World J Gastroenterol 2013 December 21; 19(47): 8940-8948
Copyright ©2013 Baishideng Publishing Group Co., Limited. All rights reserved.
Shuang Wu, Tatsuo Kanda, Shingo Nakamoto, Fumio Imazeki and Osamu Yokosuka.
Shuang Wu, Tatsuo Kanda, Shingo Nakamoto, Osamu Yokosuka, Department of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, Chiba 260-8677, Japan
Shuang Wu, Postdoctoral Fellow, Foreign Researcher of the Japan Society for Promotion of Science (JSPS), Tokyo 102-0083, Japan
Shingo Nakamoto, Department of Molecular Virology, Chiba University, Graduate School of Medicine, Chiba 260-8677, Japan
Fumio Imazeki, Safety and Health Organization, Chiba University, Chiba 263-8522, Japan
Author contributions: Wu S, Kanda T, Nakamoto S, Imazeki F and Yokosuka O contributed to this paper.
Correspondence to: Tatsuo Kanda, MD, PhD, Associate Professor, Department of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan. kandat-cib@umin.ac.jp
Telephone: +81-43-2262086 Fax: +81-43-2262088
Received September 14, 2013; Revised November 8, 2013; Accepted December 3, 2013;
Abstract
Direct-acting antiviral agents (DAAs) for hepatitis C virus (HCV) infection are one of the major advances in its medical treatment. The HCV protease inhibitors boceprevir and telaprevir were the first approved DAAs in the United States, Europe, and Japan. When combined with peginterferon plus ribavirin, these agents increase sustained virologic response rates to 70%-80% in treatment-naïve patients and previous-treatment relapsers with chronic HCV genotype 1 infection. Without peginterferon plus ribavirin, DAA mono-therapies increased DAA-resistance mutations. Several new DAAs for HCV are now in clinical development and are likely to be approved in the near future. However, it has been reported that the use of these drugs also led to the emergence of DAA-resistance mutations in certain cases. Furthermore, these mutations exhibit cross-resistance to multiple drugs. The prevalence of DAA-resistance mutations in HCV-infected patients who were not treated with DAAs is unknown, and it is as yet uncertain whether such variants are sensitive to DAAs. We performed a population sequence analysis to assess the frequency of such variants in the sera of HCV genotype 1-infected patients not treated with HCV protease inhibitors. Here, we reviewed the literature on resistance variants of HCV protease inhibitors in treatment naïve patients with chronic HCV genotype 1, as well as our experience.
Keywords: Direct-acting antiviral agent, Hepatitis C virus, Protease inhibitor, Resistance mutation, Sequence analysis
Core tip: The standard of care for the treatment of hepatitis C virus (HCV) infection was peginterferon plus ribavirin until the recent approval of telaprevir- and boceprevir-containing combination therapies. These HCV protease inhibitors occasionally cause HCV variants with resistance mutations. We reviewed the literature reports of resistance variants of HCV protease inhibitors in treatment-naïve patients with chronic HCV genotype 1, as well as our experience. Even in treatment-naïve patients with chronic HCV genotype 1, naturally occurring HCV protease inhibitor-resistance mutations exist in some cases. The combination of direct-acting antiviral agents against regions other than HCV NS3/4A could eradicate HCV with these resistance variants.
INTRODUCTION
Hepatitis C virus (HCV) is a positive-sense, single-stranded RNA virus, approximately 9600 nt in length, that belongs to the Flaviridae family. Globally, HCV infects 170 million people and approximately 120-140 million chronic HCV carriers exist[1,2]. HCV infection causes acute and chronic hepatitis, cirrhosis and hepatocellular carcinoma (HCC)[3,4]. HCV is classified into six major genotypes and > 100 subtypes[5]. HCV genotype 1 (subgenotypes 1a and 1b) is the most common genotype in western countries and Japan[5]. Treatment of HCV is complicated by the existence of different HCV genotypes. The standard of care was peginterferon plus ribavirin until the recent approval of telaprevir- and boceprevir-containing combination therapies[6-14]. Combination of peginterferon plus ribavirin results in sustained virological response (SVR) in nearly 70%-80% of patients with HCV genotype 2 or 3, but in only approximately 50% of those with HCV genotype 1[15,16]. Thus, treatment response is dependent on HCV genotypes and viral loads[17], viral sequence[18-21], host factors such as IL28B genotypes[22-35], drug adherence[36], and adverse events induced by therapeutic drugs[36].
Pharmaceutical companies are actively investigating and developing direct-acting anti-viral agents (DAAs) against HCV, which directly target specific HCV proteins such as NS3/4A protease[6-14], NS5A protein[37-39], and NS5B polymerase[40], which are important for HCV replication in hepatocytes. Two first-generation HCV protease inhibitors, boceprevir and telaprevir, were approved in combination with peginterferon plus ribavirin for treatment of chronic HCV genotype 1 in 2011[6-14]. Both protease inhibitors combined with peginterferon plus ribavirin increased SVR rates up to 70%-80% in treatment-naïve patients and previous-treatment relapsers with chronic HCV genotype 1 infection[6-14]. Next-generation HCV protease inhibitors will be available in clinics in the near future (Table 1)[41]. For example, simeprevir[42,43], faldaprevir[44,45], and vaniprevir[46-48] are currently in phase 3 trials. HCV protease inhibitors primarily are specific agents for HCV genotype 1. However, studies have demonstrated that simeprevir is fairly active against most HCV genotypes with the exception of HCV genotype 3a[42], and recently, in a phase 2 trial, the novel protease inhibitor MK-5172 showed even broader activity across HCV genotypes compared to simeprevir[49].
| Name of drug (other name) | G | Trial phase | Features of clinical trials (ClinicalTrials.gov Identifier) |
| Telaprevir (VX-950) | 1 | FDA approved | Telaprevir, PEG-IFN alpha-2a, RBV |
| 1b | 3 | Telaprevir, Daclatasvir (NS5A inhibitor), PEG-IFN alpha-2a, RBV (COMMAND-3) (NCT01492426) | |
| 1 | 3 | Telaprevir, PEG-IFN lambda-1a, RBV (NCT01598090) | |
| 4 | 2 | Telaprevir, PEG-IFN alpha-2a, RBV (NCT0050801) | |
| Boceprevir | 1 | FDA approved | Boceprevir, PEG-IFN alpha-2a, RBV |
| (SCH 503034)Simeprevir (TMC435) | 1 | 3 | Simeprevir, PEG-IFN alpha-2a, RBV (NCT01290731) |
| 1b/4 | 2 | Simeprevir, IDEX719 (NS5A inhibitor), RBV (NCT01852604) | |
| Faldaprevir (BI201335) | 1 | 3 | Faldaprevir, PEG-IFN alpha-2a, RBV |
| 1a | 2 | Faldaprevir, PPI-668 (NS5A inhibitor), BI207127 (non-nucleoside NS5B inhibitor), (+ RBV) (NCT01859962) | |
| 1b | 2 | Faldaprevir, BI207127, RBV (NCT01858961) | |
| Danoprevir (ITMN-191) | 1 | 2 | Danoprevir, PEG-IFN alpha-2a, RBV (NCT00963885) |
| 1/4 | 2 | Danoprevir, Ritonavir, PEG-IFN alpha-2a, RBV (NCT01220947) | |
| 1 | 2 | Danoprevir, Ritonavir, RO5024048 (NS5B inhibitor), RBV, (± PEG-IFN alpha-2a) (NCT01331850) | |
| Vaniprevir (MK-7900) | 1 | 3 | Vaniprevir, PEG-IFN alpha-2b, RBV (NCT01405937) |
| Asunaprevir (BMS-650032) | 1 | 3 | Asunaprevir, Daclatasvir (NCT01497834) |
| 1 | 2 | Asunaprevir, PEG-IFN lambda, RBV (NCT01309932) | |
| 1/4 | 2 | Asunaprevir, PEG-IFN alpha-2a, RBV (NCT01030432) | |
| 1a/1b/4 | 2 | Asunaprevir, Daclatasvir, BMS-791325 (NS5B inhibitor) (NCT01455090) |
The low fidelity of HCV NS5B polymerase, high replication rate, and strong selective pressures on this virus lead to emergence of viral quasispecies. The quasispecies nature exists in a mixed population of viruses, with the fittest viruses being the predominant viral populations, as observed by sequence analysis[50,51]. In addition, new populations with every potential substitution are likely created and lost each day, some of which convey various degrees of resistance to DAAs[52-54]. Due to the high sequence diversity of HCV, naturally occurring pre-existing resistance mutations have been found at a low prevalence in HCV-infected, treatment-naïve patients[55,56].
In a previous study[56], 9% of the HCV genotype 1a-infected patients who were not treated with HCV protease inhibitors had at least one pre-existing dominant protease inhibitor-resistant variant, as observed by population sequencing. In another report[57], although the number of patients was small, the prevalence of protease inhibitor-resistance mutations was high (28%) in 53 genotype 1a samples, while no mutations were found in only 5 patients infected with HCV genotype 1b. In HCV genotype 1b treatment-naïve patients, the percentage of naturally occurring pre-existing resistance mutations appears to be lower[58]. Recently, next generation sequencing technology, with a detection limit as low as < 0.1%, have shown the ability to detect most resistance variants (including high resistance variants, i.e., 155, 156 and 168) in patients infected with protease inhibitor-untreated HCV genotype 1[59]. Thus, the prevalence of naturally occurring pre-existing resistance mutations in patients infected with HCV genotype 1 who were not treated with HCV protease inhibitors remains unclear.
NATURALLY OCCURRING PREEXISTING RESISTANCE MUTATIONS IN PATIENTS INFECTED WITH HCV GENOTYPE 1B
We estimated a 98%-99% prevalence of HCV subgenotype 1b among patients infected with HCV genotype 1 in Japan[60]. Sera from 88 Japanese patients infected with HCV genotype 1b who were not treated with HCV protease inhibitors were examined. Some patients had been included in a previous study[60]. We investigated the naturally occurring pre-existing resistance mutations in these patients by using a direct-sequencing method. The study protocol was approved by the Ethics Committee of Chiba University School of Medicine.
The clinical background of the 88 patients is shown in Table 2. All but one patient had high viral loads. Population sequencing of the HCV NS3 region was performed in these 88 patients, and then the amino acid sequences were compared to the HCV NS3 amino acid sequence corresponding to the HCV genotype 1b Con1 strain. The prevalence of pre-existing variations in the HCV genotype 1b samples was 39% (34/88). Among these mutations, the resistance mutations T54S and D168N were found in 6.8% (6/88) and 1.1% (1/88) of the patients, respectively. Other resistance mutations Q80L, V170Y, V170N and V170L were found in 22% (19/88), 4.5% (4/88), 3.4% (3/88) and 1.1% (1/88) of the patients, respectively. In 5.7% (5/88) of the patients, more than one mutation was identified: four patients had T54S and Q80L, and one patient had T54S, Q80L and V170N (Table 3). We did not identify high resistance variants at 155 and 156 in protease inhibitor-untreated HCV genotype 1b-infected patients (Table 3). Suzuki et al[58] reported that amino acid substitutions conferring resistance to protease inhibitors (V36A, T54S, Q80H, and D168E) were detected in 15 of 307 (4.9%) patients infected with HCV genotype 1b who had not received DAAs previously, and T54S (3.3%) predominated over V36A (0.3%), Q80R (0.7%) and D168E (0.7%), similar to our results. Leggewie et al[61] measured the prevalence of natural resistance polymorphisms in 38 acutely human immunodeficiency virus (HIV)-HCV co-infected treatment-naïve patients by using direct and deep sequencing. They found that 26% of patients (10/38) had a majority variant resistance mutation (in order of frequency: Q80K-16%, V36M-5%, T54S-3%, V55A-3% and D168A-3%). Low-frequency mutations were detected in all samples.
| No. of patients (men/women) | 88 (43/45) |
| Age (yr) | 55 ± 14 |
| HCV RNA levels (low/high) | 1/87 |
| ALT (IU/L) | 67 ± 44 |
| WBC (x 103/mcL) | 5.2 ± 1.5 |
| Hemoglobin (g/dL) | 14 ± 1.2 |
| Platelet counts (x 104/mcL) | 20 ± 18 |
| IL28B rs8099917, TT/TG/GG/unknown | 45/29/0/14 |
| PatientNo. | V36 | T54 | V55 | Q80 | R155 | A156 | D168 | V170Y/N/L | ||
| A/M | S | A | L | K/T/Q | S/T/V | N | Y | N | L | |
| 31 | S | L | ||||||||
| 95 | L | |||||||||
| 15 | L | |||||||||
| 17 | L | |||||||||
| 24 | L | |||||||||
| 26 | S | L | ||||||||
| 29 | S | |||||||||
| 81 | S | L | ||||||||
| 61 | Y | |||||||||
| 72 | Y | |||||||||
| 11 | L | |||||||||
| 12 | L | |||||||||
| 2 | Y | |||||||||
| 53 | L | |||||||||
| 55 | L | |||||||||
| 66 | L | |||||||||
| 84 | L | |||||||||
| 85 | L | |||||||||
| 110 | L | |||||||||
| 112 | Y | |||||||||
| 114 | S | L | ||||||||
| 100 | L | |||||||||
| 101 | N | |||||||||
| 107 | N | |||||||||
| 111 | N | |||||||||
| 99 | L | |||||||||
| 92 | L | |||||||||
| 97 | S | L | N | |||||||
RESISTANCE MUTATIONS AND VIROLOGIC FAILURE
Despite extensive efforts to develop more potent next-generation protease inhibitors, the long-term efficacy of this drug class is challenged by the rapid emergence of resistance[62,63], which could result in treatment failures such as viral breakthrough or relapse. Our identified mutations associated with resistance to protease inhibitors are shown in Figure 1. In the Protease Inhibitor for Viral Evaluation (PROVE) 1 and 2 clinical trials[8,9] of telaprevir in combination with peginterferon plus ribavirin, viral breakthrough occurred in approximately 7% of patients with HCV genotype 1a infection, compared with about 2% of those with HCV genotype 1b infection; approximately 10% of patients with either subgenotype 1a or 1b suffered a relapse after cessation of HCV protease inhibitor-treatment. In both ADVANCE and Illustrating the Effects of Combination Therapy with Telaprevir (ILLUMINATE) trials[11,13], about 60% of patients treated with telaprevir-based triple therapy achieved an extended rapid virologic response (eRVR), with no virus detected at weeks 4 and 12.
Figure 1 Mutations in hepatitis C virus NS3/4A serine protease that impact susceptibility to hepatitis C virus drugs approved by the United States Food and Drug Administration and investigated in phase 2 or 3 clinical trials. The numbers indicate the positions of the amino acids of the hepatitis C virus genotype 1 Con 1 strain. The amino acids above and below the numbers indicate wild-type amino acids and their substitutions, respectively. The red color indicates the mutations detected among the population using sequencing in the present study.
HCV variants associated with on-treatment virologic failure or relapse were evaluated by using site-directed mutagenesis in HCV replicon assay[62,64]. Variants V36A/M, T54A/S, R155K/T, and A156S conferred lower levels of in vitro resistance to telaprevir (three- to 25-fold increase in telaprevir IC50), and A156V/T and V36M + R155K variants conferred higher levels of in vitro resistance to telaprevir (> 25-fold increase in telaprevir IC50). HCV replicon variants generated from patient-derived sequences showed similar results. The in vitro replication capacity of telaprevir-resistant variants was lower than that of wild-type virus in the HCV genotype 1b Con1 replicon system[64-67]. When telaprevir-resistant variants were tested for cross-resistance against representative protease inhibitors in the HCV replicon system, HCV replicons with single substitutions at position 155 or 156 and double variants with substitutions at residues 36 and 155 showed cross-resistance to all protease inhibitors tested with a wide range of sensitivities. All telaprevir-resistant variants studied remained fully sensitive to interferon-alpha, ribavirin, and representative HCV nucleoside and non-nucleoside polymerase inhibitors in the replicon system. There are limited clinical data regarding re-treating patients who have failed an HCV NS3-4A protease inhibitor-based therapy such as telaprevir monotherapy, suggesting that re-treatment with triple therapy might be useful for certain patients.
In the boceprevir Serine Protease Inhibitor Therapy 2 (SPRINT-2) trial[6], patients showing a decrease in HCV viral load ≥ 1 log10 IU/mL during the four-week lead-in period of peginterferon plus ribavirin therapy had very low rates of emergence of boceprevir-resistant mutants (4%-6%) during subsequent triple therapy, whereas those with a < 1 log10 IU/mL decrease in HCV RNA had higher rates (40%-52%) of boceprevir-resistance-associated variants (genotypic mutations of the protease conferring reduced sensitivity to boceprevir). The majority of boceprevir-treated subjects not achieving SVR had one or more specific treatment-emergent NS3 amino acid substitutions, most of which were previously shown to reduce the anti-HCV activity of boceprevir. These substitutions included V36A, V36M, T54A, T54S, V55A, V107I, R155K, A156S, A156T, A156V, V158I, D168N, I/V170A, and I/V170T. Detection of these substitutions was most common among subjects who experienced virologic breakthrough or incomplete virologic response[68].
COMBINATIONS OF DAAS FOR HCV STRAINS WITH RESISTANCE MUTATIONS
Protease inhibitors are used in combination with peginterferon plus ribavirin because monotherapy with protease inhibitors results in the early emergence of drug-resistance mutations[62,63]. As peginterferon plus ribavirin treatment is frequently associated with serious adverse events, an interferon-free DAA combination therapy such as protease inhibitors with an NS5A inhibitor and/or NS5B inhibitor would offer an ideal treatment option for patients with chronic HCV infection. However, combinations of DAA-resistant variants both in a single target protein and across multiple targets have been reported following failure of single and combination DAA regimens[55,69-71]. HCV population sequences of the complete HCV NS3 and 4A regions obtained from 2,111 HCV subgenotype 1a and HCV subgenotype 1b DAA-naïve patients were analyzed by Bartels et al[72]. It was reported that the strongest association was the combination of variants at NS3 V55, with lower-level resistance to boceprevir, and NS3 T54, with lower-level resistance to boceprevir and telaprevir[73]. The complete HCV NS3 study dataset showed that 69% (33/48) of patients with HCV NS3 V55I also had T54S. An association was also observed between HCV NS3 positions 54 and 155, with 17% (3/18) of the patients with the HCV NS3 T54S substitution also having R155K. The HCV NS3 T54S and R155K combination appeared in boceprevir and telaprevir trials. The study[73] also reported that treatment-naïve patients with viral populations containing the telaprevir-resistant variants HCV NS3 V36M, T54S or R155K at baseline achieved a 74% SVR rate with DAAs, similar to that (76%) in patients without resistant variants detected prior to treatment. Further studies are needed to confirm these findings.
DIFFERENCES IN RESISTANCE MUTATION SELECTION BETWEEN HCV GENOTYPE 1A AND HCV GENOTYPE 1B
It is possible that a different pattern of nucleotide changes is required for the resistance amino acid mutations between HCV genotypes 1a and 1b[67]. Substitutions at A156 (A156S, A156T or A156V) require only a one-nucleotide change in HCV genotype 1a and HCV genotype 1b. In contrast, substitutions at R155 with K, T, S, M or I require a two-nucleotide substitution in HCV genotype 1b isolates. However, R155K/T/S/M/I substitutions require a one-nucleotide substitution in HCV genotype 1a isolates. The need for a two-nucleotide change for substitution R155 in HCV genotype 1b could be one of the reasons that HCV genotype 1a is more resistant to protease inhibitors than HCV genotype 1b (Table 4). In the ELECTRON study[74] of NS5B inhibitor sofosbuvir, no differential resistance was observed between genotypes 1a and 1b despite 89% of the subjects being in the HCV genotype 1a population, suggesting that combination DAAs targeting other HCV regions with next-generation HCV protease inhibitors could overcome the challenges of resistance mutations. In the near future, although mutation analysis was previously performed with population sequencing using Sanger methods, ultra-deep sequencing technology should provide new information[60,75-78]. Ligand bioactive conformation also plays a critical role in the design of HCV NS3 protease inhibitors and may allow for a large variety of HCV protease drug candidates to be designed[79].
| Amino acid at position 155 | HCV genotype 1a | HCV genotype 1b |
| R | AGG | CGG |
| K | AAG | AAG |
| T | ACG | ACG |
| S | AGC | AGC |
| I | ATC | ATC |
CONCLUSION
In summary, we reviewed the literature reports of resistance variants of HCV protease inhibitors in treatment naïve patients with chronic HCV genotype 1, as well as our experience. Even in treatment-naïve patients with chronic HCV genotype 1, naturally occurring HCV protease inhibitor-resistance mutations exist in some. Monotherapy with HCV protease inhibitors should be absolutely avoided. Regarding HCV protease inhibitor-resistance mutations, attention should also be paid to DAA-treatment-experienced patients, who previously used HCV protease inhibitor-monotherapies or combination therapies with HCV protease inhibitors. HCV genotype 1a is more resistant to protease inhibitors than HCV genotype 1b, and it is easier for HCV genotype 1a strains to be resistant to the currently available HCV protease inhibitors. At present, patients should be treated according to the recommendations of several HCV clinical practice guidelines[80-86]. However, it may also be possible that the combination of DAAs against regions other than HCV NS3/4A could eradicate HCV with these resistance variants.
Footnotes
Supported by Grants from the Japan Society for Promotion of Science (JSPS); Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan; and Grants from the Ministry of Health, Labour, and Welfare of Japan
P- Reviewers: Asensi V, Guo ZS, Tatsuo K S- Editor: Song XX L- Editor: A E- Editor: Zhang DN
References
1.Brownell J, Polyak SJ. Molecular pathways: hepatitis C virus, CXCL10, and the inflammatory road to liver cancer. Clin Cancer Res. 2013;19:1347-1352. [PubMed] [DOI]
2.Te HS, Jensen DM. Epidemiology of hepatitis B and C viruses: a global overview. Clin Liver Dis. 2010;14:1-21, vii. [PubMed] [DOI]
3.Saito I, Miyamura T, Ohbayashi A, Harada H, Katayama T, Kikuchi S, Watanabe Y, Koi S, Onji M, Ohta Y. Hepatitis C virus infection is associated with the development of hepatocellular carcinoma. Proc Natl Acad Sci USA. 1990;87:6547-6549. [PubMed]
4.Di Bisceglie AM. Hepatitis C and hepatocellular carcinoma. Hepatology. 1997;26:34S-38S. [PubMed]
5.Nakano T, Lau GM, Lau GM, Sugiyama M, Mizokami M. An updated analysis of hepatitis C virus genotypes and subtypes based on the complete coding region. Liver Int. 2012;32:339-345. [PubMed] [DOI]
6.Poordad F, McCone J, Bacon BR, Bruno S, Manns MP, Sulkowski MS, Jacobson IM, Reddy KR, Goodman ZD, Boparai N. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med. 2011;364:1195-1206.[PubMed] [DOI]
7.Bacon BR, Gordon SC, Lawitz E, Marcellin P, Vierling JM, Zeuzem S, Poordad F, Goodman ZD, Sings HL, Boparai N. Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med. 2011;364:1207-1217. [PubMed] [DOI]
8.McHutchison JG, Everson GT, Gordon SC, Jacobson IM, Sulkowski M, Kauffman R, McNair L, Alam J, Muir AJ. Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection. N Engl J Med. 2009;360:1827-1838. [PubMed] [DOI]
9.Hézode C, Forestier N, Dusheiko G, Ferenci P, Pol S, Goeser T, Bronowicki JP, Bourlière M, Gharakhanian S, Bengtsson L. Telaprevir and peginterferon with or without ribavirin for chronic HCV infection. N Engl J Med. 2009;360:1839-1850. [PubMed] [DOI]
10.McHutchison JG, Manns MP, Muir AJ, Terrault NA, Jacobson IM, Afdhal NH, Heathcote EJ, Zeuzem S, Reesink HW, Garg J. Telaprevir for previously treated chronic HCV infection. N Engl J Med. 2010;362:1292-1303. [PubMed] [DOI]
11.Jacobson IM, McHutchison JG, Dusheiko G, Di Bisceglie AM, Reddy KR, Bzowej NH, Marcellin P, Muir AJ, Ferenci P, Flisiak R. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med. 2011;364:2405-2416. [PubMed] [DOI]
12.Zeuzem S, Andreone P, Pol S, Lawitz E, Diago M, Roberts S, Focaccia R, Younossi Z, Foster GR, Horban A. Telaprevir for retreatment of HCV infection. N Engl J Med. 2011;364:2417-2428. [PubMed] [DOI]
13.Sherman KE, Flamm SL, Afdhal NH, Nelson DR, Sulkowski MS, Everson GT, Fried MW, Adler M, Reesink HW, Martin M. Response-guided telaprevir combination treatment for hepatitis C virus infection. N Engl J Med. 2011;365:1014-1024. [PubMed] [DOI]
14.Kumada H, Toyota J, Okanoue T, Chayama K, Tsubouchi H, Hayashi N. Telaprevir with peginterferon and ribavirin for treatment-naive patients chronically infected with HCV of genotype 1 in Japan. J Hepatol. 2012;56:78-84. [PubMed] [DOI]
15.Kanda T, Nakamoto S, Nishino T, Takada N, Tsubota A, Kato K, Miyamura T, Maruoka D, Wu S, Tanaka T. Peginterferon Alfa-2a plus ribavirin in Japanese patients infected with hepatitis C virus genotype 2 who failed previous interferon therapy. Int J Med Sci. 2013;10:43-49. [PubMed] [DOI]
16.Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, Goodman ZD, Koury K, Ling M, Albrecht JK. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet. 2001;358:958-965. [PubMed]
17.Yokosuka O, Iwama S, Suzuki N, Takashi M, Hirai Y, Uchiumi K, Kimura M, Gotou N, Hino S, Hayasaka A. High sustained virologic response rate after interferon monotherapy in Japanese hepatitis C patients with a low HCV RNA titer and/or HCV genotype 2. A prospective study. Intervirology. 2004;47:328-334. [PubMed]
18.Enomoto N, Sakuma I, Asahina Y, Kurosaki M, Murakami T, Yamamoto C, Izumi N, Marumo F, Sato C. Comparison of full-length sequences of interferon-sensitive and resistant hepatitis C virus 1b. Sensitivity to interferon is conferred by amino acid substitutions in the NS5A region. J Clin Invest. 1995;96:224-230.[PubMed]
19.Enomoto N, Sakuma I, Asahina Y, Kurosaki M, Murakami T, Yamamoto C, Ogura Y, Izumi N, Marumo F, Sato C. Mutations in the nonstructural protein 5A gene and response to interferon in patients with chronic hepatitis C virus 1b infection. N Engl J Med. 1996;334:77-81. [PubMed]
20.Akuta N, Suzuki F, Hirakawa M, Kawamura Y, Yatsuji H, Sezaki H, Suzuki Y, Hosaka T, Kobayashi M, Kobayashi M. Amino acid substitutions in the hepatitis C virus core region of genotype 1b are the important predictor of severe insulin resistance in patients without cirrhosis and diabetes mellitus. J Med Virol. 2009;81:1032-1039. [PubMed] [DOI]
21.El-Shamy A, Nagano-Fujii M, Sasase N, Imoto S, Kim SR, Hotta H. Sequence variation in hepatitis C virus nonstructural protein 5A predicts clinical outcome of pegylated interferon/ribavirin combination therapy. Hepatology. 2008;48:38-47. [PubMed] [DOI]
22.Ge D, Fellay J, Thompson AJ, Simon JS, Shianna KV, Urban TJ, Heinzen EL, Qiu P, Bertelsen AH, Muir AJ. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature. 2009;461:399-401.[PubMed] [DOI]
23.Suppiah V, Moldovan M, Ahlenstiel G, Berg T, Weltman M, Abate ML, Bassendine M, Spengler U, Dore GJ, Powell E. IL28B is associated with response to chronic hepatitis C interferon-alpha and ribavirin therapy. Nat Genet. 2009;41:1100-1104. [PubMed] [DOI]
24.Tanaka Y, Nishida N, Sugiyama M, Kurosaki M, Matsuura K, Sakamoto N, Nakagawa M, Korenaga M, Hino K, Hige S. Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C. Nat Genet. 2009;41:1105-1109. [PubMed] [DOI]
25.Rauch A, Kutalik Z, Descombes P, Cai T, Di Iulio J, Mueller T, Bochud M, Battegay M, Bernasconi E, Borovicka J. Genetic variation in IL28B is associated with chronic hepatitis C and treatment failure: a genome-wide association study. Gastroenterology. 2010;138:1338-145, 1338-145. [PubMed] [DOI]
26.Honda M, Sakai A, Yamashita T, Nakamoto Y, Mizukoshi E, Sakai Y, Yamashita T, Nakamura M, Shirasaki T, Horimoto K. Hepatic ISG expression is associated with genetic variation in interleukin 28B and the outcome of IFN therapy for chronic hepatitis C. Gastroenterology. 2010;139:499-509. [PubMed] [DOI]
27.Lagging M, Askarieh G, Negro F, Bibert S, Söderholm J, Westin J, Lindh M, Romero A, Missale G, Ferrari C. Response prediction in chronic hepatitis C by assessment of IP-10 and IL28B-related single nucleotide polymorphisms. PLoS One. 2011;6:e17232. [PubMed] [DOI]
28.Lindh M, Lagging M, Arnholm B, Eilard A, Nilsson S, Norkrans G, Söderholm J, Wahlberg T, Wejstål R, Westin J. IL28B polymorphisms determine early viral kinetics and treatment outcome in patients receiving peginterferon/ribavirin for chronic hepatitis C genotype 1. J Viral Hepat. 2011;18:e325-e331. [PubMed] [DOI]
29.Miyamura T, Kanda T, Nakamoto S, Wu S, Fujiwara K, Imazeki F, Yokosuka O. Hepatic STAT1-nuclear translocation and interleukin 28B polymorphisms predict treatment outcomes in hepatitis C virus genotype 1-infected patients. PLoS One. 2011;6:e28617. [PubMed] [DOI]
30.Nakamoto S, Kanda T, Imazeki F, Wu S, Arai M, Fujiwara K, Yokosuka O. Simple assay based on restriction fragment length polymorphism associated with IL28B in chronic hepatitis C patients. Scand J Gastroenterol. 2011;46:955-961. [PubMed] [DOI]
31.Yu ML, Huang CF, Huang JF, Chang NC, Yang JF, Lin ZY, Chen SC, Hsieh MY, Wang LY, Chang WY. Role of interleukin-28B polymorphisms in the treatment of hepatitis C virus genotype 2 infection in Asian patients. Hepatology. 2011;53:7-13. [PubMed] [DOI]
32.Miyamura T, Kanda T, Nakamoto S, Wu S, Jiang X, Arai M, Fujiwara K, Imazeki F, Yokosuka O. Roles of ITPA and IL28B genotypes in chronic hepatitis C patients treated with peginterferon plus ribavirin. Viruses. 2012;4:1264-1278. [PubMed] [DOI]
33.Booth D, George J. Loss of function of the new interferon IFN-λ4 may confer protection from hepatitis C. Nat Genet. 2013;45:119-120. [PubMed] [DOI]
34.Prokunina-Olsson L, Muchmore B, Tang W, Pfeiffer RM, Park H, Dickensheets H, Hergott D, Porter-Gill P, Mumy A, Kohaar I. A variant upstream of IFNL3 (IL28B) creating a new interferon gene IFNL4 is associated with impaired clearance of hepatitis C virus. Nat Genet. 2013;45:164-171. [PubMed] [DOI]
35.Bibert S, Roger T, Calandra T, Bochud M, Cerny A, Semmo N, Duong FH, Gerlach T, Malinverni R, Moradpour D. IL28B expression depends on a novel TT/-G polymorphism which improves HCV clearance prediction. J Exp Med. 2013;210:1109-1116. [PubMed] [DOI]
36.McHutchison JG, Manns M, Patel K, Poynard T, Lindsay KL, Trepo C, Dienstag J, Lee WM, Mak C, Garaud JJ. Adherence to combination therapy enhances sustained response in genotype-1-infected patients with chronic hepatitis C. Gastroenterology. 2002;123:1061-1069. [PubMed] [DOI]
37.Gao M, Nettles RE, Belema M, Snyder LB, Nguyen VN, Fridell RA, Serrano-Wu MH, Langley DR, Sun JH, O’Boyle DR. Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect. Nature. 2010;465:96-100. [PubMed] [DOI]
38.Chayama K, Takahashi S, Toyota J, Karino Y, Ikeda K, Ishikawa H, Watanabe H, McPhee F, Hughes E, Kumada H. Dual therapy with the nonstructural protein 5A inhibitor, daclatasvir, and the nonstructural protein 3 protease inhibitor, asunaprevir, in hepatitis C virus genotype 1b-infected null responders. Hepatology. 2012;55:742-748. [PubMed] [DOI]
39.Lok AS, Gardiner DF, Lawitz E, Martorell C, Everson GT, Ghalib R, Reindollar R, Rustgi V, McPhee F, Wind-Rotolo M. Preliminary study of two antiviral agents for hepatitis C genotype 1. N Engl J Med. 2012;366:216-224.[PubMed] [DOI]
40.Osinusi A, Meissner EG, Lee YJ, Bon D, Heytens L, Nelson A, Sneller M, Kohli A, Barrett L, Proschan M. Sofosbuvir and ribavirin for hepatitis C genotype 1 in patients with unfavorable treatment characteristics: a randomized clinical trial. JAMA. 2013;310:804-811. [PubMed] [DOI]
41.Kanda T, Yokosuka O, Omata M. Treatment of hepatitis C virus infection in the future. Clin Transl Med. 2013;2:9. [PubMed] [DOI]
42.Lenz O, Verbinnen T, Lin TI, Vijgen L, Cummings MD, Lindberg J, Berke JM, Dehertogh P, Fransen E, Scholliers A. In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435. Antimicrob Agents Chemother. 2010;54:1878-1887. [PubMed] [DOI]
43.Fried MW, Buti M, Dore GJ, Flisiak R, Ferenci P, Jacobson I, Marcellin P, Manns M, Nikitin I, Poordad F. Once-daily simeprevir (TMC435) with pegylated interferon and ribavirin in treatment-naïve genotype 1 hepatitis C: The randomized PILLAR study. Hepatology. 2013;58:1918-1929. [PubMed] [DOI]
44.Zeuzem S, Soriano V, Asselah T, Bronowicki JP, Lohse AW, Müllhaupt B, Schuchmann M, Bourlière M, Buti M, Roberts SK. Faldaprevir and deleobuvir for HCV genotype 1 infection. N Engl J Med. 2013;369:630-639.[PubMed] [DOI]
45.Nishiguchi S, Sakai Y, Kuboki M, Tsunematsu S, Urano Y, Sakamoto W, Tsuda Y, Steinmann G, Omata M. Safety and efficacy of faldaprevir with pegylated interferon alfa-2a and ribavirin in Japanese patients with chronic genotype-1 hepatitis C infection. Liver Int. 2014;34:78-88. [PubMed] [DOI]
46.Manns MP, Gane E, Rodriguez-Torres M, Stoehr A, Yeh CT, Marcellin P, Wiedmann RT, Hwang PM, Caro L, Barnard RJ. Vaniprevir with pegylated interferon alpha-2a and ribavirin in treatment-naïve patients with chronic hepatitis C: a randomized phase II study. Hepatology. 2012;56:884-893. [PubMed] [DOI]
47.Lawitz E, Rodriguez-Torres M, Stoehr A, Gane EJ, Serfaty L, Bhanja S, Barnard RJ, An D, Gress J, Hwang P. A phase 2B study of MK-7009 (vaniprevir) in patients with genotype 1 HCV infection who have failed previous pegylated interferon and ribavirin treatment. J Hepatol. 2013;59:11-17. [PubMed] [DOI]
48.Barnard RJ, McHale CM, Newhard W, Cheney CA, Graham DJ, Himmelberger AL, Strizki J, Hwang PM, Rivera AA, Reeves JD. Emergence of resistance-associated variants after failed triple therapy with vaniprevir in treatment-experienced non-cirrhotic patients with hepatitis C-genotype 1 infection: a population and clonal analysis. Virology. 2013;443:278-284. [PubMed] [DOI]
49.Summa V, Ludmerer SW, McCauley JA, Fandozzi C, Burlein C, Claudio G, Coleman PJ, Dimuzio JM, Ferrara M, Di Filippo M. MK-5172, a selective inhibitor of hepatitis C virus NS3/4a protease with broad activity across genotypes and resistant variants. Antimicrob Agents Chemother. 2012;56:4161-4167. [PubMed] [DOI]
50.Contreras AM, Hiasa Y, He W, Terella A, Schmidt EV, Chung RT. Viral RNA mutations are region specific and increased by ribavirin in a full-length hepatitis C virus replication system. J Virol. 2002;76:8505-8517. [PubMed]
51.Kanda T, Yokosuka O, Imazeki F, Tanaka M, Shino Y, Shimada H, Tomonaga T, Nomura F, Nagao K, Ochiai T. Inhibition of subgenomic hepatitis C virus RNA in Huh-7 cells: ribavirin induces mutagenesis in HCV RNA. J Viral Hepat. 2004;11:479-487. [PubMed]
52.Adiwijaya BS, Herrmann E, Hare B, Kieffer T, Lin C, Kwong AD, Garg V, Randle JC, Sarrazin C, Zeuzem S. A multi-variant, viral dynamic model of genotype 1 HCV to assess the in vivo evolution of protease-inhibitor resistant variants. PLoS Comput Biol. 2010;6:e1000745. [PubMed] [DOI]
53.Rong L, Dahari H, Ribeiro RM, Perelson AS. Rapid emergence of protease inhibitor resistance in hepatitis C virus. Sci Transl Med. 2010;2:30ra32. [PubMed] [DOI]
54.Zeuzem S. Clinical implications of hepatitis C viral kinetics. J Hepatol. 1999;31 Suppl 1:61-64. [PubMed]
55.Bartels DJ, Zhou Y, Zhang EZ, Marcial M, Byrn RA, Pfeiffer T, Tigges AM, Adiwijaya BS, Lin C, Kwong AD. Natural prevalence of hepatitis C virus variants with decreased sensitivity to NS3.4A protease inhibitors in treatment-naive subjects. J Infect Dis. 2008;198:800-807. [PubMed] [DOI]
56.Kuntzen T, Timm J, Berical A, Lennon N, Berlin AM, Young SK, Lee B, Heckerman D, Carlson J, Reyor LL. Naturally occurring dominant resistance mutations to hepatitis C virus protease and polymerase inhibitors in treatment-naïve patients. Hepatology. 2008;48:1769-1778. [PubMed] [DOI]
57.Palanisamy N, Danielsson A, Kokkula C, Yin H, Bondeson K, Wesslén L, Duberg AS, Lennerstrand J. Implications of baseline polymorphisms for potential resistance to NS3 protease inhibitors in Hepatitis C virus genotypes 1a, 2b and 3a. Antiviral Res. 2013;99:12-17. [PubMed] [DOI]
58.Suzuki F, Sezaki H, Akuta N, Suzuki Y, Seko Y, Kawamura Y, Hosaka T, Kobayashi M, Saito S, Arase Y. Prevalence of hepatitis C virus variants resistant to NS3 protease inhibitors or the NS5A inhibitor (BMS-790052) in hepatitis patients with genotype 1b. J Clin Virol. 2012;54:352-354. [PubMed] [DOI]
59.Thomas XV, de Bruijne J, Sullivan JC, Kieffer TL, Ho CK, Rebers SP, de Vries M, Reesink HW, Weegink CJ, Molenkamp R. Evaluation of persistence of resistant variants with ultra-deep pyrosequencing in chronic hepatitis C patients treated with telaprevir. PLoS One. 2012;7:e41191. [PubMed] [DOI]
60.Wu S, Kanda T, Nakamoto S, Jiang X, Miyamura T, Nakatani SM, Ono SK, Takahashi-Nakaguchi A, Gonoi T, Yokosuka O. Prevalence of hepatitis C virus subgenotypes 1a and 1b in Japanese patients: ultra-deep sequencing analysis of HCV NS5B genotype-specific region. PLoS One. 2013;8:e73615. [PubMed] [DOI]
61.Leggewie M, Sreenu VB, Abdelrahman T, Leitch EC, Wilkie GS, Klymenko T, Muir D, Thursz M, Main J, Thomson EC. Natural NS3 resistance polymorphisms occur frequently prior to treatment in HIV-positive patients with acute hepatitis C. AIDS. 2013;27:2485-2488. [PubMed] [DOI]
62.Lin C, Gates CA, Rao BG, Brennan DL, Fulghum JR, Luong YP, Frantz JD, Lin K, Ma S, Wei YY. In vitro studies of cross-resistance mutations against two hepatitis C virus serine protease inhibitors, VX-950 and BILN 2061. J Biol Chem. 2005;280:36784-36791. [PubMed] [DOI]
63.Mo H, Lu L, Pilot-Matias T, Pithawalla R, Mondal R, Masse S, Dekhtyar T, Ng T, Koev G, Stoll V. Mutations conferring resistance to a hepatitis C virus (HCV) RNA-dependent RNA polymerase inhibitor alone or in combination with an HCV serine protease inhibitor in vitro. Antimicrob Agents Chemother. 2005;49:4305-4314.[PubMed]
64.Kieffer TL, De Meyer S, Bartels DJ, Sullivan JC, Zhang EZ, Tigges A, Dierynck I, Spanks J, Dorrian J, Jiang M. Hepatitis C viral evolution in genotype 1 treatment-naïve and treatment-experienced patients receiving telaprevir-based therapy in clinical trials. PLoS One. 2012;7:e34372. [PubMed] [DOI]
65.Susser S, Vermehren J, Forestier N, Welker MW, Grigorian N, Füller C, Perner D, Zeuzem S, Sarrazin C. Analysis of long-term persistence of resistance mutations within the hepatitis C virus NS3 protease after treatment with telaprevir or boceprevir. J Clin Virol. 2011;52:321-327. [PubMed] [DOI]
66.Zhou Y, Bartels DJ, Hanzelka BL, Müh U, Wei Y, Chu HM, Tigges AM, Brennan DL, Rao BG, Swenson L. Phenotypic characterization of resistant Val36 variants of hepatitis C virus NS3-4A serine protease. Antimicrob Agents Chemother. 2008;52:110-120. [PubMed]
67.Zhou Y, Müh U, Hanzelka BL, Bartels DJ, Wei Y, Rao BG, Brennan DL, Tigges AM, Swenson L, Kwong AD. Phenotypic and structural analyses of hepatitis C virus NS3 protease Arg155 variants: sensitivity to telaprevir (VX-950) and interferon alpha. J Biol Chem. 2007;282:22619-22628. [PubMed]
68.Susser S, Welsch C, Wang Y, Zettler M, Domingues FS, Karey U, Hughes E, Ralston R, Tong X, Herrmann E. Characterization of resistance to the protease inhibitor boceprevir in hepatitis C virus-infected patients. Hepatology. 2009;50:1709-1718. [PubMed] [DOI]
69.Sarrazin C, Zeuzem S. Resistance to direct antiviral agents in patients with hepatitis C virus infection. Gastroenterology. 2010;138:447-462. [PubMed] [DOI]
70.Zeuzem S, Asselah T, Angus P, Zarski JP, Larrey D, Müllhaupt B, Gane E, Schuchmann M, Lohse A, Pol S. Efficacy of the protease inhibitor BI 201335, polymerase inhibitor BI 207127, and ribavirin in patients with chronic HCV infection. Gastroenterology. 2011;141:2047-255; quiz e14. [PubMed] [DOI]
71.Zeuzem S, Buggisch P, Agarwal K, Marcellin P, Sereni D, Klinker H, Moreno C, Zarski JP, Horsmans Y, Mo H. The protease inhibitor, GS-9256, and non-nucleoside polymerase inhibitor tegobuvir alone, with ribavirin, or pegylated interferon plus ribavirin in hepatitis C. Hepatology. 2012;55:749-758. [PubMed] [DOI]
72.Bartels DJ, Sullivan JC, Zhang EZ, Tigges AM, Dorrian JL, De Meyer S, Takemoto D, Dondero E, Kwong AD, Picchio G. Hepatitis C virus variants with decreased sensitivity to direct-acting antivirals (DAAs) were rarely observed in DAA-naive patients prior to treatment. J Virol. 2013;87:1544-1553. [PubMed] [DOI]
73.Welsch C, Schweizer S, Shimakami T, Domingues FS, Kim S, Lemon SM, Antes I. Ketoamide resistance and hepatitis C virus fitness in val55 variants of the NS3 serine protease. Antimicrob Agents Chemother. 2012;56:1907-1915. [PubMed] [DOI]
74.Stedman CA. Current prospects for interferon-free treatment of hepatitis C in 2012. J Gastroenterol Hepatol. 2013;28:38-45. [PubMed] [DOI]
75.Nasu A, Marusawa H, Ueda Y, Nishijima N, Takahashi K, Osaki Y, Yamashita Y, Inokuma T, Tamada T, Fujiwara T. Genetic heterogeneity of hepatitis C virus in association with antiviral therapy determined by ultra-deep sequencing. PLoS One. 2011;6:e24907. [PubMed] [DOI]
76.Ninomiya M, Ueno Y, Funayama R, Nagashima T, Nishida Y, Kondo Y, Inoue J, Kakazu E, Kimura O, Nakayama K. Use of illumina deep sequencing technology to differentiate hepatitis C virus variants. J Clin Microbiol. 2012;50:857-866. [PubMed] [DOI]
77.Akuta N, Suzuki F, Seko Y, Kawamura Y, Sezaki H, Suzuki Y, Hosaka T, Kobayashi M, Hara T, Kobayashi M. Emergence of telaprevir-resistant variants detected by ultra-deep sequencing after triple therapy in patients infected with HCV genotype 1. J Med Virol. 2013;85:1028-1036. [PubMed] [DOI]
78.Abe H, Hayes CN, Hiraga N, Imamura M, Tsuge M, Miki D, Takahashi S, Ochi H, Chayama K. A translational study of resistance emergence using sequential direct-acting antiviral agents for hepatitis C using ultra-deep sequencing. Am J Gastroenterol. 2013;108:1464-1472. [PubMed] [DOI]
79.Laplante SR, Nar H, Lemke CT, Jakalian A, Aubry N, Kawai SH. Ligand Bioactive Conformation Plays a Critical Role in the Design of Drugs That Target the Hepatitis C Virus NS3 Protease. J Med Chem. 2013;:Epub ahead of print. [PubMed]
80.Ghany MG, Strader DB, Thomas DL, Seeff LB. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology. 2009;49:1335-1374. [PubMed] [DOI]
81.European Association for the Study of the Liver.EASL Clinical Practice Guidelines: management of hepatitis C virus infection. J Hepatol. 2011;55:245-264. [PubMed] [DOI]
82.Ghany MG, Nelson DR, Strader DB, Thomas DL, Seeff LB. An update on treatment of genotype 1 chronic hepatitis C virus infection: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology. 2011;54:1433-1444. [PubMed] [DOI]
83.Lagging M, Duberg AS, Wejstål R, Weiland O, Lindh M, Aleman S, Josephson F; Swedish Consensus Group.Treatment of hepatitis C virus infection in adults and children: updated Swedish consensus recommendations. Scand J Infect Dis. 2012;44:502-521. [PubMed] [DOI]
84.Leroy V, Serfaty L, Bourlière M, Bronowicki JP, Delasalle P, Pariente A, Pol S, Zoulim F, Pageaux GP. Protease inhibitor-based triple therapy in chronic hepatitis C: guidelines by the French Association for the Study of the Liver. Liver Int. 2012;32:1477-1492. [PubMed] [DOI]
85.Myers RP, Ramji A, Bilodeau M, Wong S, Feld JJ. An update on the management of hepatitis C: consensus guidelines from the Canadian Association for the Study of the Liver. Can J Gastroenterol. 2012;26:359-375.[PubMed]
86.Omata M, Kanda T, Yu ML, Yokosuka O, Lim SG, Jafri W, Tateishi R, S. Hamid S, Chuang WL, Chutaputti A, Wei L, Sollano J, Sarin SK, Kao JH, McCaughan GW. APASL consensus statements and management algorithms for hepatitis C virus infection. Hepatol Int. 2012;6:409-435. [DOI]
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