Non-epidemic HCV genotypes in low- and middle-income countries and the risk of resistance to current direct-acting antiviral regimens

Shah, Rajiv; Ahovegbe, Lucrece; Niebel, Marc; Shepherd, James G.; Thomson, Emma C.

doi:10.1016/j.jhep.2021.04.045

Cited by 38 publications

(33 citation statements)

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“…In vitro studies showed that 30K and 31M RAS conferred high levels of resistance to NS5A inhibitors. 31,32 It was reported that in mainland China, 96% of genotype 3b isolates carried the RAS combination A30K + L31M, 33 and a Dutch nationwide cohort study showed all genotype 3b patients had 30K and 31M RAS, which were associated with a lower SVR (63%). 34 Y93H was the most prevalent RAS at the end of treatment and was detected in 71.4% of non-SVR patients (Figure 3B).…”

Section: Discussionmentioning

confidence: 99%

Efficacy and safety of direct‐acting antiviral therapies and baseline predictors for treatment outcomes in hepatitis C patients: A multicenter, real‐world study in Guangdong, China

Xie

Deng

Yang

et al. 2022

Journal of Medical Virology

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The data on direct-acting antivirals (DAAs) in chronic hepatitis C (CHC) patients in southern China with multiple genotypes circulating are limited. This study aims to evaluate the efficacy and safety of DAA regimens among CHC patients in Guangdong, China. A total of 220 patients receiving a variety of DAA were enrolled. The primary outcome was sustained virologic response (SVR) at 12 weeks. Resistance associated substitutions (RASs) were evaluated by deep sequencing. The overall SVR rate was 96.4%, and was 97.7% for genotype 1, 100% for genotype 2, 91.9% for genotype 3, 95.7% for genotype 6, and 100% for untyped. The overall incidence of adverse events (AEs) was 8.2% (18/220) and all the AEs were mild. Nonstructural proteins 5A RAS, 30K/31M, and Y93H were most prevalent at baseline and the end of treatment in non-SVR patients, respectively. Logistics regression showed that elevated alanine aminotransferase (ALT) and aspartate aminotransferase (AST) at baseline were specifically associated with non-SVR in patients with genotype 3 and 6 infections (p = 0.029 and p = 0.017) but not genotype 1 infection (p = 0.746 and p = 0.971), and baseline AST was the best predictor for SVR in genotypes 3 and 6 patients (area under curve = 0.890). Our studies demonstrated all DAA regimens achieved ideal SVR and

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Section: Discussionmentioning

confidence: 99%

Efficacy and safety of direct‐acting antiviral therapies and baseline predictors for treatment outcomes in hepatitis C patients: A multicenter, real‐world study in Guangdong, China

Xie

Deng

Yang

et al. 2022

Journal of Medical Virology

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“…Within our cohort there are six countries which report unusual subtypes among their patient population. Unusual subtypes are more challenging to treat as SVR rates tend to be lower potentially due to the natural variation at baseline of these subtypes [12,33,34]. Countries where these unusual subtypes are highly prevalent among the countries with the highest HCV prevalence in the world [11].…”

Section: Discussionmentioning

confidence: 99%

The European Prevalence of Resistance Associated Substitutions among Direct Acting Antiviral Failures

Popping

Cento

Seguin-Devaux

et al. 2021

Viruses

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Background: Approximately 71 million people are still in need of direct-acting antiviral agents (DAAs). To achieve the World Health Organization Hepatitis C elimination goals, insight into the prevalence and influence of resistance associated substitutions (RAS) is of importance. Collaboration is key since DAA failure is rare and real-life data are scattered. We have established a European collaboration, HepCare, to perform in-depth analysis regarding RAS prevalence, patterns, and multiclass occurrence. Methods: Data were extracted from the HepCare cohort of patients who previously failed DAA therapy. Geno—and subtypes were provided by submitters and mostly based on in-house assays. They were reassessed using the Comet HCV subtyping tool. We considered RAS to be relevant if they were associated with DAA failure in vivo previously reported in literature. Results: We analyzed 938 patients who failed DAA therapy from ten different European countries. There were 239 genotypes (GT) 1a, 380 GT1b, 19 GT2c, 205 GT3a, 14 GT4a, and 68 GT4d infections. Several unusual subtypes (n = 15) (GT1b/g/l, GT3b, GT4k/n/r/t) were present. RAS appeared in over 80% of failures and over a quarter had three or more RAS. Multiclass RAS varied over target region and genotype between 0–48%. RAS patterns such as the Q30R + L31M and Q30R + Y93H in GT1a, the L31V + Y93H and L31V + Y93H for GT1b, and A30K + L31M and A30K/V + Y93H for GT3a all occurred with a prevalence below 5%. Conclusion: RAS occur frequently after DAA failures and follow a specific genotype and drug related pattern. Interpretation of the influence of RAS on retreatment is challenging due to various patterns, patients’ characteristics, and previous treatment history. Moving towards HCV elimination, an ongoing resistance surveillance is essential to track the presence of RAS, RAS patterns and gather data for a re-treatment algorithm.

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“…HCV harbors a 10 kb-long RNA genome which displays a high level of genetic variation due to the lack of a proof-reading activity of its RNA-dependent RNA polymerase enzyme, resulting in the emergence of different HCV genotypes and subtypes across the globe [ 4 ]. So far, at least six (6) genotypes of HCV have been identified, with multiple subtypes [ 5 ]. Different HCV genotypes are prevalent in different parts of the world.…”

Section: Introductionmentioning

confidence: 99%

“…Genotypes 1 and 3 are the two most common genotypes of HCV [ 6 , 7 ]. Genotypes 2, 3, 4, 5, and 6 are found predominantly in West Africa and Americas, the Indian sub-continent and Southeast Asia, Central and East Africa, South Africa, and Southeast Asia, respectively [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

Hesperidin identified from Citrus extracts potently inhibits HCV genotype 3a NS3 protease

Khan

Rauf

Habib

et al. 2022

BMC Complement Med Ther

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Background Hepatitis C virus infection is the main cause of liver ailments across the globe. Several HCV genotypes have been identified in different parts of the world. Effective drugs for combating HCV infections are available but not affordable, particularly to infected individuals from resource-limited countries. Hence, cost-effective drugs need to be developed against important HCV drug targets. As Citrus fruits naturally contain bioactive compounds with antiviral activities, the current study was designed to identify antiviral inhibitors from Citrus fruit extracts against an important drug target, NS3 protease, of HCV genotype 3a which is found predominantly in South Asian countries. Methods The full-length NS3 protease alone and the NS3 protease domain in fusion with the cognate NS4A cofactor were expressed in Escherichia coli, and purified by chromatographic techniques. Using the purified protein as a drug target, Citrus extracts were evaluated in a FRET assay, and active ingredients, identified using ESI–MS/MS, were docked to observe the interaction with active site residues of NS3. The best interacting compound was further confirmed through the FRET assay as the inhibitor of NS3 protease. Results Fusion of the NS3 protease domain to the NS4A cofactor significantly improved the purification yield, and NS3-NS4A was functionally more active than the full-length NS3 alone. The purified protein (NS3-NS4A) was successfully employed in a validated FRET assay to evaluate 14 Citrus fruit extracts, revealing that the mesocarp extract of Citrus paradisi, and whole fruit extracts of C. sinesis, C. aurantinum, and C. reticulata significantly inhibited the protease activity of HCV NS3 protease (IC50 values of 5.79 ± 1.44 µg/mL, 37.19 ± 5.92 µg/mL, 42.62 ± 6.89 µg/mL, and 57.65 ± 3.81 µg/mL, respectively). Subsequent ESI-MSn analysis identified a flavonoid, hesperidin, abundantly present in all the afore-mentioned Citrus extracts. Importantly, docking studies suggested that hesperidin interacts with active site residues, and acts as a potent inhibitor of NS3 protease, exhibiting an IC50 value of 11.34 ± 3.83 µg/mL. Conclusions A FRET assay was developed using NS3-NS4A protease, which was successfully utilized for the evaluation of Citrus fruit extracts. Hesperidin, a compound present in the Citrus extracts, was identified as the main flavonoid, which can serve as a cost-effective potent inhibitor of NS3 protease, and could be developed as a drug for antiviral therapy against HCV genotype 3a.

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Non-epidemic HCV genotypes in low- and middle-income countries and the risk of resistance to current direct-acting antiviral regimens

Cited by 38 publications

References 50 publications

Efficacy and safety of direct‐acting antiviral therapies and baseline predictors for treatment outcomes in hepatitis C patients: A multicenter, real‐world study in Guangdong, China

Efficacy and safety of direct‐acting antiviral therapies and baseline predictors for treatment outcomes in hepatitis C patients: A multicenter, real‐world study in Guangdong, China

The European Prevalence of Resistance Associated Substitutions among Direct Acting Antiviral Failures

Hesperidin identified from Citrus extracts potently inhibits HCV genotype 3a NS3 protease

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