treatment of chronic hepatitis C virus infection." Expert Opinion on Investigational Drugs 22, no. 10 (August 9, 2013): 1337–46. http://dx.doi.org/10.1517/13543784.2013.826189.

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DEBNATH, Prasanta, Sanjay CHANDNANI, Pravin RATHI, Sujit NAIR, Vinay PAWAR, and Qais CONTRACTOR. "COMBINED NS5A & NS5B NUCLEOTIDE INHIBITOR THERAPY FOR PATIENTS WITH CHRONIC HEPATITIS C WITH STAGE 5 CHRONIC KIDNEY DISEASE ON HEMODIALYSIS." Arquivos de Gastroenterologia 57, no. 1 (February 2020): 39–44. http://dx.doi.org/10.1590/s0004-2803.202000000-08.

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ABSTRACT BACKGROUND: Hepatitis C virus (HCV) infection is the most common hepatotropic viral infection affecting the patients on maintenance hemodialysis. Treatment of chronic HCV infection in stage 4 and 5 CKD includes a combination of elbasvir/grazoprevir and glecaprevir/pibrentasvir, which are not available in many countries. OBJECTIVE: Hence, we have conducted this study to look for the safety and efficacy of sofosbuvir combination therapy in this difficult to treat population. METHODS: We conducted a single-center, prospective, open-label study in which Stage 5 CKD patients on maintenance hemodialysis with HCV infection. Total of 18 patients was included. sofosbuvir with daclatasvir or ledipasvir was used according to genotype for 12 weeks. HCV RNA, genotype, transient elastography (TE) was considered for every patient. HCV RNA was quantified at 4th week, 12th week and 12 weeks post-treatment to look for sustained virologic response (SVR 12). RESULTS: Infection due to genotype 1 was seen in 12 (66.7%) patients followed by genotype 3 in 4 (22.3%) with each patient of genotype 2 and 5. The median value of HCV RNA was 2,35,000 IU/mL. On TE, all had liver stiffness of <9.4 KPa. All patients had HCV RNA of <15 IU/mL at 4th and 12th week of treatment and 12 weeks post-treatment. No significant change in hemoglobin, eGFR and liver stiffness was observed. CONCLUSION: Full dose sofosbuvir i.e. 400 mg, in combination with NS5A inhibitors daclatasvir or ledipasvir is found to be safe and effective in patients with end stage renal disease, who are on maintenance hemodialysis.

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Wong, Kelly A., Angela Worth, Ross Martin, Evguenia Svarovskaia, Diana M. Brainard, Eric Lawitz, Michael D. Miller, and Hongmei Mo. "Characterization of Hepatitis C Virus Resistance from a Multiple-Dose Clinical Trial of the Novel NS5A Inhibitor GS-5885." Antimicrobial Agents and Chemotherapy 57, no. 12 (July 22, 2013): 6333–40. http://dx.doi.org/10.1128/aac.02193-12.

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ABSTRACTGS-5885 is a novel hepatitis C virus (HCV) NS5A inhibitor. In a 3-day monotherapy study in treatment-naive genotype 1a (GT1a) and GT1b HCV-infected subjects, median viral load reductions ranged from 2.3 to 3.3 log10HCV RNA IU/ml across dosing cohorts (1, 3, 10, 30, or 90 mg once daily). Here, we report viral sequencing and phenotypic analysis of clinical isolates from this study. Detection of baseline NS5A amino acid substitutions at positions 28, 30, 31, or 93 in GT1a was associated with a reduced treatment response. In the GT1b cohort, Y93H was detected in 100% of subjects at day 4 or 14. In the Gt1a cohort, population sequencing detected NS5A resistance-associated mutations at day 4 or 14 for 3/10 subjects at the 1-mg dose and for all subjects dosed at ≥3 mg. A subset of mutants that confer a low level of reduced susceptibility to GS-5885 was not detected by population sequencing at the 30- and 90-mg doses. Subject-derived M28T, Q30R, L31M, and Y93C mutations all conferred >30-fold reductions in GS-5885 and daclatasvir susceptibilitiesin vitro. Site-directed NS5A mutants also showed reduced susceptibility to GS-5885. However, all NS5A mutants tested remained fully susceptible to other classes of direct-acting antivirals (DAAs), interferon alpha, and ribavirin. Importantly, the nonoverlapping resistance profile and high potency of GS-5885 support its further development with other direct-acting antivirals for the treatment of chronic HCV. (This study has been registered at ClinicalTrials.gov under registration number NCT01193478.)

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Teraoka, Yuji, Takuro Uchida, Michio Imamura, Nobuhiko Hiraga, Mitsutaka Osawa, Hiromi Kan, Yuhei Saito, et al. "Limitations of daclatasvir/asunaprevir plus beclabuvir treatment in cases of NS5A inhibitor treatment failure." Journal of General Virology 99, no. 8 (August 1, 2018): 1058–65. http://dx.doi.org/10.1099/jgv.0.001091.

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Lee, Wei-Ping, Keng-Li Lan, Shi-Xian Liao, Yi-Hsiang Huang, Ming-Chih Hou, and Keng-Hsin Lan. "Inhibitory Effects of Amentoflavone and Orobol on Daclatasvir-Induced Resistance-Associated Variants of Hepatitis C Virus." American Journal of Chinese Medicine 46, no. 04 (January 2018): 835–52. http://dx.doi.org/10.1142/s0192415x18500441.

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Hepatitis C virus (HCV) is recognized as a major causative agent of chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Despite rapid progress in the development of direct-acting antivirals (DAA) against HCV infection in recent years, cost-effective antiviral drugs with more affordable prices still need to be developed. In this study, we screened a library of natural compounds to identify natural HCV inhibitors. The library of the pure compounds extracted from Chinese herbs deposited in the chemical bank of National Research Institute of Chinese Medicine (NRICM), Taiwan was screened in the cell culture-derived HCV (HCVcc) system. We identified the flavone or flavan-based compounds amentoflavone, 7,4[Formula: see text]-dihydroxyflavanone, and orobol with the inhibition of viral entry, replication, and translation of the HCV life cycle. Amentoflavone and orobol also showed inhibitory effects on resistant-associated variants to the NS5A inhibitor daclatasvir. The results of this study have the potential to benefit patients who are intolerant to the adverse effect of pegylated interferon or who harbor resistant strains refractory to treatment by current direct-acting antiviral agents.

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Garimella, T., R. Wang, W. L. Luo, P. Wastall, H. Kandoussi, M. DeMicco, R. D. Bruce, C. Hwang, R. Bertz, and M. Bifano. "Assessment of Drug-Drug Interactions between Daclatasvir and Methadone or Buprenorphine-Naloxone." Antimicrobial Agents and Chemotherapy 59, no. 9 (June 29, 2015): 5503–10. http://dx.doi.org/10.1128/aac.00478-15.

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ABSTRACTHepatitis C virus (HCV) infection is common among people who inject drugs, including those managed with maintenance opioids. Pharmacokinetic interactions between opioids and emerging oral HCV antivirals merit evaluation. Daclatasvir is a potent pangenotypic inhibitor of the HCV NS5A replication complex recently approved for HCV treatment in Europe and Japan in combination with other antivirals. The effect of steady-state daclatasvir (60 mg daily) on stable plasma exposure to oral opioids was assessed in non-HCV-infected subjects receiving methadone (40 to 120 mg;n= 14) or buprenorphine plus naloxone (8 to 24 mg plus 2 to 6 mg;n= 11). No relevant interaction was inferred if the 90% confidence interval (CI) of the geometric mean ratio (GMR) of opioid area under the plasma concentration-time curve over the dosing interval (AUCτ) or maximum concentration in plasma (Cmax) with versus without daclatasvir was within literature-derived ranges of 0.7 to 1.43 (R- andS-methadone) or 0.5 to 2.0 (buprenorphine and norbuprenorphine). Dose-normalized AUCτ forR-methadone (GMR, 1.08; 90% CI, 0.94 to 1.24),S-methadone (1.13; 0.99 to 1.30), and buprenorphine (GMR, 1.37; 90% CI, 1.24 to 1.52) were within the no-effect range. The norbuprenorphine AUCτ was slightly elevated in the primary analysis (GMR, 1.62; 90% CI, 1.30 to 2.02) but within the no-effect range in a supplementary analysis of all evaluable subjects. Dose-normalizedCmaxfor both methadone enantiomers, buprenorphine and norbuprenorphine, were within the no-effect range. Standardized assessments of opioid pharmacodynamics were unchanged throughout daclatasvir administration with methadone or buprenorphine. Daclatasvir pharmacokinetics were similar to historical data. Coadministration of daclatasvir and opioids was generally well tolerated. In conclusion, these data suggest that daclatasvir can be administered with buprenorphine or methadone without dose adjustments.

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Garimella, Tushar, Reena Wang, Wen-Lin Luo, Carey Hwang, Diane Sherman, Hamza Kandoussi, Thomas Marbury, Harry Alcorn, Richard Bertz, and Marc Bifano. "The Effect of Renal Impairment on Single-Dose Pharmacokinetics of Daclatasvir, an HCV NS5A Inhibitor." American Journal of Gastroenterology 109 (October 2014): S170—S171. http://dx.doi.org/10.14309/00000434-201410002-00582.

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O’Boyle, Donald R., Peter T. Nower, Jin-Hua Sun, Robert Fridell, Chunfu Wang, Lourdes Valera, and Min Gao. "A 96-well based analysis of replicon elimination with the HCV NS5A replication complex inhibitor daclatasvir." Journal of Virological Methods 193, no. 1 (October 2013): 68–76. http://dx.doi.org/10.1016/j.jviromet.2013.04.024.

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Aghemo, Alessio, and Massimo Colombo. "Selection of Resistant–Associated Variants to the NS5A Inhibitor Daclatasvir: Revenge of the Hepatitis C Virus." Gastroenterology 145, no. 1 (July 2013): 247–49. http://dx.doi.org/10.1053/j.gastro.2013.05.028.

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Bailly, François, Pierre Pradat, Victor Virlogeux, and Fabien Zoulim. "Antiviral Therapy in Patients with Hepatitis C Virus-Induced Cirrhosis." Digestive Diseases 33, no. 4 (2015): 613–23. http://dx.doi.org/10.1159/000375359.

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Background: Opportunities to treat infection with hepatitis C virus (HCV) are evolving rapidly. From the introduction of interferon (IFN)-α monotherapy in the early 1990s to the approval of telaprevir- and boceprevir-based triple therapies with pegylated (PEG)-IFN-α and ribavirin (RBV) in 2011, the chances of curing patients infected with HCV genotype 1 have improved dramatically to reach approximately 70%. Significant further improvements that may cure virtually all HCV patients with an all-oral, IFN-free regimen are becoming progressively available. Key Messages: Historically, a PEG-IFN/RBV combination therapy of patients with liver cirrhosis was associated with lower virological rates and a worse safety profile. The advent of the first protease inhibitor-based triple therapy was long expected, but the promise fell rapidly because of the numerous side effects and the requirement for intensive clinical management in cirrhotic patients. The newer direct-acting antivirals (DAAs) target the viral polymerase with either nucleos(t)ide analogues or nonnucleosidic inhibitors, the viral protease and the viral NS5A protein. Several clinical trials have now shown that a combination of sofosbuvir (nucleosidic polymerase inhibitor) with daclatasvir or ledipasvir (NS5A inhibitors), or sofosbuvir with simeprevir (protease inhibitor), or a combination of ABT-450 (protease inhibitor) with ritonavir (ABT-450/r), the nonnucleosidic polymerase inhibitor ABT-333 and the NS5A inhibitor ABT-267, can achieve a sustained virological response in up to 95% of naive patients or previously treated patients, even in those who failed prior treatment with first-generation protease inhibitors. The best treatment regimens enable the achievement of comparable results even in cirrhotics, while other regimens still require RBV or a longer treatment duration to achieve optimal results. This improved risk/benefit ratio justifies early access programs of IFN-free regimens for cirrhotic patients. The remaining difficult-to-treat patients are cirrhotics infected with HCV genotype 3 and those with decompensated cirrhosis, for whom novel DAA combinations should be evaluated in clinical trials. Conclusions: As new DAAs are becoming available in early access treatment programs, treatment strategy studies are being performed to optimize treatment regimens with respect to the choice of DAAs and treatment duration, based on viral genotypes, prior treatment response and the presence of liver cirrhosis. In the near future, this should allow: (i) a decrease in the complications of HCV-induced cirrhosis, (ii) liver transplantations to be performed in virally cured patients, and (iii) the rescue of patients in the worst clinical situation (decompensated cirrhosis and HCV recurrence on liver graft).

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Tarao, Kazuo, and Akira Sato. "A Hepatitis C Virus-Associated Chronic Hepatitis Patient Developing Various Adverse Events Including Severe Gingivitis, Gingival Bleeding, and Inflammation of Genital Vulva during the Course of Antiviral Therapy with Elbasvir/Grazoprevir." Case Reports in Gastroenterology 11, no. 3 (November 29, 2017): 736–41. http://dx.doi.org/10.1159/000484135.

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Oral direct-acting antivirals comprise the main therapy for hepatitis C virus (HCV)-associated liver disease in Japan. Daclatasvir/asunaprevir is the primary agent and sofosbuvir/ledipasvir is the secondary agent for HCV genotype 1b. Ombitasvir/paritaprevir/ritonavir was also recommended as a therapy for HCV genotype 1b. More recently, elbasvir (NS5A inhibitor)/grazoprevir (NS3/4A protease inhibitor) was also recommended as a potent therapy for HCV genotype 1b infection. This agent achieved an SVR12 as high as 96.5% for HCV virus-associated chronic hepatitis. We recently encountered a case treated with this agent and the female patient showed various adverse events, such as severe gingivitis, gingival bleeding, severe tonsillitis, inflammation of the genital vulva, and the sustained sensation of being hungry. In spite of the gingival bleeding, there was no depletion of the platelet count, nor elongation of the prothrombin time. She tolerated these adverse events and finally completed the therapy and achieved SVR12.

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Belema, Makonen, and Nicholas A. Meanwell. "Discovery of Daclatasvir, a Pan-Genotypic Hepatitis C Virus NS5A Replication Complex Inhibitor with Potent Clinical Effect." Journal of Medicinal Chemistry 57, no. 12 (April 21, 2014): 5057–71. http://dx.doi.org/10.1021/jm500335h.

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Galmozzi, Enrico, Alessio Aghemo, and Massimo Colombo. "Low rates of naturally occurring resistant variants to the NS5A inhibitor daclatasvir in HCV-1 null responders." Hepatology 57, no. 5 (February 4, 2013): 2087. http://dx.doi.org/10.1002/hep.25924.

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Sacramento, Carolina Q., Natalia Fintelman-Rodrigues, Jairo R. Temerozo, Aline de Paula Dias Da Silva, Suelen da Silva Gomes Dias, Carine dos Santos da Silva, André C. Ferreira, et al. "In vitro antiviral activity of the anti-HCV drugs daclatasvir and sofosbuvir against SARS-CoV-2, the aetiological agent of COVID-19." Journal of Antimicrobial Chemotherapy 76, no. 7 (April 21, 2021): 1874–85. http://dx.doi.org/10.1093/jac/dkab072.

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Abstract Background Current approaches of drug repurposing against COVID-19 have not proven overwhelmingly successful and the SARS-CoV-2 pandemic continues to cause major global mortality. SARS-CoV-2 nsp12, its RNA polymerase, shares homology in the nucleotide uptake channel with the HCV orthologue enzyme NS5B. Besides, HCV enzyme NS5A has pleiotropic activities, such as RNA binding, that are shared with various SARS-CoV-2 proteins. Thus, anti-HCV NS5B and NS5A inhibitors, like sofosbuvir and daclatasvir, respectively, could be endowed with anti-SARS-CoV-2 activity. Methods SARS-CoV-2-infected Vero cells, HuH-7 cells, Calu-3 cells, neural stem cells and monocytes were used to investigate the effects of daclatasvir and sofosbuvir. In silico and cell-free based assays were performed with SARS-CoV-2 RNA and nsp12 to better comprehend the mechanism of inhibition of the investigated compounds. A physiologically based pharmacokinetic model was generated to estimate daclatasvir’s dose and schedule to maximize the probability of success for COVID-19. Results Daclatasvir inhibited SARS-CoV-2 replication in Vero, HuH-7 and Calu-3 cells, with potencies of 0.8, 0.6 and 1.1 μM, respectively. Although less potent than daclatasvir, sofosbuvir alone and combined with daclatasvir inhibited replication in Calu-3 cells. Sofosbuvir and daclatasvir prevented virus-induced neuronal apoptosis and release of cytokine storm-related inflammatory mediators, respectively. Sofosbuvir inhibited RNA synthesis by chain termination and daclatasvir targeted the folding of secondary RNA structures in the SARS-CoV-2 genome. Concentrations required for partial daclatasvir in vitro activity are achieved in plasma at Cmax after administration of the approved dose to humans. Conclusions Daclatasvir, alone or in combination with sofosbuvir, at higher doses than used against HCV, may be further fostered as an anti-COVID-19 therapy.

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Wang, Chunfu, Lingling Jia, Donald R. O'Boyle, Jin-Hua Sun, Karen Rigat, Lourdes Valera, Peter Nower, et al. "Comparison of Daclatasvir Resistance Barriers on NS5A from Hepatitis C Virus Genotypes 1 to 6: Implications for Cross-Genotype Activity." Antimicrobial Agents and Chemotherapy 58, no. 9 (June 16, 2014): 5155–63. http://dx.doi.org/10.1128/aac.02788-14.

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ABSTRACTA comparison of the daclatasvir (DCV [BMS-790052]) resistance barrier on authentic or hybrid replicons containing NS5A from hepatitis C virus (HCV) genotypes 1 to 6 (GT-1 to -6) was completed using a replicon elimination assay. The data indicated that genotype 1b (GT-1b) has the highest relative resistance barrier and genotype 2a (GT-2a M31) has the lowest. The rank order of resistance barriers to DCV was 1b > 4a ≥ 5a > 6a ≅ 1a > 2a JFH > 3a > 2a M31. Importantly, DCV in combination with a protease inhibitor (PI) eliminated GT-2a M31 replicon RNA at a clinically relevant concentration. Previously, we reported the antiviral activity and resistance profiles of DCV on HCV genotypes 1 to 4 evaluated in the replicon system. Here, we report the antiviral activity and resistance profiles of DCV against hybrid replicons with NS5A sequences derived from HCV GT-5a and GT-6a clinical isolates. DCV was effective against both GT-5a and -6a hybrid replicon cell lines (50% effective concentrations [EC50s] ranging from 3 to 7 pM for GT-5a, and 74 pM for GT-6a). Resistance selection identified amino acid substitutions in the N-terminal domain of NS5A. For GT-5a, L31F and L31V, alone or in combination with K56R, were the major resistance variants (EC50s ranging from 2 to 40 nM). In GT-6a, Q24H, L31M, P32L/S, and T58A/S were identified as resistance variants (EC50s ranging from 2 to 250 nM). Thein vitrodata suggest that DCV has the potential to be an effective agent for HCV genotypes 1 to 6 when used in combination therapy.

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Murakami, Eisuke, Michio Imamura, C. Nelson Hayes, Hiromi Abe, Nobuhiko Hiraga, Yoji Honda, Atsushi Ono, et al. "Ultradeep Sequencing Study of Chronic Hepatitis C Virus Genotype 1 Infection in Patients Treated with Daclatasvir, Peginterferon, and Ribavirin." Antimicrobial Agents and Chemotherapy 58, no. 4 (January 27, 2014): 2105–12. http://dx.doi.org/10.1128/aac.02068-13.

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ABSTRACTDirect-acting antivirals (DAAs) are either part of the current standard of care or are in advanced clinical development for the treatment of patients chronically infected with hepatitis C virus (HCV) genotype 1, but concern exists with respect to the patients who fail these regimens with emergent drug-resistant variants. In the present study, ultradeep sequencing was performed to analyze resistance to daclatasvir (DCV), which is a highly selective nonstructural protein 5A (NS5A) inhibitor. Eight patients with HCV genotype 1b, who were either treatment naive or prior nonresponders to pegylated interferon plus ribavirin (Rebetol; Schering-Plough) (PEG-IFN/RBV) therapy, were treated with DCV combined with PEG-IFN alpha-2b (Pegintron; Schering-Plough, Kenilworth, NJ) and RBV. To identify the cause of viral breakthrough, the preexistence and emergence of DCV-resistant variants at NS5A amino acids were analyzed by ultradeep sequencing. Sustained virological response (SVR) was achieved in 6 of 8 patients (75%), with viral breakthrough occurring in the other 2 patients (25%). DCV-resistant variant Y93H preexisted as a minor population at higher frequencies (0.1% to 0.5%) in patients who achieved SVR. In patients with viral breakthrough, DCV-resistant variant mixtures emerged at NS5A-31 over time that persisted posttreatment with Y93H. Although enrichment of DCV-resistant variants was detected, the preexistence of a minor population of the variant did not appear to be associated with virologic response in patients treated with DCV/PEG-IFN/RBV. Ultradeep sequencing results shed light on the complexity of DCV-resistant quasispecies emerging over time, suggesting that multiple resistance pathways are possible within a patient who does not rapidly respond to a DCV-containing regimen. (This study has been registered at ClinicalTrials.gov under registration no. NCT01016912.)

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McPhee, Fiona, Jacques Friborg, Steven Levine, Chaoqun Chen, Paul Falk, Fei Yu, Dennis Hernandez, et al. "Resistance Analysis of the Hepatitis C Virus NS3 Protease Inhibitor Asunaprevir." Antimicrobial Agents and Chemotherapy 56, no. 7 (April 16, 2012): 3670–81. http://dx.doi.org/10.1128/aac.00308-12.

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ABSTRACTAsunaprevir (BMS-650032) is a potent hepatitis C virus (HCV) NS3 protease inhibitor demonstrating efficacy in alfa interferon-sparing, direct-acting antiviral dual-combination regimens (together with the NS5A replication complex inhibitor daclatasvir) in patients chronically infected with HCV genotype 1b. Here, we describe a comprehensivein vitrogenotypic and phenotypic analysis of asunaprevir-associated resistance against genotypes 1a and 1b using HCV replicons and patient samples obtained from clinical studies of short-term asunaprevir monotherapy. During genotype 1a resistance selection using HCV replicons, the primary NS3 protease substitutions identified were R155K, D168G, and I170T, which conferred low- to moderate-level asunaprevir resistance (5- to 21-fold) in transient-transfection susceptibility assays. For genotype 1b, a higher level of asunaprevir-associated resistance was observed at the same selection pressures, ranging from 170- to 400-fold relative to the wild-type control. The primary NS3 protease substitutions identified occurred predominantly at amino acid residue D168 (D168A/G/H/V/Y) and were associated with high-level asunaprevir resistance (16- to 280-fold) and impaired replication capacity. In asunaprevir single-ascending-dose and 3-day multiple-ascending-dose studies in HCV genotype 1a- or 1b-infected patients, the predominant pre-existing NS3 baseline polymorphism was NS3-Q80K. This substitution impacted initial virologic response rates in a single-ascending-dose study, but its effects after multiple doses were more ambiguous. Interestingly, for patient NS3 protease sequences containing Q80 and those containing K80, susceptibilities to asunaprevir were comparable when tested in an enzyme assay. No resistance-associated variants emerged in these clinical studies that significantly impacted susceptibility to asunaprevir. Importantly, asunaprevir-resistant replicons remained susceptible to an NS5A replication complex inhibitor, consistent with a role for asunaprevir in combination therapies.

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Hézode, Christophe, Laurent Alric, Ashley Brown, Tarek Hassanein, Mario Rizzetto, Maria Buti, Marc Bourlière, et al. "Randomized controlled trial of the NS5A inhibitor daclatasvir plus peginterferon and ribavirin for HCV genotype-4 (COMMAND-4)." Antiviral Therapy 20, no. 3 (2015): 195–205. http://dx.doi.org/10.3851/imp2985.

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Wang, Chunfu, Jin-Hua Sun, Donald R. O'Boyle, Peter Nower, Lourdes Valera, Susan Roberts, Robert A. Fridell, and Min Gao. "Persistence of Resistant Variants in Hepatitis C Virus-Infected Patients Treated with the NS5A Replication Complex Inhibitor Daclatasvir." Antimicrobial Agents and Chemotherapy 57, no. 5 (February 12, 2013): 2054–65. http://dx.doi.org/10.1128/aac.02494-12.

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ABSTRACTDaclatasvir (DCV; BMS-790052) is a hepatitis C virus (HCV) NS5A replication complex inhibitor (RCI) with picomolar to low nanomolar potency and broad genotypic coveragein vitro. Viral RNA declines have been observed in the clinic for both alpha interferon-ribavirin (IFN-α–RBV) and IFN-RBV-free regimens that include DCV. Follow-up specimens (up to 6 months) from selected subjects treated with DCV in 14-day monotherapy studies were analyzed for genotype and phenotype. Variants were detected by clonal sequencing in specimens from baseline and were readily detected by population sequencing following viral RNA breakthrough and posttreatment. The major amino acid substitutions generating resistancein vivowere at residues M28, Q30, L31, and Y93 for genotype 1a (GT-1a) and L31 and Y93 for GT-1b, similar to the resistance substitutions observed with thein vitroreplicon system. The primary difference in the resistance patterns observedin vitroandin vivowas the increased complexity of linked variant combinations observed in clinical specimens. Changes in the percentage of individual variants were observed during follow-up; however, the overall percentage of variants in the total population persisted up to 6 months. Our results suggest that during the 14-day monotherapy, most wild-type virus was eradicated by DCV. After the end of DCV treatment, viral fitness, rather than DCV resistance, probably determines which viral variants emerge as dominant in populations.

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Yoshimi, Satoshi, Michio Imamura, Eisuke Murakami, Nobuhiko Hiraga, Masataka Tsuge, Yoshiiku Kawakami, Hiroshi Aikata, et al. "Long term persistence of NS5A inhibitor-resistant hepatitis C virus in patients who failed daclatasvir and asunaprevir therapy." Journal of Medical Virology 87, no. 11 (June 16, 2015): 1913–20. http://dx.doi.org/10.1002/jmv.24255.

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Sulkowski, M., D. Gardiner, E. Lawitz, F. Hinestrosa, D. Nelson, P. Thuluvath, M. Rodriguez-Torres, et al. "1422 POTENT VIRAL SUPPRESSION WITH ALL-ORAL COMBINATION OF DACLATASVIR (NS5A INHIBITOR) AND GS-7977 (NS5B INHIBITOR), +/− RIBAVIRIN, IN TREATMENT-NAIVE PATIENTS WITH CHRONIC HCV GT1, 2, OR 3." Journal of Hepatology 56 (April 2012): S560. http://dx.doi.org/10.1016/s0168-8278(12)61433-0.

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KAMAL, Ahmed, Cecil MATTA, Heba Akram MOHSIN, Abeer Shawki ELHADIDI, Ramy Mohamed GHAZY, Heba Hany OMAR, Mona TAHOUN, and Nema Abdelhameed MOHAMED. "ASSESSING PREDICTORS OF DIRECTLY ACTING ANTIVIRALS’ FAILURE AS A FURTHER STEP TOWARDS MORE EFFICIENT HCV ELIMINATION PROGRAMS: IL28B (IFNL4) GENE POLYMORPHISM HAS NO ROLE WHILE HIGHER ESTIMATED CREATININE CLEARANCE IS A FORGOTTEN FACTOR." Arquivos de Gastroenterologia 59, no. 2 (June 2022): 177–83. http://dx.doi.org/10.1590/s0004-2803.202202000-33.

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ABSTRACT Background: Sustained virologic response (SVR) rates after directly acting antivirals (DAAs) for hepatitis C virus (HCV) exceed 95%. This encouraged policymakers to put plans to achieve HCV elimination by 2030. The remaining percentage of non-SVR12 can affect HCV eradication strategies in the real-world especially the compliance of large numbers of treated persons to follow up for assessment of virologic response cannot be guaranteed. Objective: We aimed to assess predictors of failure to achieve SVR after receiving sofosbuvir plus NS5A inhibitor as an important step towards achieving better HCV eradication strategies. Methods: During the period from 1st November 2018 to 1st November 2019, 1581 treatment-naive patients received sofosbuvir plus daclatasvir ± ribavirin at our unit and 10 patients were referred to us with HCV relapse after the same regimens. A total of 163 out of the 1581 patients were lost for follow-up before assessment of virologic response and excluded from the analysis. 20 out of the remaining patients failed to achieve SVR12. Data from the 30 patients with non-SVR12 were included in the case-control analysis. Results: Every unit increase in estimated creatinine clearance using modification of diet in renal disease study (MDRD) score, total bilirubin, and INR was associated with 1.03, 13.92, and 80.08 times greater odds of non-SVR12 (P<0.001, P=0.0016, P=0.02) respectively. The presence of liver cirrhosis on ultrasonography increases the odds by 10.03. (P=0.009). Conclusion: Higher MDRD score, INR, total bilirubin, and presence of sonographic features of liver cirrhosis are predictors of failure to achieve SVR12 using sofosbuvir plus NS5A inhibitor.

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Bifano, Marc, Carey Hwang, Berend Oosterhuis, Jan Hartstra, Dennis Grasela, Renger Tiessen, Maria Velinova-Donga, Hamza Kandoussi, Heather Sevinsky, and Richard Bertz. "Assessment of pharmacokinetic interactions of the HCV NS5A replication complex inhibitor daclatasvir with antiretroviral agents: ritonavir-boosted atazanavir, efavirenz and tenofovir." Antiviral Therapy 18, no. 7 (2013): 931–40. http://dx.doi.org/10.3851/imp2674.

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Hu, Chengguang, Guosheng Yuan, Junwei Liu, Huaping Huang, Yanyu Ren, Yinping Li, Xuefu Chen, et al. "Sofosbuvir-Based Therapies for Patients with Hepatitis C Virus Infection: Real-World Experience in China." Canadian Journal of Gastroenterology and Hepatology 2018 (November 13, 2018): 1–8. http://dx.doi.org/10.1155/2018/3908767.

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Background and Aims. There is scarcity of data in literature regarding the treatment response to sofosbuvir- (SOF-) based therapies in Chinese patients with chronic Hepatitis C Virus (HCV) infection. The aim of this study was to evaluate the efficacy and safety of SOF-based regimens for chronic hepatitis C (CHC) patients without cirrhosis in a real-world setting in mainland China.Methods. A total of 226 patients receiving SOF plus daclatasvir (DCV), ledipasvir (LDV), or velpatasvir (VEL) were enrolled from December 2014 to June 2017. The primary observation point was the percentage of patients with a sustained virologic response (SVR) at posttreatment week 12 (SVR12), and all adverse events were monitored during treatment and follow-up period.Results. The overall SVR12 rate was 96% (216/226), and individual SVR12 ranged from 93% to 100% in different treatment groups. No significant differences of efficacy were detected between genotypes 1b and 6a (98% for GT 1b versus 100% for GT 6a, P=0.322). Comparing the high success rates in GT 1b and 6a patients, SVR12 was relatively low in GT 3a and 3b patients. A significant difference in efficacy was observed between GT 3 and not GT 3 patients (77% versus 98%, respectively, P<0.001). No significant differences in efficacy were detected among different regimens (93% versus 97% versus 100%, respectively, P=0.153), gender (95% for male versus 96% for female, P=0.655), or baseline HCV RNA lever (96% versus 95%, respectively, P=0.614). Similar SVR rates were also obtained in naïve and previously treated patients (98% versus 93%, respectively, P=0.100).Conclusions. NS5B polymerase inhibitor SOF plus one of the NS5A inhibitors, such as DCV, LDV, or VEL for 12 weeks was associated with high SVR12 rates and well tolerated in HCV-infected patients without cirrhosis. Moreover, patients with DAAs failure should be retreated with more effective regimens like SOF/VEL.

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Wahsh, Engy A., Amal K. Hussein, Ahmed A. Gomaa, Mohamed A. Baraka, and Mohie Al-deen Abead. "Real Life Egyptian Experience of Daclatasvir Plus Sofosbuvir with Ribavirin in Naïve Difficult to Treat HCV Patients." Infectious Disorders - Drug Targets 20, no. 1 (February 14, 2020): 43–48. http://dx.doi.org/10.2174/1871526518666180716141806.

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Background: Chronic infection with Hepatitis C virus (HCV) is considered as a major cause for developing liver cirrhosis and hepatocellular carcinoma. A new era in HCV treatment is ongoing using Direct Acting Antiviral activity (DAA). The first approved DAA drug was Sofosbuvir which has a high tolerability and preferable pharmacokinetic profile. Another recently developed drug is Daclatasvir a first-in-class HCV NS5A replication complex inhibitor. Both drugs are administered orally once daily and have potent antiviral activity with wide genotypic coverage. Methods: In the outpatient clinic, one hundred and fifty naïve difficult to treat chronic HCV patients were recruited from Tropical Medicine Department at Fayoum public hospital. A combination of Daclatasvir (60 mg) and Sofosbuvir (400 mg) (DCV/SOF) has been administered for those patients once daily with Ribavirin (1200 mg or 1000 mg based on patients’ weight on two divided doses) over a period of 12 weeks. All patients have been followed up for clinical, laboratory assessment and HCV PCR to detect the efficacy and safety of the therapy. Results: Sustained Virologic Response rate (SVR12) was achieved in the vast majority of patients (90.67%). Cirrhotic patients showed lower SVR compared to non-cirrhotic patients (88.89% vs 90.91%, respectively). Around half of the patients (49.33%) developed adverse events (AEs) during treatment. The most common AEs were headache, fatigue and abdominal pain Conclusion: The available evidence seems to suggest that combination therapy of (DCV/SOF with RBV) in the treatment of chronic HCV genotype IV naïve difficult to treat patients either cirrhotic or non-cirrhotic is safe and effective. Monitoring for clinical and laboratory hepatic parameters was the basis for these findings.

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Pol, Stanislas. "Daclatasvir, an efficient inhibitor of the hepatitis C virus replication complex protein NS5A: review of virologic data, treatment rationale and clinical trials." Clinical Investigation 3, no. 2 (February 2013): 191–207. http://dx.doi.org/10.4155/cli.12.158.

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Guedj, Jeremie, Harel Dahari, Susan L. Uprichard, and Alan S. Perelson. "The hepatitis C virus NS5A inhibitor daclatasvir has a dual mode of action and leads to a new virus half-life estimate." Expert Review of Gastroenterology & Hepatology 7, no. 5 (July 2013): 397–99. http://dx.doi.org/10.1586/17474124.2013.811050.

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Kurniawan, Juferdy, Rino Alvani Gani, Irsan Hasan, Andri Sanityoso Sulaiman, Cosmas Rinaldi A. Lesmana, Chynthia Olivia Maurine Jasirwan, Kemal Fariz Kalista, Saut Horas Hatoguan Nababan, and Steven Zulkifly. "Comparative efficacy of sofosbuvir-ribavirin versus sofosbuvir-daclatasvir for treatment of chronic hepatitis C in an area with limited NS5A inhibitor availability." Indian Journal of Gastroenterology 37, no. 6 (November 2018): 520–25. http://dx.doi.org/10.1007/s12664-018-0921-2.

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Lok, A., D. Gardiner, C. Hezode, E. Lawitz, M. Bourliere, G. Everson, P. Marcellin, et al. "1415 CONFIRMATION THAT QUADRUPLE THERAPY WITH DACLATASVIR (NS5A INHIBITOR), ASUNAPREVIR (NS3 INHIBITOR) AND PEGINTERFERON/RIBAVIRIN RESULTS IN HIGH RATE OF SVR4 IN HCV GENOTYPE 1 NULL RESPONDERS." Journal of Hepatology 56 (April 2012): S557. http://dx.doi.org/10.1016/s0168-8278(12)61426-3.

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Guedj, J., H. Dahari, L. Rong, N. D. Sansone, R. E. Nettles, S. J. Cotler, T. J. Layden, S. L. Uprichard, and A. S. Perelson. "Modeling shows that the NS5A inhibitor daclatasvir has two modes of action and yields a shorter estimate of the hepatitis C virus half-life." Proceedings of the National Academy of Sciences 110, no. 10 (February 19, 2013): 3991–96. http://dx.doi.org/10.1073/pnas.1203110110.

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Suzuki, F., K. Ikeda, J. Toyota, Y. Karino, T. Ohmura, K. Chayama, S. Takahashi, et al. "14 DUAL ORAL THERAPY WITH THE NS5A INHIBITOR DACLATASVIR (BMS-790052) AND NS3 PROTEASE INHIBITOR ASUNAPREVIR (BMS-650032) IN HCV GENOTYPE 1B-INFECTED NULL RESPONDERS OR INELIGIBLE/INTOLERANT TO PEGINTERFERON/RIBAVIRIN." Journal of Hepatology 56 (April 2012): S7—S8. http://dx.doi.org/10.1016/s0168-8278(12)60028-2.

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Kai, Yugo, Hayato Hikita, Tomohide Tatsumi, Tasuku Nakabori, Yoshinobu Saito, Naoki Morishita, Satoshi Tanaka, et al. "Emergence of hepatitis C virus NS5A L31V plus Y93H variant upon treatment failure of daclatasvir and asunaprevir is relatively resistant to ledipasvir and NS5B polymerase nucleotide inhibitor GS-558093 in human hepatocyte chimeric mice." Journal of Gastroenterology 50, no. 11 (July 25, 2015): 1145–51. http://dx.doi.org/10.1007/s00535-015-1108-6.

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Zhang, Yang, Jingyi Zou, Xiaomin Zhao, Zhenghong Yuan, and Zhigang Yi. "Hepatitis C virus NS5A inhibitor daclatasvir allosterically impairs NS4B-involved protein–protein interactions within the viral replicase and disrupts the replicase quaternary structure in a replicase assembly surrogate system." Journal of General Virology 100, no. 1 (January 1, 2019): 69–83. http://dx.doi.org/10.1099/jgv.0.001180.

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SHULPEKOVA, Y. O., N. V. SHULPEKOVA, M. C. SEMENISTAYA, A. A. USANOVA, and C. S. PAVLOV. "TREATMENT OF HCV INFECTION BY A COMBINATION OF SOFOSBUVIR AND DACLATASVIR." Medical Council, no. 4 (May 26, 2017): 36–41. http://dx.doi.org/10.21518/2079-701x-2017-4-36-41.

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The purpose of the review is to evaluate the efficacy and safety of using pangenotypic combination «of Sofosbuvir/Daclatasvir» — the direct action antiviral drugs in the treatment of chronic HCV infection at different stages of liver damage.Main provisions: Sofosbuvir is the antisense nucleotide, inhibiting RNA-dependent RNA-polymerase NS5B, this drug has earned a reputation as one of the strongest anti-replication drugs, including when there is interferon resistance. Daclatasvir is a powerful non-nucleotide inhibitor of NS5А protein, catalyzing formation of replicative complexes. Both components are proven to be effect against HCV genotypes 1-6. Their combination provides pangenotypic activity, and the mutual strengthening effect diminishes the risk of development of drug resistance. Indications for the administration of a combination «Sofosbuvir/Daclatasvi» are: treatment of HCV infection at the stage of acute hepatitis (for genotypes 1–6 of the virus), treatment for HCV infection at the stage of chronic hepatitis (for genotypes 1–6 of the virus), treatment of HCV infection in co-infection with HIV, treatment of HCV infection at the stage of liver cirrhosis, treatment of recurrent HCV infection after liver transplantation, treatment of HCV infection with immune manifestations.Conclusion: the combination «Sofosbuvir/Daclatasvir» is shown to be highly effective in the treatment of HCV infection of genotypes 1-6 with a frequency of SVR 93—97% at the stage of the hepatitis and 88—95% — at the stage of cirrhosis. Good tolerance and high efficiency has led to active use of this combination фе the stage of cirrhosis. This combination has been successfully used for the treatment of recurrence of HCV infection in the liver graft, including co-infection with HIV.

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Vallet-Pichard, Anaïs, and Stanislas Pol. "Grazoprevir/elbasvir combination therapy for HCV infection." Therapeutic Advances in Gastroenterology 10, no. 1 (October 17, 2016): 155–67. http://dx.doi.org/10.1177/1756283x16671293.

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Interferon-free regimens combine different second-wave direct-acting antiviral agents (DAAs), which target the main viral proteins involved in the replication cycle of hepatitis C virus (HCV): NS3/4A protease inhibitors (simeprevir or paritaprevir boosted by ritonavir), NS5B nucleos(t)idic (sofosbuvir) and nonnucleos(t)idic (dasabuvir) polymerase inhibitors, NS5A replication complex inhibitors (daclatasvir, ledipasvir, elbasvir, velpatasvir). Combinations of two or three DAAs, given for 8–24 weeks reach sustained virology response (SVR) rates greater than 90% with good tolerance. SVR rates and safety are similar in clinical trials and in real life, usually higher than 95% in the per-protocol analysis. Next-generation DAAs are now expected. To be competitive, these new combinations need to prove their added value regarding the pill burden, the reduced duration of treatment, the drug–drug interaction profile and safety. Zepatier is a fixed-dose combination product coformulating MK-5172 [grazoprevir (GZR), 100 mg QD] and MK-8742 [elbasvir or (EBR) 50 mg QD]: it combines highly potent inhibitors of the HCV NS3/4A protease and NS5A replication complex, respectively. This review provides a summary of the main evidence available for the use of GZR/EBR and highlights the strength of this combination.

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Geddawy, Ayman, Yasmine F. Ibrahim, Nabil M. Elbahie, and Mohammad A. Ibrahim. "Direct acting anti-hepatitis C virus drugs: Clinical pharmacology and future direction." Journal of Translational Internal Medicine 5, no. 1 (March 31, 2017): 8–17. http://dx.doi.org/10.1515/jtim-2017-0007.

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Abstract Chronic hepatitis C virus (HCV) infection is a leading cause of chronic liver disease. The introduction of direct acting antiviral agents (DAAs) for its treatment represents a major advance in terms of sustained virologic response (SVR) rates and adverse effect profiles. Mechanistically, DAAs inhibit specific HCV non-structural proteins (NS) that are vital for its replication. Boceprevir, telaprevir, simeprevir, asunaprevir, grazoprevir and paritaprevir are NS3/4A inhibitors. Ombitasvir, ledipasvir, daclatasvir, elbasvir and velpatasvir are NS5A inhibitors. Sofosbuvir and dasabuvir are NS5B inhibitors. Currently, a combination of two or more DAAs is the corner stone for the treatment of HCV infection. However, the success of DAA therapy is facing several challenges, including the potential of drug-drug interactions and resistant variance. Moreover, the shortage of relevant clinical pharmacological data and drug interaction regarding DAA is a clinical concern. The present review discusses the clinical pharmacology of DAAs with special emphasis on drug-drug interaction.

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Belema, Makonen, Van N. Nguyen, Carol Bachand, Dan H. Deon, Jason T. Goodrich, Clint A. James, Rico Lavoie, et al. "Hepatitis C Virus NS5A Replication Complex Inhibitors: The Discovery of Daclatasvir." Journal of Medicinal Chemistry 57, no. 5 (February 12, 2014): 2013–32. http://dx.doi.org/10.1021/jm401836p.

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Irekeola, Ahmad Adebayo, Engku Nur Syafirah EAR, Nur Amalin Zahirah Mohd Amin, Nazri Mustaffa, and Rafidah Hanim Shueb. "Antivirals against HCV infection: the story thus far." Journal of Infection in Developing Countries 16, no. 02 (February 28, 2022): 231–43. http://dx.doi.org/10.3855/jidc.14485.

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Remarkable scientific breakthroughs have been made in the stride towards the development of potent and tolerable hepatitis C regimens within the last three decades. Earlier approaches involved the use of pegylated interferon alfa and ribavirin as standard-of-care treatment. Treating genotype 1a infection with this regimen which was at that time considered the gold standard for hepatitis C virus therapy was rife with challenges; safety and toxicity issues necessitated a rigorous quest for alternative regimens. Deeper understanding of the pathogenesis of hepatitis C virus ushered in the era of direct acting antiviral agents. These agents have been the subject of intensive research in the last two decades, leading to the development of drug classes such as protease inhibitors (e.g., grazoprevir), NS5A inhibitors (e.g., daclatasvir) and NS5B inhibitors (e.g., sofosbuvir). While many are still under development, several have been approved for hepatitis C therapy. A number of studies investigating the combination of direct acting antiviral agents with or without pegylated interferon and/or ribavirin for the treatment of chronic hepatitis have demonstrated sustained virologic response of > 90%. Given the array of direct acting antiviral agents currently available, the present landscape of hepatitis C therapy is now characterized by a gradual transition to all-oral interferon-free regimens. Despite these milestones, the WHO global target of eliminating hepatitis C as a public health problem by 2030 seems uncertain. In this review, we provide a concise account of the evolution and advancements in the development of anti-HCV regimens.

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Horváth, Gábor, Tünde Halász, Mihály Makara, and Béla Hunyady. "Korszakváltás a krónikus C-vírus hepatitis terápiájában – új direkt ható antivirális szerek." Orvosi Hetilap 156, no. 21 (May 2015): 841–48. http://dx.doi.org/10.1556/650.2015.30177.

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Chronic hepatitis C, without treatment, can cause liver cirrhosis, liver failure and liver cancer. The availability of new oral direct acting antivirals, such as the protease inhibitors simeprevir, asunaprevir and paritaprevir, the NS5A inhibitors daclatasvir, ledipasvir, and ombitasvir, the polymerase inhibitors Sofosbuvir and dasabuvir have resulted an enormous progress in the treatment of chronic hepatitis C, leading to >90% sustained viral response rates. Even the hard-to-treat or previously treatment ineligible patients can be cured with the combination of these drugs. Furthermore the treatment duration is much shorter, and the side effects are minimal. Today, treatment of all hepatitis C virus infected patients is recommended, and the best choices are the interferon-free options. Eradication of hepatitis C virus has become realistic, however, appropriate screening programs are mandatory to achieve this goal. Orv. Hetil., 2015, 156(21), 841–848.

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Zhavoronok, S. V., V. R. Gutmane, T. M. Baryash, O. V. Soldatenko, T. V. Znovets, V. M. Mitsura, E. V. Voropaev, et al. "RESULTS OF THE USE OF SOFOSBUVIR IN COMBINATION WITH LEDIPASVIR OR DACLATASVIR FOR CHRONIC HEPATITIS C TREATMENT IN THE REPUBLIC OF BELARUS." Journal Infectology 10, no. 3 (October 7, 2018): 77–83. http://dx.doi.org/10.22625/2072-6732-2018-10-3-77-83.

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To evaluate the efficacy of therapy with sofosbuvir in combination with ledipasvir or daclatasvir, the results of treatment of 299 patients with chronic hepatitis C, including 128 non-responders to combined interferon plus ribavirin therapy, who have prognostically unfavorable single nucleotide polymorphisms 39743165T> G (rs8099917) and 39738787C> T (rs12979860) of interleukin-28B gene, were analyzed. 57 people had liver cirrhosis. 80,9% (242) had genotype 1 of hepatitis C virus, 5% (15) – genotype 2, 13,7% (41) – genotype 3, and 0,4% (1) – genotype 4.All 299 patients, who adhered to the recommendations of the European Association for the Study of the Liver 2016 and the American Association for the Study of the Liver Disease 2017, achieved a sustained virologic response 12 weeks after the end of therapy. The clinical case of treatment failure, associated with the lack of confirmation of the elimination of hepatitis C virus by means of highly sensitive polymerase chain reaction methods and with the later identified amino acid substitution in position Y93H of NS5A (resistance to NS5A inhibitors), is shown.It is necessary to carry out monitoring of effectiveness of therapy only by means of highly sensitive polymerase chain reaction (from 10 ME/ml). If the virus elimination delays in patients with advanced stages of liver fibrosis it is needed to use the prolonged schemes of treatment. Repeated treatment of patients with existence of a mutation of Y93H requires the use of new NS5A inhibitors or combined drugs.

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Journal articles on the topic 'Daclatasvir, NS5A inhibitor'

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