Detection of Hepatitis C Virus Resistant Mutants in the era of Direct Acting Antivirals

AbstractRecent emergence of direct acting antivirals (DAAs) targeting hepatitis C virus (HCV) proteins has considerably enhanced the success of antiviral therapy. However, the appearance of DAA resistant-associated variants is a cause of treatment failure, and the high cost of DAAs renders the therapy not accessible in countries with inadequate medical infrastructures. Therefore, search for new inhibitors and with lower cost of production should be pursued. In this context, crude extract ofJuncus maritimusLam. was shown to exhibit high antiviral activity against HCV in cell culture. Bio-guided fractionation allowed isolating and identifying the active compound, dehydrojuncusol. A time-of-addition assay showed that dehydrojuncusol significantly inhibited HCV infection when added after virus inoculation of HCV genotype 2a (EC50= 1.35 µM). This antiviral activity was confirmed with a HCV subgenomic replicon and no effect on HCV pseudoparticle entry was observed. Antiviral activity of dehydrojuncusol was also demonstrated in primary human hepatocytes. Noin vitrotoxicity was observed at active concentrations. Dehydrojuncusol is also efficient on HCV genotype 3a and can be used in combination with sofosbuvir. Interestingly, dehydrojuncusol was able to inhibit replication of two frequent daclatasvir resistant mutants (L31M or Y93H in NS5A). Finally, resistant mutants to dehydrojuncusol were obtained and showed that HCV NS5A protein is the target of the molecule. In conclusion, dehydrojuncusol, a natural compound extracted fromJ. maritimus, inhibits infection of different HCV genotypes by targeting NS5A protein and is active against HCV resistant variants frequently found in patients with treatment failure.ImportanceTens of millions of people are infected with hepatitis C virus (HCV) worldwide. Recently marketed direct acting antivirals (DAAs) targeting HCV proteins have enhanced the efficacy of the treatment. However, due to its high cost, this new therapy is not accessible to the vast majority of infected patients. Furthermore, treatment failures have also been reported due to appearance of viral resistance. Here we report on the identification of a new HCV inhibitor, dehydrojuncusol that targets HCV NS5A and is able to inhibit replication of replicons harboring resistance mutations to anti-NS5A DAAs used in current therapy. Dehydrojuncusol is a natural compound isolated fromJuncus maritimus, a halophilic plant species very common in the coastlines worldwide. This molecule might serve as a lead for the development of new therapy more accessible to hepatitis C patients in the future.

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Faculty Opinions recommendation of Is there a role for ribavirin in the era of hepatitis C virus direct-acting antivirals?

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.716298015.791652971 ◽

2012 ◽

Author(s):

Varun Garg

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Direct Acting Antivirals ◽

Direct Acting

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Faculty Opinions recommendation of Characterization of virologic escape in hepatitis C virus genotype 1b patients treated with the direct-acting antivirals daclatasvir and asunaprevir.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.717969197.793470534 ◽

2013 ◽

Author(s):

Cihan Yurdaydin

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Direct Acting Antivirals ◽

Virus Genotype ◽

Genotype 1B ◽

Direct Acting

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Real-world efficacy and safety of pangenotypic direct-acting antivirals against hepatitis C virus infection in Taiwan

Scientific Reports ◽

10.1038/s41598-021-93095-x ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Kao-Chi Chang ◽

Shui-Yi Tung ◽

Kuo-Liang Wei ◽

Chen-Heng Shen ◽

Yung-Yu Hsieh ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Real World ◽

Population Analysis ◽

Virologic Response ◽

Efficacy And Safety ◽

Hepatitis C Virus Infection ◽

Direct Acting Antivirals ◽

Evaluable Population ◽

Direct Acting

AbstractClinical trials showed pangenotypic direct-acting antivirals’ (DAAs) excellent efficacy and safety when treating hepatitis C virus (HCV). Two pangenotypic regimens were examined, glecaprevir/pibrentasvir (GLE/PIB) and sofosbuvir/velpatasvir (SOF/VEL), in a real-world Taiwanese setting, including all HCV patients treated with GLE/PIB or SOF/VEL from August 2018 to April 2020. The primary endpoint was sustained virologic response 12 weeks after treatment cessation (SVR12), including adverse events (AEs). A total of 1,356 HCV patients received pangenotypic DAA treatment during the study: 742 and 614 received GLE/PIB and SOF/VEL, respectively. The rates of SVR12 for GLE/PIB and SOF/VEL were 710/718 (98.9%) and 581/584 (99.5%), respectively, by per-protocol analysis, and 710/742 (95.7%) and 581/614 (94.6%), respectively, by evaluable population analysis. Eleven (GLE/PIB: 8, SOF/VEL: 3) did not achieve SVR12. The most common AEs for GLE/PIB and SOF/VEL were pruritus (17.4% vs. 2.9%), abdominal discomfort (5.8% vs. 4.4%), dizziness (4.2% vs. 2%), and malaise (3.1% vs. 2.9%). Laboratory abnormalities were uncommon; only < 1% exhibited elevated total bilirubin or aminotransferase levels with both regimens. Five drug discontinuations occurred due to AEs (bilirubin elevation: 3; dermatological issues: 2). Pangenotypic DAAs GLE/PIB and SOF/VEL are effective and well tolerated, achieving high SVR12 rates for patients with all HCV genotypes.

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The challenges of administering a new treatment: the case of direct-acting antivirals for hepatitis C virus

Public Health ◽

10.1016/j.puhe.2020.02.009 ◽

2021 ◽

Vol 190 ◽

pp. 116-122

Author(s):

S. Mondschein ◽

N. Yankovic ◽

O. Matus

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Direct Acting Antivirals ◽

New Treatment ◽

Direct Acting

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Risk of extrahepatic cancer in a nationwide cohort of hepatitis C virus infected persons treated with direct acting antivirals

GastroHep ◽

10.1002/ygh2.456 ◽

2021 ◽

Author(s):

Charlotte Lybeck ◽

Daniel Bruce ◽

Scott M Montgomery ◽

Soo Aleman ◽

Ann‐Sofi Duberg

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Direct Acting Antivirals ◽

Direct Acting

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Direct, indirect and total effect of HIV coinfection on the risk of non‐liver‐related cancer in hepatitis C virus‐infected patients treated by direct‐acting antivirals: a mediation analysis

HIV Medicine ◽

10.1111/hiv.13153 ◽

2021 ◽

Author(s):

Mathieu Chalouni ◽

Stanislas Pol ◽

Philippe Sogni ◽

Helene Fontaine ◽

Karine Lacombe ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Mediation Analysis ◽

Total Effect ◽

Direct Acting Antivirals ◽

Hiv Coinfection ◽

Direct Acting

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Improvement of Gut Diversity and Composition After Direct-Acting Antivirals in Hepatitis C Virus–Infected Patients With or Without Human Immunodeficiency Virus Coinfection

The Journal of Infectious Diseases ◽

10.1093/infdis/jiab094 ◽

2021 ◽

Author(s):

Natthaya Chuaypen ◽

Thananya Jinato ◽

Anchalee Avihingsanon ◽

Sakkarin Chirapongsathorn ◽

Supapon Cheevadhanarak ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Hepatitis C Virus ◽

Hepatitis C ◽

Gut Microbiota ◽

Alpha Diversity ◽

Healthy Controls ◽

Direct Acting Antivirals ◽

Microbial Dysbiosis ◽

Immunodeficiency Virus ◽

Direct Acting

Abstract Background The influence of direct-acting antivirals (DAAs) on the composition of gut microbiota in hepatitis C virus (HCV)–infected patients with or without human immunodeficiency virus (HIV) is unclear. Methods We enrolled 62 patients with HCV monoinfection and 24 patients with HCV/HIV coinfection receiving elbasvir-grazoprevir from a clinical trial. Fecal specimens collected before treatment and 12 weeks after treatment were analyzed using amplicon-based 16S ribosomal RNA sequencing. Results Sustained virological response rates in the monoinfection and coinfection groups were similar (98.4% vs 95.8%). Pretreatment bacterial communities in the patient groups were less diverse and distinct from those of healthy controls. Compared with HCV-monoinfected patients, HCV/HIV-coinfected individuals showed comparable microbial alpha diversity but decreased Firmicutes-Bacteroidetes ratios. The improvement of microbial dysbiosis was observed in responders achieving sustained virological response across fibrosis stages but was not found in nonresponders. Responders with a low degree of fibrosis exhibited a recovery in alpha diversity to levels comparable to those in healthy controls. Reciprocal alterations of increased beneficial bacteria and reduced pathogenic bacteria were also observed in responders. Conclusions This study indicates a short-term effect of direct-acting antivirals in restoration of microbial dysbiosis. The favorable changes in gut microbiota profiles after viral eradication might contribute toward the reduction of HCV-related complications among infected individuals.

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