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Auteur : Grafiati
Publié le 11 septembre 2023

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1

Flint, Mike, Stanley Mullen, Anne M. Deatly, Wei Chen, Lynn Z. Miller, Robert Ralston, Colin Broom, Emilio A. Emini et Anita Y. M. Howe. « Selection and Characterization of Hepatitis C Virus Replicons Dually Resistant to the Polymerase and Protease Inhibitors HCV-796 and Boceprevir (SCH 503034) ». Antimicrobial Agents and Chemotherapy 53, no 2 (20 octobre 2008) : 401–11. http://dx.doi.org/10.1128/aac.01081-08.

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ABSTRACT HCV-796 is a nonnucleoside inhibitor of the hepatitis C virus (HCV) nonstructural protein 5B (NS5B) polymerase, and boceprevir is an inhibitor of the NS3 serine protease. The emergence of replicon variants resistant to the combination of HCV-796 and boceprevir was evaluated. Combining the inhibitors greatly reduced the frequency with which resistant colonies arose; however, some resistant replicon cells could be isolated by the use of low inhibitor concentrations. These replicons were approximately 1,000-fold less susceptible to HCV-796 and 9-fold less susceptible to boceprevir. They also exhibited resistance to anthranilate nonnucleoside inhibitors of NS5B but were fully sensitive to inhibitors of different mechanisms: a pyranoindole, Hsp90 inhibitors, an NS5B nucleoside inhibitor, and pegylated interferon (Peg-IFN). The replicon was cleared from the combination-resistant cells by extended treatment with Peg-IFN. Mutations known to confer resistance to HCV-796 (NS5B C316Y) and boceprevir (NS3 V170A) were present in the combination-resistant replicons. These changes could be selected together and coexist in the same genome. The replicon bearing both changes exhibited reduced sensitivity to inhibition by HCV-796 and boceprevir but had a reduced replicative capacity.
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Andonov, Anton, Kamran Kadkhoda, Carla Osiowy et Kelly Kaita. « Pretreatment Resistance to Hepatitis C Virus Protease Inhibitors Boceprevir/Telaprevir in Hepatitis C Subgenotype 1A-Infected Patients from Manitoba ». Canadian Journal of Gastroenterology 27, no 7 (2013) : 414–16. http://dx.doi.org/10.1155/2013/273856.

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BACKGROUND: Traditional therapy with pegylated interferon and ribavirin combined with the new protease inhibitors boceprevir or telaprevir has demonstrated improved outcomes in hepatitis C virus (HCV)-infected patients. Prevalence data regarding pre-existing drug-resistant variants to these two new virus inhibitors in the Canadian population are not available.OBJECTIVE: To detect pre-existing mutations conferring resistance to boceprevir and/or telaprevir in Canadian patients infected with HCV genotype 1a.METHODS: Resistance-associated mutations (RAMs) were evaluated in 85 patients infected with HCV genotype 1a who had not yet received antiviral therapy. TheNS3protease gene was sequenced and common RAMs were identified based on a recently published list.RESULTS: The overall prevalence of pre-existing RAMs to boceprevir and telaprevir was higher compared with other similar studies. All of the observed RAMs were associated with a low level of resistance. A surprisingly high proportion of patients had the V55A RAM (10.6%). None of the mutations associated with a high level of resistance were observed. The simultaneous presence of two low-level resistance mutations (V36L and V55A) was observed in only one patient. Three other patients had both T54S RAM and V55I mutations, which may require a higher concentration of the protease drugs. The prevalence of various mutations in Aboriginal Canadian patients was higher (37.5%) compared with Caucasians (16.39%) (P=0.038).CONCLUSIONS: The present study was the first to investigate pre-existing drug resistance to boceprevir/telaprevir in Canadian HCV-infected patients. A relatively high proportion of untreated HCV genotype 1a patients in Manitoba harbour low-level RAMs, especially patients of Aboriginal descent, which may contribute to an increased risk of treatment failure.
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Barnard, Richard J. O., John A. Howe, Robert A. Ogert, Stefan Zeuzem, Fred Poordad, Stuart C. Gordon, Robert Ralston et al. « Analysis of boceprevir resistance associated amino acid variants (RAVs) in two phase 3 boceprevir clinical studies ». Virology 444, no 1-2 (septembre 2013) : 329–36. http://dx.doi.org/10.1016/j.virol.2013.06.029.

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Welsch, Christoph, Sabine Schweizer, Tetsuro Shimakami, Francisco S. Domingues, Seungtaek Kim, Stanley M. Lemon et Iris Antes. « Ketoamide Resistance and Hepatitis C Virus Fitness in Val55 Variants of the NS3 Serine Protease ». Antimicrobial Agents and Chemotherapy 56, no 4 (17 janvier 2012) : 1907–15. http://dx.doi.org/10.1128/aac.05184-11.

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ABSTRACTDrug-resistant viral variants are a major issue in the use of direct-acting antiviral agents in chronic hepatitis C. Ketoamides are potent inhibitors of the NS3 protease, with V55A identified as mutation associated with resistance to boceprevir. Underlying molecular mechanisms are only partially understood. We applied a comprehensive sequence analysis to characterize the natural variability at Val55 within dominant worldwide patient strains. A residue-interaction network and molecular dynamics simulation were applied to identify mechanisms for ketoamide resistance and viral fitness in Val55 variants. An infectious H77S.3 cell culture system was used for variant phenotype characterization. We measured antiviral 50% effective concentration (EC50) and fold changes, as well as RNA replication and infectious virus yields from viral RNAs containing variants. Val55 was found highly conserved throughout all hepatitis C virus (HCV) genotypes. The conservative V55A and V55I variants were identified from HCV genotype 1a strains with no variants in genotype 1b. Topology measures from a residue-interaction network of the protease structure suggest a potential Val55 key role for modulation of molecular changes in the protease ligand-binding site. Molecular dynamics showed variants with constricted binding pockets and a loss of H-bonded interactions upon boceprevir binding to the variant proteases. These effects might explain low-level boceprevir resistance in the V55A variant, as well as the Val55 variant, reduced RNA replication capacity. Higher structural flexibility was found in the wild-type protease, whereas variants showed lower flexibility. Reduced structural flexibility could impact the Val55 variant's ability to adapt for NS3 domain-domain interaction and might explain the virus yield drop observed in variant strains.
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Serre, Stéphanie B. N., Sanne B. Jensen, Lubna Ghanem, Daryl G. Humes, Santseharay Ramirez, Yi-Ping Li, Henrik Krarup, Jens Bukh et Judith M. Gottwein. « Hepatitis C Virus Genotype 1 to 6 Protease Inhibitor Escape Variants:In VitroSelection, Fitness, and Resistance Patterns in the Context of the Infectious Viral Life Cycle ». Antimicrobial Agents and Chemotherapy 60, no 6 (28 mars 2016) : 3563–78. http://dx.doi.org/10.1128/aac.02929-15.

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Hepatitis C virus (HCV) NS3 protease inhibitors (PIs) are important components of novel HCV therapy regimens. Studies of PI resistance initially focused on genotype 1. Therefore, knowledge about the determinants of PI resistance for the highly prevalent genotypes 2 to 6 remains limited. Using Huh7.5 cell culture-infectious HCV recombinants with genotype 1 to 6 NS3 protease, we identified protease positions 54, 155, and 156 as hot spots for the selection of resistance substitutions under treatment with the first licensed PIs, telaprevir and boceprevir. Treatment of a genotype 2 isolate with the newer PIs vaniprevir, faldaprevir, simeprevir, grazoprevir, paritaprevir, and deldeprevir identified positions 156 and 168 as hot spots for resistance; the Y56H substitution emerged for three newer PIs. Substitution selection also depended on the specific recombinant. The substitutions identified conferred cross-resistance to several PIs; however, most substitutions selected under telaprevir or boceprevir treatment conferred less resistance to certain newer PIs. In a single-cycle production assay, across genotypes, PI treatment primarily decreased viral replication, which was rescued by PI resistance substitutions. The substitutions identified resulted in differential effects on viral fitness, depending on the original recombinant and the substitution. Across genotypes, fitness impairment induced by resistance substitutions was due primarily to decreased replication. Most combinations of substitutions that were identified increased resistance or fitness. Combinations of resistance substitutions with fitness-compensating substitutions either rescued replication or compensated for decreased replication by increasing assembly. This comprehensive study provides insight into the selection patterns and effects of PI resistance substitutions for HCV genotypes 1 to 6 in the context of the infectious viral life cycle, which is of interest for clinical and virological HCV research.
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Tong, X., A. Arasappan, F. Bennett, R. Chase, B. Feld, Z. Guo, A. Hart et al. « Preclinical Characterization of the Antiviral Activity of SCH 900518 (Narlaprevir), a Novel Mechanism-Based Inhibitor of Hepatitis C Virus NS3 Protease ». Antimicrobial Agents and Chemotherapy 54, no 6 (2 mars 2010) : 2365–70. http://dx.doi.org/10.1128/aac.00135-10.

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ABSTRACT Small-molecule hepatitis C virus (HCV) NS3 protease inhibitors such as boceprevir (SCH 503034) have been shown to have antiviral activity when they are used as monotherapy and in combination with pegylated alpha interferon and ribavirin in clinical trials. Improvements in inhibitor potency and pharmacokinetic properties offer opportunities to increase drug exposure and to further increase the sustained virological response. Exploration of the structure-activity relationships of ketoamide inhibitors related to boceprevir has led to the discovery of SCH 900518, a novel ketoamide protease inhibitor which forms a reversible covalent bond with the active-site serine. It has an overall inhibition constant (K*i) of 7 nM and a dissociation half-life of 1 to 2 h. SCH 900518 inhibited replicon RNA at a 90% effective concentration (EC90) of 40 nM. In biochemical assays, SCH 900518 was active against proteases of genotypes 1 to 3. A 2-week treatment with 5× EC90 of the inhibitor reduced the replicon RNA level by 3 log units. Selection of replicon cells with SCH 900518 resulted in the outgrowth of several resistant mutants (with the T54A/S and A156S/T/V mutations). Cross-resistance studies demonstrated that the majority of mutations for resistance to boceprevir and telaprevir caused similar fold losses of activity against all three inhibitors; however, SCH 900518 retained more activity against these mutants due to its higher intrinsic potency. Combination treatment with alpha interferon enhanced the inhibition of replicon RNA and suppressed the emergence of resistant replicon colonies, supporting the use of SCH 900518-pegylated alpha interferon combination therapy in the clinic. In summary, the results of the preclinical characterization of the antiviral activity of SCH 900518 support its evaluation in clinical studies.
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Jensen, Sanne B., Stéphanie B. N. Serre, Daryl G. Humes, Santseharay Ramirez, Yi-Ping Li, Jens Bukh et Judith M. Gottwein. « Substitutions at NS3 Residue 155, 156, or 168 of Hepatitis C Virus Genotypes 2 to 6 Induce Complex Patterns of Protease Inhibitor Resistance ». Antimicrobial Agents and Chemotherapy 59, no 12 (21 septembre 2015) : 7426–36. http://dx.doi.org/10.1128/aac.01953-15.

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ABSTRACTVarious protease inhibitors (PIs) currently are becoming available for treatment of hepatitis C virus (HCV). For genotype 1, substitutions at NS3 protease positions 155, 156, and 168 are the main determinants of PI resistance. For other genotypes, similar substitutions were selected during PI treatment but were not characterized systematically. To elucidate the impact of key PI resistance substitutions on genotypes 2 to 6, we engineered the substitutions R155A/E/G/H/K/Q/T, A156G/S/T/V, and D/Q168A/E/G/H/N/V into HCV recombinants expressing genotype 2 to 6 proteases. We evaluated viral fitness and sensitivity to nine PIs (telaprevir, boceprevir, simeprevir, asunaprevir, vaniprevir, faldaprevir, paritaprevir, deldeprevir, and grazoprevir) in Huh7.5 cells. We found that most variants showed decreased fitness compared to that of the original viruses. Overall, R155K, A156G/S, and D/Q168A/E/H/N/V variants showed the highest fitness; however, genotype 4 position 168 variants showed strong fitness impairment. Most variants tested were resistant to several PIs. Resistance levels varied significantly depending on the specific substitution, genotype, and PI. For telaprevir and boceprevir, specific 155 and 156, but not 168, variants proved resistant. For the remaining PIs, most genotype 2, 4, 5, and 6, but not genotype 3, variants showed various resistance levels. Overall, grazoprevir (MK-5172) had the highest efficacy against original viruses and variants. This is the first comprehensive study revealing the impact of described key PI resistance substitutions on fitness and PI resistance of HCV genotypes 2 to 6. In conclusion, the studied substitutions induced resistance to a panel of clinically relevant PIs, including the newer PIs paritaprevir, deldeprevir, and grazoprevir. We discovered complex patterns of resistance, with the impact of substitutions varying from increased sensitivity to high resistance.
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Nagpal, Neha, Sukriti Goyal, Divya Wahi, Ritu Jain, Salma Jamal, Aditi Singh, Preeti Rana et Abhinav Grover. « Molecular principles behind Boceprevir resistance due to mutations in hepatitis C NS3/4A protease ». Gene 570, no 1 (octobre 2015) : 115–21. http://dx.doi.org/10.1016/j.gene.2015.06.008.

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Susser, Simone, Christoph Welsch, Yalan Wang, Markus Zettler, Francisco S. Domingues, Ursula Karey, Eric Hughes et al. « Characterization of resistance to the protease inhibitor boceprevir in hepatitis C virus-infected patients ». Hepatology 50, no 6 (4 août 2009) : 1709–18. http://dx.doi.org/10.1002/hep.23192.

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Brass, Clifford A., Richard J. Barnard, John A. Howe, Robert A. Ogert, Robert Ralston, Navdeep Boparai, Margaret Burroughs, Vilma Sniukiene, Patricia Mendez et Janice K. Albrecht. « Sustained Virologic Response and Boceprevir Resistance-Associated Variants Observed in Patients Infected With HCV Genotype 1A/1b When Treated With Boceprevir Plus Peginterferon Alfa-2B/Ribavirin ». Gastroenterology 140, no 5 (mai 2011) : S—942—S—943. http://dx.doi.org/10.1016/s0016-5085(11)63909-7.

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Brass, C., R. J. O. Barnard, J. A. Howe, R. A. Ogert, R. Ralston, N. Boparai, M. Burroughs, V. Sniukiene, P. Mendez et J. Albrecht. « 1194 SUSTAINED VIROLOGIC RESPONSE AND BOCEPREVIR RESISTANCE-ASSOCIATED VARIANTS OBSERVED IN PATIENTS INFECTED WITH HCV GENOTPYPE 1A/1B WHEN TREATED WITH BOCEPREVIR PLUS PEGINTERFERON ALFA-2B/RIBAVIRIN ». Journal of Hepatology 54 (mars 2011) : S471—S472. http://dx.doi.org/10.1016/s0168-8278(11)61196-3.

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Strahotin, Cristina Simona, et Michael Babich. « Hepatitis C Variability, Patterns of Resistance, and Impact on Therapy ». Advances in Virology 2012 (2012) : 1–10. http://dx.doi.org/10.1155/2012/267483.

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Hepatitis C (HCV), a leading cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma, is the most common indication for liver transplantation in the United States. Although annual incidence of infection has declined since the 1980s, aging of the currently infected population is expected to result in an increase in HCV burden. HCV is prone to develop resistance to antiviral drugs, and despite considerable efforts to understand the virus for effective treatments, our knowledge remains incomplete. This paper reviews HCV resistance mechanisms, the traditional treatment with and the new standard of care for hepatitis C treatment. Although these new treatments remain PEG-IFN-α- and ribavirin-based, they add one of the newly FDA approved direct antiviral agents, telaprevir or boceprevir. This new “triple therapy” has resulted in greater viral cure rates, although treatment failure remains a possibility. The future may belong to nucleoside/nucleotide analogues, non-nucleoside RNA-dependent RNA polymerase inhibitors, or cyclophilin inhibitors, and the treatment of HCV may ultimately parallel that of HIV. However, research should focus not only on effective treatments, but also on the development of a HCV vaccine, as this may prove to be the most cost-effective method of eradicating this disease.
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Chae, Hee Bok, Seon Mee Park et Sei Jin Youn. « Direct-Acting Antivirals for the Treatment of Chronic Hepatitis C : Open Issues and Future Perspectives ». Scientific World Journal 2013 (2013) : 1–9. http://dx.doi.org/10.1155/2013/704912.

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Currently, two direct-acting antivirals (DAAs) show well-established efficacy against hepatitis C virus (HCV), namely, first-wave protease inhibitors telaprevir and boceprevir. Most clinical trials have examined DAAs in combination with standard of care (SOC) regimens. Future therapeutic drugs were divided into three categories. They are second-wave protease inhibitors, second-generation protease inhibitors, and polymerase inhibitors. Second-wave protease inhibitors are more improved form and can be administered once a day. Oral drug combinations can be favored because interferon (IFN) not only has to be given as intradermal injection, but also can cause several serious side effects. Combination of drugs with different mechanisms shows a good sustained virological response (SVR). But several mutations are associated with viral resistance to DAAs. Therefore, genotypic resistance data may provide insights into strategies aimed at maximizing SVR rates and minimizing resistance. Combined drug regimens are necessary to prevent the emergence of drug-resistant HCV. Many promising DAA candidates have been identified. Of these, a triple regimen containing sofosbuvir shows promise, and treatment with daclatasvir plus asunaprevir yields a high SVR rate (95%). Oral drug combinations will be standard of care in the near future.
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López-Labrador, F. Xavier, Andrés Moya et Fernando Gonzàlez-Candelas. « Mapping Natural Polymorphisms of Hepatitis C virus NS3/4A Protease and Antiviral Resistance to Inhibitors in Worldwide Isolates ». Antiviral Therapy 13, no 4 (mai 2008) : 481–94. http://dx.doi.org/10.1177/135965350801300413.

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Background Several inhibitors for the hepatitis C virus (HCV) NS3/4A protease are under development. Although previous studies identified viral resistance mutations, there is little information on the natural variability of proteases from the different viral subtypes. Here, we aimed to determine both the natural variability and presence of resistance or compensatory mutations to new protease inhibitors (PI) in NS3/4A proteases from worldwide HCV isolates. Methods A comprehensive analysis was performed in 380 HCV NS3 sequences (275 genotype 1; 105 other genotypes) from public HCV databases (EuHCVdb and Los Alamos). Amino acid polymorphism and signature patterns were deduced in the protease domain, including all sites associated with resistance to the PIs BILN-2061, Telaprevir (VX-950), Boceprevir (SCH-503034), SCH-6 and ITMN-191. Results Few of the residues in the catalytic triad or in substrate/metal-binding sites were polymorphic, and were identified in only 4/380 isolates. However, a relevant polymorphism was found in sites associated either with resistance to PI (V36, I170 and D168) or with compensatory mutations (I71, T72, Q86 and I153). Furthermore, some unique genotype-specific signature patterns associated with resistance to PI were also identified. Conclusions We describe for the first time the relevant natural polymorphisms of the HCV NS3/4A protease in worldwide isolates. Although the prevalence of major resistance mutations is very low, many compensatory sites are naturally polymorphic among proteases from several HCV subtypes. These data will help to determine whether HCV resistance is likely to be selected with new PIs and will aid the design of genotypic resistance testing.
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Cuypers, Lize, Pieter Libin, Yoeri Schrooten, Kristof Theys, Velia Chiara Di Maio, Valeria Cento, Maja M. Lunar et al. « Exploring resistance pathways for first-generation NS3/4A protease inhibitors boceprevir and telaprevir using Bayesian network learning ». Infection, Genetics and Evolution 53 (septembre 2017) : 15–23. http://dx.doi.org/10.1016/j.meegid.2017.05.007.

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Salam, Kazi Abdus, et Nobuyoshi Akimitsu. « Hepatitis C Virus NS3 Inhibitors : Current and Future Perspectives ». BioMed Research International 2013 (2013) : 1–9. http://dx.doi.org/10.1155/2013/467869.

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Currently, hepatitis C virus (HCV) infection is considered a serious health-care problem all over the world. A good number of direct-acting antivirals (DAAs) against HCV infection are in clinical progress including NS3-4A protease inhibitors, RNA-dependent RNA polymerase inhibitors, and NS5A inhibitors as well as host targeted inhibitors. Two NS3-4A protease inhibitors (telaprevir and boceprevir) have been recently approved for the treatment of hepatitis C in combination with standard of care (pegylated interferon plus ribavirin). The new therapy has significantly improved sustained virologic response (SVR); however, the adverse effects associated with this therapy are still the main concern. In addition to the emergence of viral resistance, other targets must be continually developed. One such underdeveloped target is the helicase portion of the HCV NS3 protein. This review article summarizes our current understanding of HCV treatment, particularly with those of NS3 inhibitors.
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Macartney, Malcolm J., Dianne Irish, Simon H. Bridge, Ana Garcia-Diaz, Clare L. Booth, Adele L. McCormick, Wendy Labbett et al. « Telaprevir or boceprevir based therapy for chronic hepatitis C infection : Development of resistance-associated variants in treatment failure ». Antiviral Research 105 (mai 2014) : 112–17. http://dx.doi.org/10.1016/j.antiviral.2014.02.019.

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Tornai, István. « A hepatitis C-vírus-bázispolimorfizmus jelentősége a kezelésben ». Orvosi Hetilap 156, no 21 (mai 2015) : 849–54. http://dx.doi.org/10.1556/650.2015.30180.

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The treatment of chronic hepatitis C has developed significantly during the last 25 years. In patients with genotype 1 infection 40–50% sustained virologic response could be achieved using pegylated interferon and ribavirin dual combination, which could be increased significantly with the introduction of direct acting antivirals. Three major groups of direct acting antivirals are known, which directly inhibit different phases of viral life cycle, by inhibiting the function of several non-structural proteins (NS3/4A protease, NS5A protein and NS5B polymerase). Due to the rapid replication rate of hepatitis C virus and the error-prone NS5B polymerase activity, mutant virions are generated, which might have reduced susceptibility to direct acting antiviral therapy. Since these resistance associated variants might exist before the antiviral therapy, they are still able to replicate during the direct acting antiviral treatment. Due to this selection pressure, the resistant virus will replace the wild type. This was especially detected during monotherapy, therefore, the first generation of direct acting antivirals have been combined with pegylated interferon and ribavirin, while recently interferon-free combinations are being developed including 2 or 3 direct acting antivirals. Using the first generation protease inhibitors boceprevir and telaprevir, it could have been seen, that the rate of resistance associated variants is higher and the therapeutic outcome is worse in patients with hepatitis C virus genotype 1a, than in 1b. Similar phenomenon was seen with the second generation of NS3/4A protease inhibitors as well as with NS5A or NS5B polymerase. This is due to the lower genetic barrier to resistance, ie. usually fewer mutations are enough for the emergence of resistance in genotype 1a. The selection of resistance associated variants is one of the most important challenges during the interferon-free therapy. Orv. Hetil., 2015, 156(21), 849–854.
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Summa, Vincenzo, Steven W. Ludmerer, John A. McCauley, Christine Fandozzi, Christine Burlein, Giuliano Claudio, Paul J. Coleman et al. « MK-5172, a Selective Inhibitor of Hepatitis C Virus NS3/4a Protease with Broad Activity across Genotypes and Resistant Variants ». Antimicrobial Agents and Chemotherapy 56, no 8 (21 mai 2012) : 4161–67. http://dx.doi.org/10.1128/aac.00324-12.

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ABSTRACTHCV NS3/4a protease inhibitors are proven therapeutic agents against chronic hepatitis C virus infection, with boceprevir and telaprevir having recently received regulatory approval as add-on therapy to pegylated interferon/ribavirin for patients harboring genotype 1 infections. Overcoming antiviral resistance, broad genotype coverage, and a convenient dosing regimen are important attributes for future agents to be used in combinations without interferon. In this communication, we report the preclinical profile of MK-5172, a novel P2-P4 quinoxaline macrocyclic NS3/4a protease inhibitor currently in clinical development. The compound demonstrates subnanomolar activity against a broad enzyme panel encompassing major hepatitis C virus (HCV) genotypes as well as variants resistant to earlier protease inhibitors. In replicon selections, MK-5172 exerted high selective pressure, which yielded few resistant colonies. In both rat and dog, MK-5172 demonstrates good plasma and liver exposures, with 24-h liver levels suggestive of once-daily dosing. When administered to HCV-infected chimpanzees harboring chronic gt1a or gt1b infections, MK-5172 suppressed viral load between 4 to 5 logs at a dose of 1 mg/kg of body weight twice daily (b.i.d.) for 7 days. Based on its preclinical profile, MK-5172 is anticipated to be broadly active against multiple HCV genotypes and clinically important resistance variants and highly suited for incorporation into newer all-oral regimens.
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Behmard, Esmaeil, et Ebrahim Barzegari. « Insights into resistance mechanism of hepatitis C virus nonstructural 3/4A protease mutant to boceprevir using umbrella sampling simulation study ». Journal of Biomolecular Structure and Dynamics 38, no 7 (31 mai 2019) : 1938–45. http://dx.doi.org/10.1080/07391102.2019.1621212.

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Schaefer, Daniel, et Xinlai Cheng. « Recent Advances in Covalent Drug Discovery ». Pharmaceuticals 16, no 5 (28 avril 2023) : 663. http://dx.doi.org/10.3390/ph16050663.

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In spite of the increasing number of biologics license applications, the development of covalent inhibitors is still a growing field within drug discovery. The successful approval of some covalent protein kinase inhibitors, such as ibrutinib (BTK covalent inhibitor) and dacomitinib (EGFR covalent inhibitor), and the very recent discovery of covalent inhibitors for viral proteases, such as boceprevir, narlaprevir, and nirmatrelvir, represent a new milestone in covalent drug development. Generally, the formation of covalent bonds that target proteins can offer drugs diverse advantages in terms of target selectivity, drug resistance, and administration concentration. The most important factor for covalent inhibitors is the electrophile (warhead), which dictates selectivity, reactivity, and the type of protein binding (i.e., reversible or irreversible) and can be modified/optimized through rational designs. Furthermore, covalent inhibitors are becoming more and more common in proteolysis, targeting chimeras (PROTACs) for degrading proteins, including those that are currently considered to be ‘undruggable’. The aim of this review is to highlight the current state of covalent inhibitor development, including a short historical overview and some examples of applications of PROTAC technologies and treatment of the SARS-CoV-2 virus.
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Susser, Simone, Johannes Vermehren, Nicole Forestier, Martin Walter Welker, Natalia Grigorian, Caterina Füller, Dany Perner, Stefan Zeuzem et Christoph Sarrazin. « Analysis of long-term persistence of resistance mutations within the hepatitis C virus NS3 protease after treatment with telaprevir or boceprevir ». Journal of Clinical Virology 52, no 4 (décembre 2011) : 321–27. http://dx.doi.org/10.1016/j.jcv.2011.08.015.

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Black, S., P. McMonagle, R. Chase, S. Curry, R. J. O. Barnard, D. J. Hazuda, A. Y. Howe, J. A. Howe et R. A. Ogert. « 1198 HCV NS3/4A PROTEASE RESISTANCE-ASSOCIATED VARIANTS (RAVS) IDENTIFIED IN GENOTYPE 1A PATIENTS EXHIBIT DIFFERENCES IN PHENOTYPIC RESISTANCE TO BOCEPREVIR AND TELAPREVIR IN GENOTYPE 1A REPLICON CELLS ». Journal of Hepatology 56 (avril 2012) : S475. http://dx.doi.org/10.1016/s0168-8278(12)61210-0.

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Fonseca-Coronado, S., A. Escobar-Gutierrez, K. Ruiz-Tovar, M. Y. Cruz-Rivera, P. Rivera-Osorio, M. Vazquez-Pichardo, J. C. Carpio-Pedroza, J. A. Ruiz-Pacheco, F. Cazares et G. Vaughan. « Specific Detection of Naturally Occurring Hepatitis C Virus Mutants with Resistance to Telaprevir and Boceprevir (Protease Inhibitors) among Treatment-Naive Infected Individuals ». Journal of Clinical Microbiology 50, no 2 (23 novembre 2011) : 281–87. http://dx.doi.org/10.1128/jcm.05842-11.

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Cento, V., V. C. Di Maio, D. Di Paolo, F. De Luca, V. Micheli, M. Tontodonati, M. C. Bellocchi et al. « 63 CORRELATION OF EARLY DETECTION OF HCV NS3-RESISTANCE AND VIROLOGICAL FAILURE IN PATIENTS TREATED WITH TRIPLE THERAPY INCLUDING TELAPREVIR OR BOCEPREVIR ». Journal of Hepatology 58 (avril 2013) : S29. http://dx.doi.org/10.1016/s0168-8278(13)60065-3.

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Zeuzem, Stefan, Richard J. Barnard, John A. Howe, Robert A. Ogert, Robert Ralston, Navdeep Boparai, Clifford A. Brass et al. « Boceprevir Resistance-Associated Variants (Ravs) Are Observed More Frequently in HCV (GT1)-Infected Patients With Poor Response to Peginterferon Alfa-2B/Ribavirin ». Gastroenterology 140, no 5 (mai 2011) : S—943. http://dx.doi.org/10.1016/s0016-5085(11)63911-5.

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Larrat, Sylvie, Sophie Vallet, Sandra David-Tchouda, Alban Caporossi, Jennifer Margier, Christophe Ramière, Caroline Scholtes et al. « Naturally Occurring Resistance-Associated Variants of Hepatitis C Virus Protease Inhibitors in Poor Responders to Pegylated Interferon-Ribavirin ». Journal of Clinical Microbiology 53, no 7 (29 avril 2015) : 2195–202. http://dx.doi.org/10.1128/jcm.03633-14.

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The pretherapeutic presence of protease inhibitor (PI) resistance-associated variants (RAVs) has not been shown to be predictive of triple-therapy outcomes in treatment-naive patients. However, they may influence the outcome in patients with less effective pegylated interferon (pegIFN)-ribavirin (RBV) backbones. Using hepatitis C virus (HCV) population sequence analysis, we retrospectively investigated the prevalence of baseline nonstructural 3 (NS3) RAVs in a multicenter cohort of poor IFN-RBV responders (i.e., prior null responders or patients with a viral load decrease of <1 log IU/ml during the pegIFN-RBV lead-in phase). The impact of the presence of these RAVs on the outcome of triple therapy was studied. Among 282 patients, the prevalances (95% confidence intervals) of baseline RAVs ranged from 5.7% (3.3% to 9.0%) to 22.0% (17.3% to 27.3%), depending to the algorithm used. Among mutations conferring a >3-fold shift in 50% inhibitory concentration (IC50) for telaprevir or boceprevir, T54S was the most frequently detected mutation (3.9%), followed by A156T, R155K (0.7%), V36M, and V55A (0.35%). Mutations were more frequently found in patients infected with genotype 1a (7.5 to 23.6%) than 1b (3.3 to 19.8%) (P= 0.03). No other sociodemographic or viroclinical characteristic was significantly associated with a higher prevalence of RAVs. No obvious effect of baseline RAVs on viral load was observed. In this cohort of poor responders to IFN-RBV, no link was found with a sustained virological response to triple therapy, regardless of the algorithm used for the detection of mutations. Based on a cross-study comparison, baseline RAVs are not more frequent in poor IFN-RBV responders than in treatment-naive patients and, even in these difficult-to-treat patients, this study demonstrates no impact on treatment outcome, arguing against resistance analysis prior to treatment.
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Zeuzem, S., R. J. Barnard, J. A. Howe, R. A. Ogert, R. Ralston, N. Boparai, C. A. Brass et al. « 9 BOCEPREVIR RESISTANCE-ASSOCIATED VARIANTS (RAVS) ARE OBSERVED MORE FREQUENTLY IN HCV (GT1)-INFECTED PATIENTS WITH POOR RESPONSE TO PEGINTERFERON ALFA-2B/RIBAVIRIN ». Journal of Hepatology 54 (mars 2011) : S4—S5. http://dx.doi.org/10.1016/s0168-8278(11)60011-1.

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Curry, Stephanie, Ping Qiu et Xiao Tong. « Analysis of HCV resistance mutations during combination therapy with protease inhibitor boceprevir and PEG-IFN α-2b using TaqMan mismatch amplification mutation assay ». Journal of Virological Methods 153, no 2 (novembre 2008) : 156–62. http://dx.doi.org/10.1016/j.jviromet.2008.07.020.

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Ogert, Robert A., Patricia Mendez, Janice K. Albrecht, Clifford A. Brass, Jianmin Long, John A. Howe, Robert Ralston, Richard J. Barnard et Daria Hazuda. « Presence of Baseline Boceprevir (Boc) Resistance-Associated Variants (Ravs) Appears Not to Influence Treatment Outcomes in the Majority of Patients Following Boc/PR Treatment ». Gastroenterology 140, no 5 (mai 2011) : S—946. http://dx.doi.org/10.1016/s0016-5085(11)63921-8.

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Gottwein, Judith M., Sanne B. Jensen, Stéphanie B. N. Serre, Lubna Ghanem, Troels K. H. Scheel, Tanja B. Jensen, Henrik Krarup, Nathalie Uzcategui, Lotte S. Mikkelsen et Jens Bukh. « Adapted J6/JFH1-Based Hepatitis C Virus Recombinants with Genotype-Specific NS4A Show Similar Efficacies against Lead Protease Inhibitors, Alpha Interferon, and a Putative NS4A Inhibitor ». Antimicrobial Agents and Chemotherapy 57, no 12 (23 septembre 2013) : 6034–49. http://dx.doi.org/10.1128/aac.01176-13.

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ABSTRACTTo facilitate studies of hepatitis C virus (HCV) NS4A, we aimed at developing J6/JFH1-based recombinants with genotype 1- to 7-specific NS4A proteins. We developed efficient culture systems expressing NS4A proteins of genotypes (isolates) 1a (H77 and TN), 1b (J4), 2a (J6), 4a (ED43), 5a (SA13), 6a (HK6a), and 7a (QC69), with peak infectivity titers of ∼3.5 to 4.5 log10focus-forming units per ml. Except for genotype 2a (J6), growth depended on adaptive mutations identified in long-term culture. Genotype 1a, 1b, and 4a recombinants were adapted by amino acid substitutions F772S (p7) and V1663A (NS4A), while 5a, 6a, and 7a recombinants required additional substitutions in the NS3 protease and/or NS4A. We demonstrated applicability of the developed recombinants for study of antivirals. Genotype 1 to 7 NS4A recombinants showed similar responses to the protease inhibitors telaprevir (VX-950), boceprevir (Sch503034), simeprevir (TMC435350), danoprevir (ITMN-191), and vaniprevir (MK-7009), to alpha interferon 2b, and to the putative NS4A inhibitor ACH-806. The efficacy of ACH-806 was lower than that of protease inhibitors and was not influenced by changes at amino acids 1042 and 1065 (in the NS3 protease), which have been suggested to mediate resistance to ACH-806 in replicons. Genotype 1a, 1b, and 2a recombinants showed viral spread under long-term treatment with ACH-806, without acquisition of resistance mutations in the NS3-NS4A region. Relatively high concentrations of ACH-806 inhibited viral assembly, but not replication, in a single-cycle production assay. The developed HCV culture systems will facilitate studies benefitting from expression of genotype-specific NS4A in a constant backbone in the context of the complete viral replication cycle, including functional studies and evaluations of the efficacy of antivirals.
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Ogert, Robert A., John A. Howe, John M. Vierling, Paul Y. Kwo, Eric J. Lawitz, Jonathan McCone, Eugene R. Schiff et al. « Resistance-associated amino acid variants associated with boceprevir plus pegylated interferon-α2b and ribavirin in patients with chronic hepatitis C in the SPRINT-1 Trial F ». Antiviral Chemistry and Chemotherapy 18, no 3 (2013) : 387–97. http://dx.doi.org/10.3851/imp2549.

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Howe, John A., Ping Qiu, Robert A. Ogert, Patricia Mendez, Clifford A. Brass, Janice K. Albrecht, Robert Ralston, Richard J. Barnard et Daria Hazuda. « Frequencies of Resistance-Associated Amino Acid Variants Detected by 454 Sequencing During Combination Treatment With Boceprevir Plus Pegintron (Peginterferon Alfa-2B)/Ribavirin in HCV (G1)-Infected Patients ». Gastroenterology 140, no 5 (mai 2011) : S—944. http://dx.doi.org/10.1016/s0016-5085(11)63914-0.

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Yau, Alan Hoi Lun, et 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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Howe, J. A., P. Qiu, R. A. Ogert, P. Mendez, C. A. Brass, J. Albrecht, R. Ralston, R. J. O. Barnard et D. Hazuda. « 433 FREQUENCIES OF RESISTANCE-ASSOCIATED AMINO ACID VARIANTS DETECTED BY 454-SEQUENCING DURING COMBINATION TREATMENT WITH BOCEPREVIR PLUS PEGINTRON (PEGINTERFERON ALFA-2B)/RIBAVIRIN IN HCV (GT1)-INFECTED PATIENTS ». Journal of Hepatology 54 (mars 2011) : S176. http://dx.doi.org/10.1016/s0168-8278(11)60435-2.

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Di Maio, V. C., D. Armenia, V. Cento, D. Di Paolo, M. Tontodonati, V. Micheli, M. C. Bellocchi et al. « Does ultra-deep-sequencing in HCV patients treated with boceprevir/telaprevir-based therapy provide an added value in comparison to standard population-sequencing in the detection of resistance ? » Digestive and Liver Disease 46 (février 2014) : e47-e48. http://dx.doi.org/10.1016/j.dld.2014.01.105.

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Kjellin, Midori, Terése Wesslén, Erik Löfblad, Johan Lennerstrand et Anders Lannergård. « The effect of the first-generation HCV-protease inhibitors boceprevir and telaprevir and the relation to baseline NS3 resistance mutations in genotype 1 : experience from a small Swedish cohort ». Upsala Journal of Medical Sciences 123, no 1 (2 janvier 2018) : 50–56. http://dx.doi.org/10.1080/03009734.2018.1441928.

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Makara, Mihály, Gábor Horváth, Judit Gervain, Alajos Pár, Ferenc Szalay, László Telegdy, István Tornai, Eszter Újhelyi et Béla Hunyady. « Hungarian consensus guideline for the diagnosis and treatment of B, C, and D viral hepatitis ». Orvosi Hetilap 153, no 10 (mars 2012) : 375–94. http://dx.doi.org/10.1556/oh.2012.29338.

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More than 1% of the Hungarian population is infected with hepatitis B, C, or D viruses. Since 2006 the diagnostics and therapy of these infections are carried out in treatment centers according to national guidelines – since 2010 according to financial protocols. The consensus-based guidelines for 2012 are published in this paper. The guidelines stress the importance of quick and detailed virologic evaluations, the applicability of transient elastography as an acceptable alternative of liver biopsy in this regard, as well as the relevance of appropriate consistent follow up schedule for viral response during therapy. The first choice of therapy in chronic hepatitis B infection is pegylated interferon for 48 weeks or continuous entecavir therapy. The later must be continued for at least 6 months after hepatitis B surface antigen (HBsAg) seroconversion. Tenofovir disoproxil fumarat is not yet reimbursed by the National Health Insurance Fund. Adefovir dipivoxil is recommended mainly in combination therapy. Lamivudine is no longer a first choice; patients currently taking lamivudine must switch if response is inadequate. Appropriate treatment of patients taking immunosuppressive medications is highly recommended. Pegylated interferon based therapy is recommended for the treatment of concomitant hepatitis D infection. Treatment naive chronic hepatitis C patients should initially receive pegylated interferon and ribavirin dual combination therapy. In genotype 1 infection if response is insufficient at 4 or 12 weeks one of the two new direct acting antivirals (boceprevir or telaprevir) should be added. The length of treatment is usually 48 weeks; in cases of extended early viral response shorter courses are recommended. Previous treatment failure patients with genotype 1 infection should receive a protease inhibitor backed triple combination therapy, mostly for 48 weeks. However, relapsers without cirrhosis and with extended rapid viral response, shorter telaprevir based combination therapy is sufficient. Drug-drug interactions as well as emergence of viral resistance are of particular importance. For genotype 2 or 3 HCV infections 24 weeks, for genotype 4 infections 24, 48 or 72 weeks of pegylated interferon plus ribavirin therapy is recommended in general. The guidelines published here become protocols when published as official publications of the Hungarian Health Authority. Orv. Hetil., 2012, 153, 375–394.
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Howe, John A., Jianmin Long, Stuart Black, Robert Chase, Patricia McMonagle, Stephanie Curry, Seth Thompson, Mark J. DiNubile et Anita Y. M. Howe. « Clinical Implications of Detectable Baseline Hepatitis C Virus-Genotype 1 NS3/4A-Protease Variants on the Efficacy of Boceprevir Combined With Peginterferon/Ribavirin ». Open Forum Infectious Diseases 1, no 2 (2014). http://dx.doi.org/10.1093/ofid/ofu078.

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Abstract Background. We analyzed the impact of pretreatment variants conferring boceprevir-resistance on sustained virologic response (SVR) rates achieved with boceprevir plus peginterferon-α/ribavirin (P/R) for hepatitis C virus (HCV)-genotype-1 infection. Methods. NS3-protease-polymorphisms emerging coincident with virologic failure on boceprevir/P/R regimens were identified as resistance-associated variants (RAVs). Baseline samples pooled from 6 phase II or phase III clinical trials were analyzed for RAVs by population sequencing. Interferon (IFN)-responsiveness was predefined as &gt;1 log reduction in HCV-RNA level during the initial 4-week lead-in treatment with P/R before boceprevir was added. The effective boceprevir-concentration inhibiting RAV growth by 50% (EC50) was determined using a replicon assay relative to the wild-type referent. Results. Sequencing was performed in 2241 of 2353 patients (95.2%) treated with boceprevir. At baseline, RAVs were detected in 178 patients (7.9%), including 153 of 1498 genotype-1a infections (10.2%) and 25 of 742 genotype-1b infections (3.4%) (relative risk, 3.03; 95% confidence interval [CI], [2.01, 4.58]). For IFN-responders, SVR24 (SVR assessed 24 weeks after discontinuation of all study medications) rates were 78% and 76% with or without RAVs detected at baseline, respectively. For the 510 poor IFN-responders, SVR24 rates were 8 of 36 subjects (22.2% [11.7%, 38.1%]) when baseline RAVs were detected vs 174 of 474 subjects (36.7% [32.5%, 41.1%]) when baseline RAVs were not detected (relative likelihood of SVR24 [95% CI], 0.61 [0.32, 1.05]). Sustained virologic response was achieved in 7 of 8 (87.5%) IFN-nonresponders with baseline variants exhibiting ≤2-fold increased EC50 for boceprevir in a replicon assay, whereas only 1 of 15 (7%) IFN-nonresponders with baseline RAVs associated with ≥3-fold increased EC50 achieved SVR. Conclusions. Baseline protease-variants appear to negatively impact SVR rates for boceprevir/P/R regimens only when associated with decreased boceprevir susceptibility in vitro after a poor IFN-response during the lead-in period.
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« P094 : Naturally occuring cross - resistance mutation to boceprevir and telaprevir in a naive chronic hepatitis-C patient : Presentation of a case ». Journal of Viral Hepatitis 22 (juin 2015) : 68. http://dx.doi.org/10.1111/jvh.89_12425.

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