NS5A resistance-associated substitutions in patients with genotype 1 hepatitis C virus: Prevalence and effect on treatment outcome

Zeuzem, Stefan; Mizokami, Masashi; Pianko, Stephen; Mangia, Alessandra; Han, Kwang Hyub; Martin, Ross; Svarovskaia, Evguenia; Dvory‐Sobol, Hadas; Doehle, Brian P.; Hedskog, Charlotte; Yun, Chohee; Brainard, Diana M.; Knox, Steven J.; McHutchison, John G.; Miller, Michael D.; Mo, Hongmei; Chuang, Wan‐Long; Jacobson, Ira M.; Dore, Gregory J.; Sulkowski, Mark S.

doi:10.1016/j.jhep.2017.01.007

Cited by 183 publications

(187 citation statements)

References 20 publications

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“…It has been reported that the presence of baseline NS5A RAVs does not impact the treatment outcome in HCV GT1b patients treated with ledipasvir plus sofosbuvir for 12 weeks if they were not previously treated with HCV NS5A inhibitors [21]. Pretreatment ledipasvir-specific RAVs impact the treatment outcome in some patient groups such as treatment-experienced patients with HCV GT1a [22]. …”

Section: Discussionmentioning

confidence: 99%

Real-World Experiences with the Combination Treatment of Ledipasvir plus Sofosbuvir for 12 Weeks in HCV Genotype 1-Infected Japanese Patients: Achievement of a Sustained Virological Response in Previous Users of Peginterferon plus Ribavirin with HCV NS3/4A Inhibitors

Yasui

Nakamura

Suzuki

et al. 2017

IJMS

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The aim of this study was to characterize the treatment response and serious adverse events of ledipasvir plus sofosbuvir therapies in Japanese patients infected with hepatitis C virus (HCV) genotype 1 (GT1). This retrospective study analyzed 240 Japanese HCV GT1 patients treated for 12 weeks with 90 mg of ledipasvir plus 400 mg of sofosbuvir daily. Sustained virological response at 12 weeks post-treatment (SVR12) was achieved in 236 of 240 (98.3%) patients. Among treatment-naïve patients, SVR12 was achieved in 136 of 138 (98.6%) patients, and among treatment-experienced patients, SVR12 was achieved in 100 of 102 (98.0%) patients. In patients previously treated with peginterferon plus ribavirin with various HCV NS3/4A inhibitors, 100% SVR rates (25/25) were achieved. Two relapsers had HCV NS5A resistance-associated variants (RAVs), but no HCV NS5B-S282 was observed after they relapsed. We experienced two patients with cardiac events during treatment. In conclusion, combination of ledipasvir plus sofosbuvir for 12 weeks is a potential therapy for HCV GT1 patients. Caution is needed for HCV NS5A RAVs, which were selected by HCV NS5A inhibitors and cardiac adverse events.

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Section: Discussionmentioning

confidence: 99%

Real-World Experiences with the Combination Treatment of Ledipasvir plus Sofosbuvir for 12 Weeks in HCV Genotype 1-Infected Japanese Patients: Achievement of a Sustained Virological Response in Previous Users of Peginterferon plus Ribavirin with HCV NS3/4A Inhibitors

Yasui

Nakamura

Suzuki

et al. 2017

IJMS

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“…From these studies, particularly in the highly prevalent GT1, certain amino acid positions in NS3 and NS5A have been identified to be associated with the emergence of resistance. For example, the presence of resistance-associated substitutions in NS5A can in part account for lower response rates, particularly in GT1a (21,22). Since there is limited information on the prevalence and impact of NS3 and NS5A amino acid substitutions coupled with a dearth of knowledge on the contribution of GT4 subtypes to disease progression and clinical response, the activities of elbasvir, an NS5A inhibitor, and grazoprevir, an NS3/4A inhibitor, were investigated in GT4 clinical isolates prior to commencing clinical studies.…”

Section: Discussionmentioning

confidence: 99%

Antiviral Activity and Resistance Analysis of NS3/4A Protease Inhibitor Grazoprevir and NS5A Inhibitor Elbasvir in Hepatitis C Virus GT4 Replicons

Asante‐Appiah

Curry

McMonagle

et al. 2017

Antimicrob Agents Chemother

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Although genotype 4 (GT4)-infected patients represent a minor overall percentage of the global hepatitis C virus (HCV)-infected population, the high prevalence of the genotype in specific geographic regions coupled with substantial sequence diversity makes it an important genotype to study for antiviral drug discovery and development. We evaluated two direct-acting antiviral agents-grazoprevir, an HCV NS3/4A protease inhibitor, and elbasvir, an HCV NS5A inhibitor-in GT4 replicons prior to clinical studies in this genotype. Following a bioinformatics analysis of available GT4 sequences, a set of replicons bearing representative GT4 clinical isolates was generated. For grazoprevir, the 50% effective concentration (EC 50 ) against the replicon bearing the reference GT4a (ED43) NS3 protease and NS4A was 0.7 nM. The median EC 50 for grazoprevir against chimeric replicons encoding NS3/4A sequences from GT4 clinical isolates was 0.2 nM (range, 0.11 to 0.33 nM; n ϭ 5). The difficulty in establishing replicons bearing NS3/4A resistance-associated substitutions was substantially overcome with the identification of a G162R adaptive substitution in NS3. Single NS3 substitutions D168A/V identified from de novo resistance selection studies reduced grazoprevir antiviral activity by 137-and 47-fold, respectively, in the background of the G162R replicon. For elbasvir, the EC 50 against the replicon bearing the reference full-length GT4a (ED43) NS5A gene was 0.0002 nM. The median EC 50 for elbasvir against chimeric replicons bearing clinical isolates from GT4 was 0.0007 nM (range, 0.0002 to 34 nM; n ϭ 14). De novo resistance selection studies in GT4 demonstrated a high propensity to suppress the emergence of amino acid substitutions that confer high-potency reductions to elbasvir. Phenotypic characterization of the NS5A amino acid substitutions identified (L30F, L30S, M31V, and Y93H) indicated that they conferred 15-, 4-, 2.5-, and 7.5-fold potency losses, respectively, to elbasvir. The activity profiles of grazoprevir and elbasvir supported the testing of the direct-acting antivirals in clinical studies.KEYWORDS HCV, genotype 4, resistance, antiviral, elbasvir, grazoprevir, NS5A, NS3/4A, antiviral agents, drug resistance mechanisms, hepatitis C virus H epatitis C virus (HCV) is a leading cause of chronic liver disease, with an estimated 170 million people infected globally (1, 2). The World Health Organization estimates that more than 350,000 people die every year from hepatitis C-related liver diseases (3). Approximately 20% of individuals chronically infected with HCV can be expected to develop liver cirrhosis and, of these, 6% will decompensate to end-stage liver disease, with an additional 4% developing hepatocellular carcinoma. A number of treatment options are now available with combinations of interferon-free direct-acting

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“…Consequently, GT1a replicons likely require higher levels of drug pressure to effectively inhibit replication, despite the synergistic interactions between DAAs. Additionally, DAAs (particularly the NS3/4a protease inhibitors and NS5A inhibitors) often have a lower genetic barrier to resistance for GT1a HCV, resulting in higher frequencies of HCV harboring resistance-associated variants (RAVs) (Sarrazin et al, 2016; Zeuzem et al, 2017). These RAVs have been shown to significantly reduce the susceptibility of GT1a HCV to DAA treatment; however, the impact of RAVs on the susceptibility of GT1b HCV is substantially lower (Liu et al, 2015; Sarrazin et al, 2016; Zeuzem et al, 2017).…”

Section: Short Communicationmentioning

confidence: 99%

Searching for synergy: Identifying optimal antiviral combination therapy using Hepatitis C virus (HCV) agents in a replicon system

et al. 2017

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Direct acting antiviral agents (DAAs) are potent inhibitors of Hepatitis C virus (HCV) that have revolutionized the treatment landscape for this important viral disease. There are currently four classes of DAAs that inhibit HCV replication via distinct mechanisms of action: nonstructural protein (NS) 3/4a protease inhibitors, NS5A inhibitors, NS5B nucleoside polymerase inhibitors, and NS5B non-nucleoside polymerase inhibitors. Combination therapy with two or more DAAs has great potential to further enhance antiviral potency. The purpose of this study was to identify optimal combinations of DAAs against genotype 1 HCV replicons that maximized the inhibition of replicon replication. All possible two-drug combinations were evaluated against genotype 1a and 1b HCV replicons using a 96-well plate luciferase-based assay in triplicate. The Greco Universal Response Surface Area mathematical model was fit to the luciferase data to identify drug-drug interactions (i.e.: synergy, additivity, and antagonism) for antiviral effect against both genotypes. This information was used to rank-order combinations of DAAs based on their ability to inhibit replicon replication against genotype 1a and 1b HCV. These preclinical findings can provide information as to which antiviral regimens should move on in the development process.

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NS5A resistance-associated substitutions in patients with genotype 1 hepatitis C virus: Prevalence and effect on treatment outcome

Cited by 183 publications

References 20 publications

Real-World Experiences with the Combination Treatment of Ledipasvir plus Sofosbuvir for 12 Weeks in HCV Genotype 1-Infected Japanese Patients: Achievement of a Sustained Virological Response in Previous Users of Peginterferon plus Ribavirin with HCV NS3/4A Inhibitors

Real-World Experiences with the Combination Treatment of Ledipasvir plus Sofosbuvir for 12 Weeks in HCV Genotype 1-Infected Japanese Patients: Achievement of a Sustained Virological Response in Previous Users of Peginterferon plus Ribavirin with HCV NS3/4A Inhibitors

Antiviral Activity and Resistance Analysis of NS3/4A Protease Inhibitor Grazoprevir and NS5A Inhibitor Elbasvir in Hepatitis C Virus GT4 Replicons

Searching for synergy: Identifying optimal antiviral combination therapy using Hepatitis C virus (HCV) agents in a replicon system

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