Characterization of NS5A polymorphisms and their impact on response rates in patients with HCV genotype 2 treated with daclatasvir-based regimens

Zhou, Nannan; Han, Zhou; Hartman-Neumann, Sandra; DeGray, Brenda; Ueland, Joseph; Vellucci, Vincent F.; Hernandez, Dennis; McPhee, Fiona

doi:10.1093/jac/dkw336

Cited by 23 publications

(20 citation statements)

References 48 publications

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“…However, the NS5A F28C polymorphism was only detected in patients infected with subtype 2c, and 11 of 18 GT2c‐infected patients carried this polymorphism at baseline. Similarly, in studies with daclatasvir the NS5A polymorphism F28C was predominantly observed in patients infected with subtype 2c . Although the presence of NS5A F28C in a GT2a replicon was found to reduce the in vitro activity of daclatasvir and ledipasvir, baseline presence of this polymorphism in GT2c‐infected patients did not appear to affect the outcome to the daclatasvir‐based regimens studied .…”

Section: Discussionmentioning

confidence: 86%

JNJ‐4178 (AL‐335, Odalasvir, and Simeprevir) for 6 or 8 Weeks in Hepatitis C Virus‐Infected Patients Without Cirrhosis: OMEGA‐1

Zeuzem

Bourgeois

Greenbloom³

et al. 2019

Hepatology

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The combination of three direct‐acting antiviral agents (AL‐335, odalasvir, and simeprevir: JNJ‐4178 regimen) for 6 or 8 weeks demonstrated good efficacy and safety in a phase IIa study in chronic hepatitis C virus (HCV) genotype (GT)‐1‐infected patients without cirrhosis and has now been evaluated in a larger phase IIb study, OMEGA‐1. This multicenter, randomized, open‐label study (NCT02765490) enrolled treatment‐naïve and interferon (±ribavirin) treatment‐experienced patients with HCV GT1, 2, 4, 5, or 6 infection. Patients with HCV GT3 infection and/or liver cirrhosis were excluded. Patients received AL‐335 800 mg, odalasvir 25 mg, and simeprevir 75 mg once daily for 6 or 8 weeks. The primary endpoint was sustained virologic response 12 weeks after the end of treatment (SVR12). In total, 365 patients (GT1a, 29.3%; GT1b, 42.5%; GT2, 12.3%; GT4, 14.2%; GT5, 1.4%; GT6, 0%) were randomized to receive 6 weeks (n = 183) or 8 weeks (n = 182) of treatment. SVR12 rates after 6 weeks (98.9%) or 8 weeks (97.8%) of treatment were noninferior to a historical control (98%). Viral relapse occurred in 5 patients (1.4%; 4 with HCV GT2c; 1 with GT1a). With the exception of 4 patients in the 8‐week group, including 3 patients with missing data at the SVR24 timepoint, all patients who achieved SVR12 also achieved SVR24. One GT1a‐infected patient experienced late viral relapse after achieving SVR18. Most adverse events (AEs) were mild with no treatment‐related serious AEs. All randomized patients completed treatment. Conclusion: In HCV‐infected patients, 6 and 8 weeks of treatment with JNJ‐4178 resulted in SVR12 rates of 98.9% and 97.8%, respectively, and was well tolerated.

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Section: Discussionmentioning

confidence: 86%

JNJ‐4178 (AL‐335, Odalasvir, and Simeprevir) for 6 or 8 Weeks in Hepatitis C Virus‐Infected Patients Without Cirrhosis: OMEGA‐1

Zeuzem

Bourgeois

Greenbloom³

et al. 2019

Hepatology

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“…Some of these samples had amino acid polymorphisms within the NS5A N-terminal region at positions associated with resistance to some NS5A inhibitors (10, 13, 14). For example, methionine (M) and leucine (L) are commonly seen at NS5A amino acid position 31 of genotype 2; genotype 2a and 2b samples with NS5A M31 are less susceptible to daclatasvir, ledipasvir, and elbasvir than those with L31 (23, 26). In the panel of patient samples that we analyzed, 5/6 of the genotype 2a and 4/11 of the genotype 2b samples had M31 in NS5A.…”

Section: Resultsmentioning

confidence: 99%

“…Ledipasvir has EC 50 s of 4 to 31 pM for genotype 1 but has reduced potency against other genotypes, especially for genotypes 2a and 3a (EC 50 s, ≥16,000 pM) (20). Genotype 2 with the common NS5A M31 polymorphism is less susceptible to daclatasvir than genotype 2 with NS5A L31 (genotype 2a with M31, EC 50 of 6,700 pM; genotype 2b with M31, EC 50 of 64,000 pM) (26). Genotype 2b with the NS5A M31 polymorphism is also less susceptible to elbasvir (EC 50 , 3,000 pM) than genotype 2b with L31 (23).…”

Section: Discussionmentioning

confidence: 99%

“…Among the non-genotype 1 substitutions tested, Y93H in genotype 3a confers a high level of resistance (20- to >2,500-fold) to other NS5A inhibitors (daclatasvir, ledipasvir, ombitasvir, elbasvir, and velpatasvir) (21, 22, 25, 28, 31) but has little impact on the potency of pibrentasvir (2.3-fold increase in EC 50 ). In addition, the common genotype 2 polymorphism M31, which confers resistance to daclatasvir, ledipasvir, and elbasvir, as discussed above (23, 24, 26), has no impact on the activity of pibrentasvir.…”

Section: Discussionmentioning

confidence: 99%

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In Vitro Antiviral Activity and Resistance Profile of the Next-Generation Hepatitis C Virus NS5A Inhibitor Pibrentasvir

Krishnan

Pilot‐Matias

et al. 2017

Antimicrob Agents Chemother

128

142

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Pibrentasvir (ABT-530) is a novel and pan-genotypic hepatitis C virus (HCV) NS5A inhibitor with 50% effective concentration (EC50) values ranging from 1.4 to 5.0 pM against HCV replicons containing NS5A from genotypes 1 to 6. Pibrentasvir demonstrated similar activity against a panel of chimeric replicons containing HCV NS5A of genotypes 1 to 6 from clinical samples. Resistance selection studies were conducted using HCV replicon cells with NS5A from genotype 1a, 1b, 2a, 2b, 3a, 4a, 5a, or 6a at a concentration of pibrentasvir that was 10- or 100-fold over its EC50 for the respective replicon. With pibrentasvir at 10-fold over the respective EC50, only a small number of colonies (0.00015 to 0.0065% of input cells) with resistance-associated amino acid substitutions were selected in replicons containing genotype 1a, 2a, or 3a NS5A, and no viable colonies were selected in replicons containing NS5A from other genotypes. With pibrentasvir at 100-fold over the respective EC50, very few colonies (0.0002% of input cells) were selected by pibrentasvir in genotype 1a replicon cells while no colonies were selected in other replicons. Pibrentasvir is active against common resistance-conferring substitutions in HCV genotypes 1 to 6 that were identified for other NS5A inhibitors, including those at key amino acid positions 28, 30, 31, or 93. The combination of pibrentasvir with HCV inhibitors of other classes produced synergistic inhibition of HCV replication. In summary, pibrentasvir is a next-generation HCV NS5A inhibitor with potent and pan-genotypic activity, and it maintains activity against common amino acid substitutions of HCV genotypes 1 to 6 that are known to confer resistance to currently approved NS5A inhibitors.

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“…In Gt 2a, HCV-NS5A F28S, L31M, C92R, and Y93H are the major resistance mutations described 42. Zhou et al 43. evaluated NS5A polymorphisms and their impact on response rates in patients with Gt 2 infection who were treated with DCV-based regimens.…”

Section: Onset Of Resistance: a Real Clinical Problem?mentioning

confidence: 99%

Efficacy and Safety of Daclatasvir in Hepatitis C: An Overview

2016

JCTH

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Hepatitis C virus (HCV) infection is a growing public health concern, with 184 million people infected worldwide. During the past decade, interferon has been the backbone of HCV treatment, even though it remains far from ideal. The latest development of the new direct antivirals has drastically changed the treatment approach for chronic hepatitis C (CHC). Inhibitors of the HCV NS5A region have garnered remarkable interest among treating physicians, due to their high potency and favourable safety profile. In particular, treatment with daclatasvir (DCV) has yielded high rates of vriologic response in patients infected with genotype (Gt) 1 and Gt 3, when used in combination with other antivirals of a different class, such as sofosbuvir. Although few data are available for DCV treatment of the other Gts, the results in patients with Gt 2 and Gt 4 infection appear promising, as do those for unique patient populations. NS5A-resistant viral variants can pre-exist or emerge after treatment failure for the HCV NS5A inhibitors. Nonetheless, DCV-resistant viral variants continue to be sensitive to interferon and other classes of antivirals such as NS3/4A and NS5B inhibitors. Herein, we aimed to provide an overview of the current knowledge about DCV in the treatment of CHC.

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Characterization of NS5A polymorphisms and their impact on response rates in patients with HCV genotype 2 treated with daclatasvir-based regimens

Abstract: High SVR rates were achieved in patients infected with GT2 treated with daclatasvir-based regimens irrespective of GT2 subtype or baseline NS5A polymorphisms.

Cited by 23 publications

References 48 publications

JNJ‐4178 (AL‐335, Odalasvir, and Simeprevir) for 6 or 8 Weeks in Hepatitis C Virus‐Infected Patients Without Cirrhosis: OMEGA‐1

JNJ‐4178 (AL‐335, Odalasvir, and Simeprevir) for 6 or 8 Weeks in Hepatitis C Virus‐Infected Patients Without Cirrhosis: OMEGA‐1

In Vitro Antiviral Activity and Resistance Profile of the Next-Generation Hepatitis C Virus NS5A Inhibitor Pibrentasvir

Efficacy and Safety of Daclatasvir in Hepatitis C: An Overview

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