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
"Wheres the study that shows Meformin makes any difference."
------------------
Here's the Metformin study I owed you ; )
Co
In Chronic Hepatitis C (HCV), Pretreatment with Thiazolidinediones (TZDs) or Metformin Decreases Insulin Resistance (IR) and HCV Viral Load and Increases Early Virologic Response (EVR)
M. Adler, J.L. Matloff, A.S. Boxer, H. Han, M. Vachon, D.C. Carriero, D.T. Dieterich, , Mount Sinai School of Medicine, New York, NY; M. Vachon, D.C. Carriero, D.T. Dieterich, Division of Liver Diseases, Mount Sinai School of Medicine, New York, NY;
Background: Chronic HCV is associated with increased incidence of insulin resistance (IR), which leads to a lower rate of sustained virologic response (SVR) following treatment with peginterferon plus ribavirin (IFN + RBV). Romero-Gomez et al. reported an SVR rate of 32.8% in genotype 1-infected patients with IR (HOMA-IR > 2) compared to 60.5% in those without IR. In addition, IR is associated with increased liver fibrosis and is characterized by a higher viral load, two other independent risk factors for decreased response to treatment. A recent study showed 0/5 EVR in patients with IR who were given a TZD at initiation of IFN + RBV. It is unknown if therapeutic intervention to improve insulin sensitivity prior to anti-viral treatment increases response to HCV treatment. Aim: To evaluate the effect of treatment with TZDs or metformin on IR and viral load prior to IFN + RBV and the impact on EVR. Methods: IRB-approved, we retrospectively reviewed charts of patients with chronic HCV from a liver clinic in our center. We included patients with IR treated with either metformin or a TZD for at least 3 months prior to initiating IFN+RBV. We compared HOMA-IR, HCV viral load, liver enzymes and BMI at baseline, after treatment with an insulin sensitizer (IS), and at week 12 of HCV treatment. Results: 17 patients met inclusion criteria. 10 were co-infected with HIV. The average age was 52.2 years, and 82% of patients were genotype 1. 11 patients were treatment-naïve to IFN+RBV. The mean stage of fibrosis was 2.7 on Metavir score in 12 patients. 11 patients received a TZD and 6 received metformin. The mean HOMA-IR decreased from 7.99 to 6.06 after treatment with an IS to 4.60 at 12 weeks of IFN + RBV. There was a significant mean decrease of 0.52 log in HCV viral load on each patient after treatment with an IS (p<0.01). An EVR was achieved in 12 patients (71%). The mean ALT value decreased from 86.2 at baseline to 72.5 (p=0.02) after treatment with an IS to 34.1 IU/L (p=0.01) after 12 weeks of IFN + RBV. BMI significantly decreased from 27.9 to 26.8 kg/m2 (p=0.02) following treatment with an IS. Conclusion: The use of a TZD or metformin improved insulin sensitivity prior to treatment with IFN + RBV. The baseline viral load, a risk factor for decreased response to treatment and until now referred to as an unmodifiable factor, was also significantly lowered. This intervention allowed a 71% rate of EVR in a population of mono and co-infected patients, the majority being genotype 1. This small pilot study suggests that targeting insulin resistance prior to treatment may enhance the chance of response to traditional treatment for chronic HCV.
------------------
Here's the Metformin study I owed you ; )
Co
In Chronic Hepatitis C (HCV), Pretreatment with Thiazolidinediones (TZDs) or Metformin Decreases Insulin Resistance (IR) and HCV Viral Load and Increases Early Virologic Response (EVR)
M. Adler, J.L. Matloff, A.S. Boxer, H. Han, M. Vachon, D.C. Carriero, D.T. Dieterich, , Mount Sinai School of Medicine, New York, NY; M. Vachon, D.C. Carriero, D.T. Dieterich, Division of Liver Diseases, Mount Sinai School of Medicine, New York, NY;
Background: Chronic HCV is associated with increased incidence of insulin resistance (IR), which leads to a lower rate of sustained virologic response (SVR) following treatment with peginterferon plus ribavirin (IFN + RBV). Romero-Gomez et al. reported an SVR rate of 32.8% in genotype 1-infected patients with IR (HOMA-IR > 2) compared to 60.5% in those without IR. In addition, IR is associated with increased liver fibrosis and is characterized by a higher viral load, two other independent risk factors for decreased response to treatment. A recent study showed 0/5 EVR in patients with IR who were given a TZD at initiation of IFN + RBV. It is unknown if therapeutic intervention to improve insulin sensitivity prior to anti-viral treatment increases response to HCV treatment. Aim: To evaluate the effect of treatment with TZDs or metformin on IR and viral load prior to IFN + RBV and the impact on EVR. Methods: IRB-approved, we retrospectively reviewed charts of patients with chronic HCV from a liver clinic in our center. We included patients with IR treated with either metformin or a TZD for at least 3 months prior to initiating IFN+RBV. We compared HOMA-IR, HCV viral load, liver enzymes and BMI at baseline, after treatment with an insulin sensitizer (IS), and at week 12 of HCV treatment. Results: 17 patients met inclusion criteria. 10 were co-infected with HIV. The average age was 52.2 years, and 82% of patients were genotype 1. 11 patients were treatment-naïve to IFN+RBV. The mean stage of fibrosis was 2.7 on Metavir score in 12 patients. 11 patients received a TZD and 6 received metformin. The mean HOMA-IR decreased from 7.99 to 6.06 after treatment with an IS to 4.60 at 12 weeks of IFN + RBV. There was a significant mean decrease of 0.52 log in HCV viral load on each patient after treatment with an IS (p<0.01). An EVR was achieved in 12 patients (71%). The mean ALT value decreased from 86.2 at baseline to 72.5 (p=0.02) after treatment with an IS to 34.1 IU/L (p=0.01) after 12 weeks of IFN + RBV. BMI significantly decreased from 27.9 to 26.8 kg/m2 (p=0.02) following treatment with an IS. Conclusion: The use of a TZD or metformin improved insulin sensitivity prior to treatment with IFN + RBV. The baseline viral load, a risk factor for decreased response to treatment and until now referred to as an unmodifiable factor, was also significantly lowered. This intervention allowed a 71% rate of EVR in a population of mono and co-infected patients, the majority being genotype 1. This small pilot study suggests that targeting insulin resistance prior to treatment may enhance the chance of response to traditional treatment for chronic HCV.
Is the 6.8 the result of a fasting blood sugar? If it is, that means that you are pre-diabetic/insulin resistant. A reading above 5.5 means pre-diabetes.
Don't start treating until you resolve the insulin resistance because that will decrease your chances of SVR.
"Glucose above 100 mg/dl (same as 5.5 mmol/l) Reduces Interferon/RBV SVR"
http://www.natap.org/2008/HCV/031008_01.htm
"Also, what do you think the chances of getting Alinia added to combo therapy? In australia of course."
---------------------
CS got his doctor to approve it. I'm sure he'll be happy to share the info he used to back up his request. (he will also be predosing the Riba).
Co
To CS....we're even....LOL
Don't start treating until you resolve the insulin resistance because that will decrease your chances of SVR.
"Glucose above 100 mg/dl (same as 5.5 mmol/l) Reduces Interferon/RBV SVR"
http://www.natap.org/2008/HCV/031008_01.htm
"Also, what do you think the chances of getting Alinia added to combo therapy? In australia of course."
---------------------
CS got his doctor to approve it. I'm sure he'll be happy to share the info he used to back up his request. (he will also be predosing the Riba).
Co
To CS....we're even....LOL
Gday CS, I had my blood test done for IR, it came back 6.8, which is in the normal range, so now i know I dont have Insulin Resistance. And we were so sure that I did werent we.
So now I dont have to worry about that when I start the tx again in Feb/March. Just have to lose a few kilos, get the weight down.
Been hearing about taking Riba for a couple of weeks before I start the interferon.
Also, what do you think the chances of getting Alinia added to combo therapy? In australia of course.
Linda
Geno 3, relapser/ fibrosis 2, tx 2004
So now I dont have to worry about that when I start the tx again in Feb/March. Just have to lose a few kilos, get the weight down.
Been hearing about taking Riba for a couple of weeks before I start the interferon.
Also, what do you think the chances of getting Alinia added to combo therapy? In australia of course.
Linda
Geno 3, relapser/ fibrosis 2, tx 2004
epi...I feel your pain...and just when we thought it was safe to come out from under our rock....but I still think a little fat w/riba is a good idea...just saying overall maybe a reduction in lipids might be wisdom...might be.....and then a return to healthy lips once the virus is clear....well.....it's just a theory, remember that. There's no absolute proof that virions couldn't steal fat from what already exists in your fat stores, so it's just a theory....but if my blood is rich in lipids, that certainly wouldn't make them have to work very hard to improve their own lipid shell would it?
Come to think of it...HR said it's the harder lipid shells that are the RESISTANT vrions, so I'm just wondering why would I offer these things a raincoat AND galoshes??
Just this month a study showed rats (closest to us genetically in reaction to food stuffs) had a much higher rate of fibrosis if on a diet rich in folic acid (green things)...
so again, normally one thinks..eat yer broccoli...but in this case, with this disease, all bets are off and we need to llok at the science of virion killing first, and then at all the rest. just my opinion.
CS....yes, please do let us know....it would be curious to see if there is a tie in somewhere. We do now know that diebetes is tied as much to lipids as to sugars, and plaque formation is also more insulin related than once thought, it wouldn't surprise me to learn that eating more healthy fats might just have been the overkill the virus needed to survive. Wouldn't that be a freakin' kicker.
mb
Come to think of it...HR said it's the harder lipid shells that are the RESISTANT vrions, so I'm just wondering why would I offer these things a raincoat AND galoshes??
Just this month a study showed rats (closest to us genetically in reaction to food stuffs) had a much higher rate of fibrosis if on a diet rich in folic acid (green things)...
so again, normally one thinks..eat yer broccoli...but in this case, with this disease, all bets are off and we need to llok at the science of virion killing first, and then at all the rest. just my opinion.
CS....yes, please do let us know....it would be curious to see if there is a tie in somewhere. We do now know that diebetes is tied as much to lipids as to sugars, and plaque formation is also more insulin related than once thought, it wouldn't surprise me to learn that eating more healthy fats might just have been the overkill the virus needed to survive. Wouldn't that be a freakin' kicker.
mb
I too have had some strange results from resent blood tests.
I'll post on the lipid thing after i get the results of a PCR test back.
Next week end most likely.
All the Best
CS
I'll post on the lipid thing after i get the results of a PCR test back.
Next week end most likely.
All the Best
CS
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