Aa
Understanding Non Response
As many already know I am a G3a 2x non responder. Twice never been UND.
Not bad for an apparently easy to treat geno type.
Now if you are a non G1 non responder there isn’t much out there specific to your genotype.
If fact looking for reasons for non response in non G1s just does your head in.
Below is what I have learnt about NR. I don’t look at Genotype much now I look more at what the virus does to us and how we contribute. I look for what is common among NRs and what is different between NRs and SVRs. Genotype doesn’t have much to do with that.
There are numerous virologic and host factors have been identified that impact the likelihood of SVR.
Viral factors impacting SVR
• Treatment Response (RVR, cEVR)
• HVL -HCV RNA above 800,000 IU/mL
More recent studies suggest above 400,000 IU/mL impacts SVR
• Genotype 1
Among host characteristics, that been demonstrated to decrease the rate of SVR
• Age
• Age at Infection
• Length of Infection
• Sex
• Cirrhosis,
• African American race
• Hispanic race
• Bodyweight/Obesity
• Hepatic Steatosis
Other factors that decrease response rates
• Alcohol
• Iron Overload (Hemochromatosis)
• Oxidative Stress
• Insulin Resistance
Below is what I have discovered about each of these negatives
Alcohol
Virology Journal http://www.virologyj.com/content/2/1/89
Effect of ethanol on innate antiviral pathways and HCV replication in human liver cells
Infection with Hepatitis C virus is a significant cause of morbidity and mortality throughout the world. With a propensity to progress to chronic infection, approximately 70% of patients with chronic viremia develop histological evidence of chronic liver diseases including chronic hepatitis, cirrhosis, and hepatocellular carcinoma.
The situation is even more dire for patients who abuse ethanol, where the risk of developing end stage liver disease is significantly higher as compared to HCV patients who do not drink [1,2].
Moreover, HCV-infected patients who abuse alcohol have extremely low response rates to IFN
therapy, but the mechanisms involved have not been clarified.
To model the molecular mechanisms behind this phenotype, we characterized the effects of ethanol on Jak-Stat and MAPK pathways in Huh7 human hepatoma cells, in HCV replicon cell lines, and in primary human hepatocytes.
High physiological concentrations of acute ethanol activated the Jak-Stat and p38 MAPK pathways and inhibited HCV replication in several independent replicon cell lines.
Moreover, acute ethanol induced Stat1 serine phosphorylation, which was partially mediated by the p38 MAPK pathway.
In contrast, when combined with exogenously applied IFN-a, ethanol inhibited the antiviral actions of IFN against HCV replication, involving inhibition of IFN-induced Stat1 tyrosine phosphorylation.
These effects of alcohol occurred independently of
i) alcohol metabolism via ADH and CYP2E1, and
ii) cytotoxic or cytostatic effects of ethanol.
In this model system, ethanol directly perturbs the Jak-Stat pathway, and HCV replication.
Ethanol did not appear to have significant effects on ISRE activity at 25 and 50 mM concentrations.
However, at concentrations of 100 and 200 mM, ethanol caused statistically significant 3.0 (p = 0.03) and 5.0 (p < 0.001) fold increases in ISRE reporter gene activity, as compared to cells not treated with ethanol.
The data suggest that high physiological doses of acute ethanol activate the ISRE, an IFN responsive promoter.
This study is interesting because it implies a number of things
1.If you drink while on TX then you have to wait until your liver breaks down the alcohol and clears it before IFN starts working again.
2. The Anti-Viral effect of Alcohol is probably Oxidative Stress related. Not Good.
3. This could happen with other substances
4. The Don’t drink cause its like throwing fuel on to a fire brigade have some basis for their views other than the cr@p on alternative treatment sites, They may actually have a point, although the effects of Alcohol on the IFN signalling pathways were dose related, with very little impact at the lower concentrations.
So once again it appears to be the quantity of alcohol not just alcohol per se.
5. Alcohol activates CYP2E1
Not bad for an apparently easy to treat geno type.
Now if you are a non G1 non responder there isn’t much out there specific to your genotype.
If fact looking for reasons for non response in non G1s just does your head in.
Below is what I have learnt about NR. I don’t look at Genotype much now I look more at what the virus does to us and how we contribute. I look for what is common among NRs and what is different between NRs and SVRs. Genotype doesn’t have much to do with that.
There are numerous virologic and host factors have been identified that impact the likelihood of SVR.
Viral factors impacting SVR
• Treatment Response (RVR, cEVR)
• HVL -HCV RNA above 800,000 IU/mL
More recent studies suggest above 400,000 IU/mL impacts SVR
• Genotype 1
Among host characteristics, that been demonstrated to decrease the rate of SVR
• Age
• Age at Infection
• Length of Infection
• Sex
• Cirrhosis,
• African American race
• Hispanic race
• Bodyweight/Obesity
• Hepatic Steatosis
Other factors that decrease response rates
• Alcohol
• Iron Overload (Hemochromatosis)
• Oxidative Stress
• Insulin Resistance
Below is what I have discovered about each of these negatives
Alcohol
Virology Journal http://www.virologyj.com/content/2/1/89
Effect of ethanol on innate antiviral pathways and HCV replication in human liver cells
Infection with Hepatitis C virus is a significant cause of morbidity and mortality throughout the world. With a propensity to progress to chronic infection, approximately 70% of patients with chronic viremia develop histological evidence of chronic liver diseases including chronic hepatitis, cirrhosis, and hepatocellular carcinoma.
The situation is even more dire for patients who abuse ethanol, where the risk of developing end stage liver disease is significantly higher as compared to HCV patients who do not drink [1,2].
Moreover, HCV-infected patients who abuse alcohol have extremely low response rates to IFN
therapy, but the mechanisms involved have not been clarified.
To model the molecular mechanisms behind this phenotype, we characterized the effects of ethanol on Jak-Stat and MAPK pathways in Huh7 human hepatoma cells, in HCV replicon cell lines, and in primary human hepatocytes.
High physiological concentrations of acute ethanol activated the Jak-Stat and p38 MAPK pathways and inhibited HCV replication in several independent replicon cell lines.
Moreover, acute ethanol induced Stat1 serine phosphorylation, which was partially mediated by the p38 MAPK pathway.
In contrast, when combined with exogenously applied IFN-a, ethanol inhibited the antiviral actions of IFN against HCV replication, involving inhibition of IFN-induced Stat1 tyrosine phosphorylation.
These effects of alcohol occurred independently of
i) alcohol metabolism via ADH and CYP2E1, and
ii) cytotoxic or cytostatic effects of ethanol.
In this model system, ethanol directly perturbs the Jak-Stat pathway, and HCV replication.
Ethanol did not appear to have significant effects on ISRE activity at 25 and 50 mM concentrations.
However, at concentrations of 100 and 200 mM, ethanol caused statistically significant 3.0 (p = 0.03) and 5.0 (p < 0.001) fold increases in ISRE reporter gene activity, as compared to cells not treated with ethanol.
The data suggest that high physiological doses of acute ethanol activate the ISRE, an IFN responsive promoter.
This study is interesting because it implies a number of things
1.If you drink while on TX then you have to wait until your liver breaks down the alcohol and clears it before IFN starts working again.
2. The Anti-Viral effect of Alcohol is probably Oxidative Stress related. Not Good.
3. This could happen with other substances
4. The Don’t drink cause its like throwing fuel on to a fire brigade have some basis for their views other than the cr@p on alternative treatment sites, They may actually have a point, although the effects of Alcohol on the IFN signalling pathways were dose related, with very little impact at the lower concentrations.
So once again it appears to be the quantity of alcohol not just alcohol per se.
5. Alcohol activates CYP2E1
If you've read Spacecost's recent post (5-7 days ago), I think he had an interesting approach (as a previous G1 relapser). Pre-dose riba, double Peg for several weeks and then Peg every 5 days insead of 7. Think he also had more than average weight-based riba. Don't know if he had anything else in the mix though.
Yeh quite like spacey's approach.
I was thinking about double dosing Pegasys every 5 days for a few weeks
then drop back to single dosing every 5 days for a few more for a few more.
You know a taper approach.
Also like the idea of taking both Pegs at the same time.
CS
I was thinking about double dosing Pegasys every 5 days for a few weeks
then drop back to single dosing every 5 days for a few more for a few more.
You know a taper approach.
Also like the idea of taking both Pegs at the same time.
CS
I double for first 4 weeks, the two on the same day. It wasn't that bad. I used Pegasys. Having used Peg-Intron the first time, I don't think I could have handles two Peg-Introns. But that was me. But, I went into tx 2 expecting to have my butt kicked so I was sort of prepared for the worst, not the best. With your thoroughness I'm sure you'll get your kiwis in a row before you launch.
Taper approach! That is the first taper I like! I too found this to be an interesting read. I had just heard about IR before, not read anything myself. Seems smart to try and do something about IR before starting tx.
I've been thinking about the genotype thing. Do you still think geno 3s without cEVR should be taken off tx at week 12? Or is this just relevant when tx'ing only 24 weeks? If a geno 3 becomes UND by week 24 and goes 72 weeks, is that not a possible approach? Why should a geno 3 be called a non-responder earlier than a geno 1?
I've been thinking about the genotype thing. Do you still think geno 3s without cEVR should be taken off tx at week 12? Or is this just relevant when tx'ing only 24 weeks? If a geno 3 becomes UND by week 24 and goes 72 weeks, is that not a possible approach? Why should a geno 3 be called a non-responder earlier than a geno 1?
Yah, the shock and awe approach is the way to go. Got me RVR. i stopped the Astragulas around wk 12 or so. Better get back on it!
Zazza - Do you still think geno 3s without cEVR should be taken off tx at week 12? Or is this just relevant when tx'ing only 24 weeks?
Yes the Negative predict is 94%. But most of us dont get a week 12 test.
Zazza - Why should a geno 3 be called a non-responder earlier than a geno 1?
Because we dont do 48 weeks very often.
Zazza - If a geno 3 becomes UND by week 24 and goes 72 weeks, is that not a possible approach?
Yes
RVR then do 24 weeks
cEVR do 48 weeks
pEVR do 72 weeks
This would work for G3s and i have seen it mentioned, but I wont be holding my breath waiting for a study to prove it.
CS
Yes the Negative predict is 94%. But most of us dont get a week 12 test.
Zazza - Why should a geno 3 be called a non-responder earlier than a geno 1?
Because we dont do 48 weeks very often.
Zazza - If a geno 3 becomes UND by week 24 and goes 72 weeks, is that not a possible approach?
Yes
RVR then do 24 weeks
cEVR do 48 weeks
pEVR do 72 weeks
This would work for G3s and i have seen it mentioned, but I wont be holding my breath waiting for a study to prove it.
CS
Have an Answer?
You are reading content posted in the Hepatitis C Community
Learn about this treatable virus.
Getting tested for this viral infection.
3 key steps to getting on treatment.
4 steps to getting on therapy.
What you need to know about Hep C drugs.
How the drugs might affect you.
These tips may up your chances of a cure.
A list of national and international resources and hotlines to help connect you to needed health and medical services.
Herpes sores blister, then burst, scab and heal.
Herpes spreads by oral, vaginal and anal sex.
STIs are the most common cause of genital sores.
Condoms are the most effective way to prevent HIV and STDs.
PrEP is used by people with high risk to prevent HIV infection.
