Dynamic Hepatitis C Virus Genotypic and Phenotypic Changes in Patients Treated With the Protease Inhibitor Telaprevir

Sarrazin, Christoph; Kieffer, Tara L.; Bartels, Doug J.; Hanzelka, Brian L.; Müh, Ute; Welker, Martin; Wincheringer, Dennis; Zhou, Yi; Chu, Hui‐May; Lin, Chao; Weegink, Christine J.; Reesink, H. W.; Zeuzem, Stefan; Kwong, Ann D.

doi:10.1053/j.gastro.2007.02.037

Cited by 573 publications

(638 citation statements)

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“…HCV NS3/4A PIs have been shown to rapidly select for the emergence of resistance mutations when administered as monotherapy. 10,12 Therefore, the effect of 3 days of pretreatment of patients with PegIFN and RBV before adding faldaprevir was assessed directly by comparing 240 mg QD dose groups with or without LI. The rationale was that the short delay of the first intake of faldaprevir would prevent the possibility of functional PI monotherapy.…”

Section: Discussionmentioning

confidence: 99%

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Faldaprevir combined with pegylated interferon alfa-2a and ribavirin in treatment-naïve patients with chronic genotype1 HCV: SILEN-C1 trial

et al. 2013

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Faldaprevir (BI 201335) is a potent, hepatitis C virus (HCV) NS3/4A protease inhibitor with pharmacokinetic properties supportive of once-daily (QD) dosing. Four hundred and twenty-nine HCV genotype (GT)-1 treatment-naïve patients without cirrhosis were randomized 1:1:2:2 to receive 24 weeks of pegylated interferon alfa-2a and ribavirin (PegIFN/RBV) in combination with placebo, faldaprevir 120 mg QD with 3 days of PegIFN/RBV lead-in (LI), 240 mg QD with LI, or 240 mg QD without LI, followed by an additional 24 weeks of PegIFN/RBV. Patients in the 240 mg QD groups achieving maintained rapid virologic response (mRVR; viral load [VL] <25 IU/mL at week 4 and undetectable at weeks 8-20) were rerandomized to cease all treatment at week 24 or continue receiving PegIFN/RBV up to week 48. VL was measured by Roche TaqMan. Sustained virologic response (SVR) rates were 56%, 72%, 72%, and 84% in the placebo, faldaprevir 120 mg QD/LI, 240 mg QD/LI, and 240 mg QD groups. Ninety-two percent of mRVR patients treated with faldaprevir 240 mg QD achieved SVR, irrespective of PegIFN/RBV treatment duration. Eighty-two percent of GT-1a patients who received faldaprevir 240 mg QD achieved SVR versus 47% with placebo. Mild gastrointestinal disorders, jaundice resulting from isolated unconjugated hyperbilirubinemia, and rash or photosensitivity were more common in the active groups than with placebo. Discontinuations resulting from adverse events occurred in 4%, 11%, and 5% of patients treated with 120 mg QD/LI, 240 mg QD/LI, and 240 mg QD of faldaprevir versus 1% with placebo. Conclusion: Faldaprevir QD with PegIFN/RBV achieved consistently high SVR rates with acceptable tolerability and safety at all dose levels. The 120 and 240 mg QD doses are currently undergoing phase 3 evaluation. (HEPATOLOGY 2013;57:2143-2154

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Section: Discussionmentioning

confidence: 99%

“…Plasma HCV RNA levels were measured using the Roche COBAS TaqMan HCV/HPS assay (Roche, Pleasanton, CA), at a central laboratory, at the time of screening and during the treatment period at days 1 and 4 and weeks 1,2,4,8,10,12,16,20,24,28,36, and 48. The LLOQ was 25 IU/mL, and the LLOD was 17 IU/mL.…”

Section: Efficacy Assessmentsmentioning

confidence: 99%

Faldaprevir combined with pegylated interferon alfa-2a and ribavirin in treatment-naïve patients with chronic genotype1 HCV: SILEN-C1 trial

et al. 2013

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“…6 Informed written consent was obtained from all patients. HCV RNA levels were determined using the Roche Cobas TaqMan HCV Test, v2.0 (lower limit of quantification, 25 IU/mL; lower limit of detection, 10 IU/mL; Roche, Pleasanton, CA) at baseline and days 1 (2,4,6,8,12,16, and 20 hours post-first dose), 2,3,4,5,7,9,11,14,15,16,17,21, and 28. Viral breakthrough was defined as an HCV RNA increase by at least 0.5 log 10 after HCV RNA nadir while receiving BMS-790052.…”

Section: Methodsmentioning

confidence: 99%

“…A slow second phase of viral decline or a slight viral rebound was observed at later time points, consistent with an accumulation of resistant variants and suggesting the adaptation or selection of resistant variants with enhanced fitness. The emergence of resistance suggests that BMS-790052, like NS3 protease inhibitors 12 and NS5B polymerase allosteric inhibitors, 13 may have a low genetic barrier for resistance. Only a single-nucleotide change (UAU or UAC to AAU or AAC) at residue 93 (Tyr to Asn) of genotype 1a NS5A is required for HCV to acquire clinical resistance to BMS-790052 (Table 2).…”

Section: Methodsmentioning

confidence: 99%

Genotypic and phenotypic analysis of variants resistant to hepatitis C virus nonstructural protein 5A replication complex inhibitor BMS-790052 in Humans: In Vitro and In Vivo Correlations

et al. 2011

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The NS5A replication complex inhibitor, BMS-790052, inhibits hepatitis C virus (HCV) replication with picomolar potency in preclinical assays. This potency translated in vivo to a substantial antiviral effect in a single-ascending dose study and a 14-day multiple-ascending dose (MAD) monotherapy study. However, HCV RNA remained detectable in genotype 1a-infected patients at the end of the MAD study. In contrast, viral breakthrough was observed less often in patients infected with genotype 1b, and, in several patients, HCV RNA declined and remained below the level of quantitation (<25 IU/mL) through the duration of treatment. Here, we report on the results of the genotypic and phenotypic analyses of resistant variants in 24 genotype 1-infected patients who received BMS-790052 (1, 10, 30, 60, and 100 mg, once-daily or 30 mg twice-daily) in the 14-day MAD study. Sequence analysis was performed on viral complementary DNA isolated from serum specimens collected at baseline and days 1 (4, 8, and 12 hours), 2, 4, 7, and 14 postdosing. Analyses of the sequence variants (1) established a correlation between resistant variants emerging in vivo with BMS-790052 treatment and those observed in the in vitro replicon system (major substitutions at residues 28, 30, 31, and 93 for genotype 1a and residues 31 and 93 for genotype 1b); (2) determined the prevalence of variants at baseline and the emergence of resistance at different times during dosing; and (3) revealed the resistance profile and replicative ability (i.e., fitness) of the variants. Conclusion: Although resistance emerged during monotherapy with BMS-790052, the substantial anti-HCV effect of this compound makes it an excellent candidate for effective combination therapy. (HEPATOLOGY 2011;54:1924-1935 T he hepatitis C virus (HCV) nonstructural protein 5A (NS5A) is a multifunctional protein with key roles in HCV replication. NS5A has also been implicated in the modulation of cellular signaling pathways. 1,2 Because it is required in vivo and in vitro for viral replication and has no known human homologs, NS5A provides an attractive target for therapeutic intervention. 3 BMS-790052 is a potent HCV NS5A replication complex inhibitor, with 50% effective concentration (EC 50 ) values of 9 and 50 pM against genotype 1b and 1a replicons, respectively. 4,5 It is also potent against live virus (genotype 2a, JFH-1), with an EC 50 of $28 pM. 4 BMS-790052 has broad genotype coverage, with EC 50 values ranging from pM to low nM for replicons with NS5A sequences derived from genotype 2a, 3a, 4a, and 5a. 4

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“…[13][14][15] In HCV genotype 1-infected patients, the use of telaprevir was associated with the emergence of resistant variants at NS3 amino acid positions 36, 54, 155, and 156. 13,15,16 In addition to these positions, the use of boceprevir has been associated with the emergence of resistance at positions 55 and 170. 14 Here we report the findings from a subanalysis of the Phase 3 telaprevir REALIZE trial, in which treatment outcomes and the emergence of viral variants were further characterized in patients with prior peginterferon/ribavirin treatment failure who did not achieve an SVR with subsequent telaprevir-based therapy.…”

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confidence: 99%

Characterization of telaprevir treatment outcomes and resistance in patients with prior treatment failure: Results from the REALIZE trial

et al. 2012

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In the Phase 3 REALIZE study, 662 genotype 1 hepatitis C virus (HCV)-infected patients with prior peginterferon/ribavirin treatment failure (including relapsers, partial, and null responders) were randomized to 12 weeks of telaprevir given immediately (T12/PR48) or following 4 weeks of peginterferon/ribavirin (lead-in T12/PR48), or 12 weeks of placebo (PR48), combined with a total of 48 weeks of peginterferon alfa-2a/ribavirin. Sustained virologic response (SVR) rates were 64% (T12/PR48), 66% (lead-in T12/PR48), and 17% (PR48). This analysis aimed to characterize treatment outcomes and viral variants emerging in telaprevir-treated patients not achieving SVR. HCV NS3Á4A population sequencing was performed at baseline, during treatment, and follow-up. Telaprevir-resistant variants were classified into lower-level (3-to 25-fold 50% inhibitory concentration [IC 50 ] increase: V36A/M, T54A/S, R155I/K/M/T, and A156S) and higher-level (>25-fold IC 50 increase: V36M1R155K and A156T/V) resistance. Resistant variants were uncommon at baseline. Overall, 18% (52%, 19%, and 1% of prior null and partial responders and relapsers, respectively) of telaprevir-treated patients had on-treatment virologic failure, with no significant difference with or without a lead-in. Virologic failure during the telaprevir-treatment phase was predominantly associated with higher-level resistance; virologic failure during the peginterferon/ribavirin-treatment phase was associated with higher-or lower-level, or wildtype variants, depending on genotype. Relapse occurred in 9% of patients completing assigned treatment and was generally associated with lower-level resistant variants or wildtype. Resistant variants were no longer detectable by study end (median follow-up of 11 months) in 58% of non-SVR patients. Conclusion: In REALIZE, variants emerging in non-SVR, telaprevir-treated patients were similar irrespective of the use of a lead-in and were consistent with those previously reported. In most patients, resistant variants became undetectable over time. (HEPATOLOGY 2012;56:2106-2115

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Dynamic Hepatitis C Virus Genotypic and Phenotypic Changes in Patients Treated With the Protease Inhibitor Telaprevir

Cited by 573 publications

References 36 publications

Faldaprevir combined with pegylated interferon alfa-2a and ribavirin in treatment-naïve patients with chronic genotype1 HCV: SILEN-C1 trial

Faldaprevir combined with pegylated interferon alfa-2a and ribavirin in treatment-naïve patients with chronic genotype1 HCV: SILEN-C1 trial

Genotypic and phenotypic analysis of variants resistant to hepatitis C virus nonstructural protein 5A replication complex inhibitor BMS-790052 in Humans: In Vitro and In Vivo Correlations

Characterization of telaprevir treatment outcomes and resistance in patients with prior treatment failure: Results from the REALIZE trial

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