Resistance Mechanisms in Hepatitis C Virus: implications for Direct-Acting Antiviral Use

Bagaglio, Sabrina; Uberti-Foppa, Caterina; Morsica, Giulia

doi:10.1007/s40265-017-0753-x

Cited by 47 publications

(34 citation statements)

References 71 publications

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“…In the recent years, new drugs acting specifically on HCV viral proteins (DAA) have been developed among which are the inhibitors of protease (telaprevir, boceprevir, and simeprevir) and the last approved RNA polymerase inhibitor, sofosbuvir [65]. Since the emergence of drug-resistant HCV variants has been recently described [66], there is an urgent need to identify novel targets for the design of new effective therapeutic strategies. In this context, targeting of redox-sensitive host-cells pathways essential for viral replication and/or persistence may represent a promising option for contrasting HCV infection.…”

mentioning

confidence: 99%

Counteraction of HCV-Induced Oxidative Stress Concurs to Establish Chronic Infection in Liver Cell Cultures

Anticoli

Amatore

Matarrese

et al. 2019

Oxidative Medicine and Cellular Longevity

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Hepatitis C virus (HCV) is a blood-borne pathogen causing acute and chronic hepatitis. A significant number of people chronically infected with HCV develop cirrhosis and/or liver cancer. The pathophysiologic mechanisms of hepatocyte damage associated with chronic HCV infection are not fully understood yet, mainly due to the lack of an in vitro system able to recapitulate the stages of infection in vivo. Several studies underline that HCV virus replication depends on redox-sensitive cellular pathways; in addition, it is known that virus itself induces alterations of the cellular redox state. However, the exact interplay between HCV replication and oxidative stress has not been elucidated. In particular, the role of reduced glutathione (GSH) in HCV replication and infection is still not clear. We set up an in vitro system, based on low m.o.i. of Huh7.5 cell line with a HCV infectious clone (J6/JFH1), that reproduced the acute and persistent phases of HCV infection up to 76 days of culture. We demonstrated that the acute phase of HCV infection is characterized by the elevated levels of reactive oxygen species (ROS) associated in part with an increase of NADPH-oxidase transcripts and activity and a depletion of GSH accompanied by high rates of viral replication and apoptotic cell death. Conversely, the chronic phase is characterized by a reestablishment of reduced environment due to a decreased ROS production and increased GSH content in infected cells that might concur to the establishment of viral persistence. Treatment with the prooxidant auranofin of the persistently infected cultures induced the increase of viral RNA titer, suggesting that a prooxidant state could favor the reactivation of HCV viral replication that in turn caused cell damage and death. Our results suggest that targeting the redox-sensitive host-cells pathways essential for viral replication and/or persistence may represent a promising option for contrasting HCV infection.

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mentioning

confidence: 99%

Counteraction of HCV-Induced Oxidative Stress Concurs to Establish Chronic Infection in Liver Cell Cultures

Anticoli

Amatore

Matarrese

et al. 2019

Oxidative Medicine and Cellular Longevity

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“…The viral serine protease NS3-NS4A is responsible for polyprotein processing and its substrate binding site is blocked by PIs. Substitutions at specific positions conferring different levels of resistance to a certain PI are well described and are genotype/subtype specific (22). Regardless of genotype and exposure to treatment, resistance mutations against DAAs were found in HCV isolates worldwide, as proofed by studies conducted on sequence databases (25,26).…”

Section: Discussionmentioning

confidence: 96%

“…The advent of the new interferon-free DAAs regimens has drastically changed the course of chronic hepatitis C infection, making it a curable disease for an impressive number of patients (>95%) (21). DAAs are targeted against NS3, NS5A, and NS5B viral proteins display different GB and, in some cases, can induce the selection of pre-existing resistance mutants (22). Currently, DAAs are recommended to be administered as double/triple combination regimens, mainly due to the relatively low GB displayed by NS5A and NS3-4A targeting compounds.…”

Section: Discussionmentioning

confidence: 99%

Detection of anti-protease inhibitors resistance mutations in HCV strains infecting treatment-naïve chronic patients from Romania

Dinu

Țârdei

Ceauşu

et al. 2018

Revista Romana De Medicina De Laborator

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Background: Severe complications of chronic hepatitis C -i.e. cirrhosis and hepatocellular carcinoma -are important causes of morbidity and mortality worldwide. Despite the overwhelming rates of sustained virologic response achieved after therapy with different combinations of direct-acting antiviral drugs (DAAs), treatment failure is still recorded, and is due to the mutations harboured by hepatitis C virus (HCV) resistance associated variants (RAVs) selected during therapy. Baseline RAVs testing was found significant for guiding treatment in the cases of treatment failure and, sometimes, in naïve patients.Methods: Romanian chronic hepatitis C patients unexposed to DAAs and infected with subtype 1b HCV were studied. Serum samples were used for Sanger population sequencing of a fragment containing NS3 viral protease, known to harbour resistance mutation against protease inhibitors (PIs).Results: Catalytic triad and zinc-binding site in the studied sequences were conserved. Low-intermediate resistance mutations to first generation PIs were detected either alone or in conjunction with resistance substitutions associated with second generation PIs. Cross-resistance and reduced susceptibility to certain DAAs were observed.Discussion: This study focused on HCV patients infected with subtype 1b strains, the most prevalent in Romania. The rate of RAVs found in this work is consistent with the results reported by similar studies from other countries. Noticeably, numerous polymorphisms of unknown significance to DAAs resistance, but reflecting the

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“…NS5A inhibitors provide a rapid and robust reduction of HCV RNA levels in the clinic, making them a key component in regimens for the treatment of viral infection. Despite their high potency and clinical activity, early NS5A inhibitors exhibited a low barrier to resistance (41,42). A number of single resistance-associated amino acid substitutions, particularly in GT1a, conferred substantial potency losses to the inhibitors (41,(43)(44)(45).…”

Section: Discussionmentioning

confidence: 99%

“…Despite their high potency and clinical activity, early NS5A inhibitors exhibited a low barrier to resistance (41,42). A number of single resistance-associated amino acid substitutions, particularly in GT1a, conferred substantial potency losses to the inhibitors (41,(43)(44)(45). Ruzasvir was designed to achieve pangenotype activity and an improved barrier to resistance compared to earlier compounds.…”

Section: Discussionmentioning

confidence: 99%

In Vitro Antiviral Profile of Ruzasvir, a Potent and Pangenotype Inhibitor of Hepatitis C Virus NS5A

Asante‐Appiah

Liu

Curry

et al. 2018

Antimicrob Agents Chemother

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Inhibition of NS5A has emerged as an attractive strategy to intervene in hepatitis C virus (HCV) replication. Ruzasvir (formerly MK-8408) was developed as a novel NS5A inhibitor to improve upon the potency and barrier to resistance of early compounds. Ruzasvir inhibited HCV RNA replication with 50% effective concentrations (ECs) of 1 to 4 pM in Huh7 or Huh7.5 cells bearing replicons for HCV genotype 1 (GT1) to GT7. The antiviral activity was modestly (10-fold) reduced in the presence of 40% normal human serum. The picomolar potency in replicon cells extended to sequences of clinical isolates available in public databases that were synthesized and tested as replicons. In GT1a, ruzasvir inhibited common NS5A resistance-associated substitutions (RASs), with the exception of M28G. resistance selection studies identified pathways with certain amino acid substitutions at residues 28, 30, 31, and 93 across genotypes. Substitutions at position 93 were more common in GT1 to -4, while changes at position 31 emerged frequently in GT5 and -6. With the exception of GT4, the reintroduction of selected RASs conferred a ≥100-fold potency reduction in the antiviral activity of ruzasvir. Common RASs from other classes of direct-acting antiviral agents (DAAs) did not confer cross-resistance to ruzasvir. The interaction of ruzasvir with an NS3/4A protease inhibitor (grazoprevir) and an NS5B polymerase prodrug (uprifosbuvir) was additive to synergistic, with no evidence of antagonism or cytotoxicity. The antiviral profile of ruzasvir supported its further evaluation in human trials in combination with grazoprevir and uprifosbuvir.

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Resistance Mechanisms in Hepatitis C Virus: implications for Direct-Acting Antiviral Use

Cited by 47 publications

References 71 publications

Counteraction of HCV-Induced Oxidative Stress Concurs to Establish Chronic Infection in Liver Cell Cultures

Counteraction of HCV-Induced Oxidative Stress Concurs to Establish Chronic Infection in Liver Cell Cultures

Detection of anti-protease inhibitors resistance mutations in HCV strains infecting treatment-naïve chronic patients from Romania

In Vitro Antiviral Profile of Ruzasvir, a Potent and Pangenotype Inhibitor of Hepatitis C Virus NS5A

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