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Hep C Discussion Forum -> Hep C News -> GT3's - (and more so, maybe "certain" GT3 sub-types) - perhaps why we have most often been considered "hard to treat"
Post Info TOPIC: GT3's - (and more so, maybe "certain" GT3 sub-types) - perhaps why we have most often been considered "hard to treat"
Tig


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RE: GT3's - (and more so, maybe "certain" GT3 sub-types) - perhaps why we have most often been considered "hard to treat
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I honestly don't know how anyone or anything could resist you, Chuck! That virus couldn't keep you down for long, just a few decades and it got wise to your plan and hauled butt! 

It continues to amaze me why it took so long for them to realize that GT 1 wasn't the worst of the bunch. Maybe it was the prevalence of it, or lack thereof that kept them thinking GT3 was rare and therefore not as concerning. I don't know honestly. I've seen so much over the years, I'm not sure where their head was at during those darkest days. Whatever the case, I'm happy they figured it out and have placed their boot on the throat of the Dragon with 3 heads before more suffered the complexity it delivered.

Cheers to all that have thus far vanquished the Beast...



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Tig

68yo GT1A - 5 Mil - A2/F3 - (1996) Intron A - Non Responder, (2013) Peg/Riba/Vic SOT:05/23/13 EOT:12/04/13 SVR 9+ years!

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Canuck


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Another study regarding rare resistance effects for certain GT3's.

 

Helio - HCV Next

IN THE JOURNALS

Common polymorphism responsible for HCV genotype 3 resistance to Sovaldi

 

Wing PAC, et al. Gastroenterol. 2019;doi:10.1016/j.gastro.2019.05.007.

May 28, 2019

Researchers identified a common polymorphism and a rare variant combination in hepatitis C genotype 3 that are responsible for a reduced response to Sovaldi, according to a study published in Gastroenterology.

Studies on [Sovaldi] resistance have been hampered by the extraordinary efficacy of the drug, which has led to very few treatment failures, Peter A.C. Wing, PhD,from the Queen Mary University of London in the United Kingdom, and colleagues wrote. Our analysis shows that reduced response to [Sovaldi] may occur if multiple viral polymorphisms are combined.

To evaluate resistance to Sovaldi (sofosbuvir, Gilead Sciences) as well as ribavirin, Wing and colleagues used capture-fusion assays to assess 14 samples of HCV genotype 3. Ten of the samples were from treatment-naive patients with advanced liver disease, while the other four were from patients who had shown response in early access programs or in vitro testing.

They found that alanine at position 150 was particularly common (40.55%) along with the valine variant (36.66%). At position 206, lysine demonstrated a frequency of 76.31% and glutamic acid presented at a frequency of 12.74%. However, an analysis of the combination of polymorphisms (A150V and K206E) showed both were present in less than 4% of the population.

Using transient replicon assay, the researchers found that each common polymorphism correlated with an eightfold reduction in sensitivity to sofosbuvir and the combination correlated with a reduced sensitivity of more than 35-fold.

The effect of these polymorphisms on ribavirin sensitivity ranged from 10-fold for K206E to more than 40-fold for A150V, but in combination, the effect was enhanced to approximately 70-fold.

For treatment naive patients, responses to [sofosbuvir] based treatments are so effective that any impact of these viral variants is likely to be minimal and we would not recommend that such patients undergo pre-treatment resistance testing, Wing and colleagues concluded. For patients who have been exposed to multiple drug regimens (including interferon and NS5a inhibitors that can lead to resistance associated polymorphisms) we speculate that the polymorphisms identified here might be of significance and we suggest that pre-treatment viral sequencing may be useful in selecting the optimal regimen for such patients.  by Talitha Bennett

Disclosure: Wing reports no relevant financial disclosures. Please see the full study for all other authors relevant financial disclosures.



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HCV/HBV 1973. HBV resolved. HCV undiagnosed to 2015. 64 y.o. F. Canada.

GT3a, Fibroscan F3/12 kPa - F4/12.6 kPa, VL log 7.01 (10,182,417), steatosis, high iron load.

SOF/VEL with/without GS-9857 trial - NCT02639338.

SOT March 10 - EOT May 5, 2016 - SOF/VEL/VOX 8 week trial.

 

(SEE UPDATES IN BIO)
Canuck


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GT3's - (and more so, maybe "certain" GT3 sub-types) - perhaps why we have most often been considered "hard to treat"
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Published in Gastroenterology

Journal Scan / Research · May 20, 2019

Resistance Analysis of Genotype 3 HCV Indicates Subtypes Inherently Resistant to Nonstructural Protein 5A Inhibitors

Hepatology (Baltimore, Md.)

TAKE-HOME MESSAGE

  • This is an interesting study wherein the authors evaluated resistance-associated substitutions (RAS) in hepatitis C virus (HCV) genotype 3 as a potential explanation as to why these infections are more difficult to treat.
  • The authors demonstrated that there are significantly higher frequencies of RAS to nonstructural protein 5A (NS5A) protease inhibitors in genotype 3 variants of HCV, which may be associated with resistance to currently approved HCV antiviral medications. This information may help tailor therapy to patients with HCV genotype 3 in the future.

Natasha VonRoenn, MD

 

Abstract

Hepatitis C virus (HCV) genotype (gt) 3 is highly prevalent globally, with non-gt3a subtypes common in Southeast Asia. Resistance-associated substitutions (RASs) have been shown to play a role in treatment failure. However, the role of RASs in gt3 is not well understood. We report the prevalence of RASs in a cohort of direct-acting antiviral treatment-naive, gt3-infected patients, including those with rarer subtypes, and evaluate the effect of these RASs on direct-acting antivirals in vitro. Baseline samples from 496 gt3 patients enrolled in the BOSON clinical trial were analyzed by next-generation sequencing after probe-based enrichment for HCV. Whole viral genomes were analyzed for the presence of RASs to approved direct-acting antivirals. The resistance phenotype of RASs in combination with daclatasvir, velpatasvir, pibrentasvir, elbasvir, and sofosbuvir was measured using the S52 N gt3a replicon model. The nonstructural protein 5A A30K and Y93H substitutions were the most common at 8.9% (n = 44) and 12.3% (n = 61), respectively, and showed a 10-fold and 11-fold increase in 50% effect concentration for daclatasvir compared to the unmodified replicon. Paired RASs (A30K + L31M and A30K + Y93H) were identified in 18 patients (9 of each pair); these combinations were shown to be highly resistant to daclatasvir, velpatasvir, elbasvir, and pibrentasvir. The A30K + L31M combination was found in all gt3b and gt3g samples. Conclusion: Our study reveals high frequencies of RASs to nonstructural protein 5A inhibitors in gt3 HCV; the paired A30K + L31M substitutions occur in all patients with gt3b and gt3g virus, and in vitro analysis suggests that these subtypes may be inherently resistant to all approved nonstructural protein 5A inhibitors for gt3 HCV.



__________________

HCV/HBV 1973. HBV resolved. HCV undiagnosed to 2015. 64 y.o. F. Canada.

GT3a, Fibroscan F3/12 kPa - F4/12.6 kPa, VL log 7.01 (10,182,417), steatosis, high iron load.

SOF/VEL with/without GS-9857 trial - NCT02639338.

SOT March 10 - EOT May 5, 2016 - SOF/VEL/VOX 8 week trial.

 

(SEE UPDATES IN BIO)
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