Understanding Non Response

[CockSparrow]

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

[CockSparrow]

Oxidative Stress
Using the breakdown (metabolisim) of alcohol as an example of Oxidative Stress.

Alcohol Research & Health  Vol. 25, No. 4, 2001
Alcohol and Hepatitis C - Charles S. Lieber, M.D., M.A.C.P.

Alcohol (chemically referred to as ethanol) is broken down mainly by the enzyme alcohol dehydrogenase (ADH), which converts ethanol to acetaldehyde and hydrogen.

Excess hydrogen causes a number of metabolic disorders, including fat accumulation in the liver (i.e., fatty liver) (Lieber 1995).
The acetaldehyde, which itself is a toxic substance, subsequently is further metabolized by another enzyme (Lieber 1995).

Acetaldehyde contributes to various toxic and metabolic effects of alcohol, but cannot account for all disorders found in alcoholics. Instead, another metabolic pathway called the microsomal ethanol-oxidizing system (MEOS) (Lieber and DeCarli 1970), which also converts ethanol to acetaldehyde, plays a role in some of alcohol’s adverse effects.
The physiologic role of the MEOS is to generate the sugar glucose from various precursors; metabolize certain components of fat molecules (i.e., fatty acids); and detoxify foreign substances, including alcohol (Lieber 1999a). Chronic alcohol consumption strongly increases the activity of the MEOS, including that of an enzyme called cytochrome P-450. Several variants of cytochrome P-450 exist, including one called CYP2E1 whose activity is markedly enhanced after chronic alcohol consumption.

In addition to its beneficial physiologic function, the MEOS can have some adverse metabolic effects. For example, CYP2E1 has a high capacity to break down some commonly used drugs (e.g., the over-the-counter pain medication acetaminophen [Tylenol]) into toxic metabolites and to generate substances that promote the development of certain cancers.
In addition, the MEOS generates toxic free radicals when it has been induced by alcohol. In patients with HCV infection, these free radicals most likely potentiate the HCV-associated oxidative stress and the resulting liver damage. This hypothesis is supported by the observation that in a clinical study, an antioxidant (i.e., vitamin E) that should reduce the level of oxidative stress improved the liver function of patients with HCV-induced liver damage (Von Herbay et al. 1997). The improvement was only partial, however, and occurred in only one-half of the patients.

Hepatitis C virus core protein, cytochrome P450 2E1, and alcohol produce combined mitochondrial injury and cytotoxicity in hepatoma cells.
Gastroenterology. 2005 Jan;128(1):96-107.

CONCLUSIONS: Mitochondrial reactive oxygen species production is induced by hepatitis C virus core and cytochrome P450 2E1, resulting in a reduction of mitochondrial antioxidant capacity and sensitivity to oxidants and tumor necrosis factor alpha. Alcohol further depletes mitochondrial reduced glutathione, which exacerbates depolarization and cell death. Sensitization of mitochondria to oxidative insults is thus a potential mechanism for alcohol-related exacerbation of liver injury in chronic hepatitis C.

So what else causes Oxidative Stress
Well HCV does, being Cirrhotic does. Iron OverLoad does Insulin Resistance does, Being Overweight does.
In other words most of the negative SVR predicts are associated with Oxidative Stress and activation of the Cytochrome P450 enzyme CYP2E1.

Interplay between oxidative stress and hepatic steatosis in the progression of chronic hepatitis C
Journal of Hepatology 48 (2008) 399–406

Oxidative stress is increasingly recognized as a feature of chronic hepatitis C (CHC). CHC patients show increased serum and liver levels of oxidation products as well as a reduction of the liver antioxidant defences. Proteins adducted by lipid peroxidation products are also detectable by immunohistochemistry in the liver biopsies from CHC patients. Several factors might contribute to oxidative stress associated with HCV infection. Early studies have proposed liver iron deposition along with an increased formation of reactive oxygen species (ROS) by inflammatory cells as a possible cause of oxidative injury during CHC.

However, lipid peroxidation markers are evident also in asymptomatic HCV carriers [11].

Consistently, the expression of HCV core proteins in hepatoma cells lines induces ROS production within the mitochondria. Oxidative damage is also evident before biochemical and histological signs of hepatitis in HCV-transgenic mice, indicating that HCV ‘‘per se’’ might promote oxidative stress.

The effect of iron depletion on chronic hepatitis C virus infection
Hepatol Int

Kaito and colleagues found that iron-reduction therapy by phlebotomy significantly reduced lipid peroxidation and oxidative stress, which mediate the deleterious effect of iron overload on the liver.

Hepatitis C virus and oxidative stress: a dangerous liaison
Future Virol. (2006) 1(2), 223–232

Markers of oxidative stress in HCV in chronic hepatitis C
The presence of markers of OS with chronic HCV infection has been evaluated by determining the levels of a panel of OS markers and antioxidants [7]. This study demonstrated a significant elevation in 8-isoprostane (a marker of lipid peroxidation) and the ratio of oxidizedto-reduced glutathione (GSH), indicating the presence of OS in HCV-infected patients compared with age- and gender-matched controls. In addition, there was a significant reduction in the antioxidants GSH, selenium and vitamins A, C and E.
Abnormal findings were more pronounced in cirrhotic patients, although significant increases in OS markers and reduction in antioxidants were found in patients with milder noncirrhotic histology.

Fibrosis scores correlated positively with markers of lipid peroxidation and hepatic fibrogenesis, and negatively with antioxidant levels, thus confirming the presence of OS in both early and late HCV-related liver disease. Similarly, in situ examination of hepatic tissue has demonstrated that HCV infection is associated with increased immunohistochemical staining for aldehyde metabolites of polyunsaturated fatty acid (PUFA) peroxidation [8]

Mechanisms of Liver Injury III. Oxidative stress in the pathogenesis of hepatitis C virus

Possible Sources of ROS/RNS
• Activation of NAD(P)H oxidase of Kupffer cells and PMN cells during inflammation.
• Iron overload and lipid peroxidation.
• Activation of NAD(P)H oxidase by NS3 protein
• Increased production of mitochondrial ROS/RNS by the electron transport chain due to core and NS5A proteins.
• Decreased GSH output due to liver damage
• Decreased antioxidants and antioxidant gene expression
• Alcohol, drugs, and other chemicals
• Increased cytokines that increase ROS
• Increased expression/activity of COX-2
• Increased expression of CYP2E1

[CockSparrow]

Insulin Resistance

from http://www.wjgnet.com/1007-9327/12/7075.asp
Insulin resistance and hepatitis C - World J Gastroenterol 2006 November 28;12(44):7075-7080
Manuel Romero-Gómez

insulin resistance has been found as a common denominator in patients difficult-to-treat like cirrhotics,
overweight,
HIV coinfected and
Afro-American.

Insulin resistance together with fibrosis and genotype has been found to be independently associated with impaired response rate to peginterferon plus ribavirin.
Indeed, in genotype 1, the sustained response rate was twice (60%) in patients with HOMA ≤ 2 than patients with HOMA > 2. In experiments carried out on Huh-7 cells transfected by full length HCVRNA, interferon alpha blocks HCV replication. However, when insulin (at doses of 128 mU/mL, similar that seen in the hyperinsulinemic state) was added to interferon, the ability to block HCV replication disappeared, and the PKR synthesis was abolished.

In summary, hepatitis C promotes insulin resistance and insulin resistance induces interferon resistance, steatosis and fibrosis progression.

Two types of insulin resistance could be defined in patients with chronic hepatitis C:
“metabolic” insulin resistance and “viral” insulin resistance.

In a cross-sectional survey including 9841 persons, Mehta et al found that HCV-positive persons who were older than 40 years had an increased risk for type 2 diabetes mellitus higher than 3 times compared with persons without HCV-infection

Insulin resistance is the main pathogenic factor in the development of steatosis in chronic hepatitis C, both viral insulin resistance and metabolic insulin resistance could be implied in the development of steatosis.

The main deleterious effect of insulin resistance in chronic hepatitis C is the ability to promote fibrosis progression. High serum glucose levels have been found associated with an increased rate of fibrosis progression, greater even than overweight[16]. Mean HOMA index increases with the stage of fibrosis[17] and could help to differentiate stages of fibrosis. Recently, Sud et al[18], proposed an index to predict fibrosis containing age, cholesterol, gammaglutamyl transpeptidase and alcohol consumption together with HOMA.
The mechanisms by which insulin resistance promotes fibrosis progression include:
(a) steatosis,
(b) hyperleptinemia,
(c) increased TNF production, and
(d) impaired expression of PPARγ receptors.

In patients with chronic hepatitis C receiving peginterferon plus ribavirin insulin resistance measured by HOMA, decreased in patient with HCV RNA clearance at mo 6, but not in non-responders. At the end of follow-up sustained responders showed a significantly lower HOMA in comparison with baseline insulin resistance index.
However, in relapser patients, the HOMA index increased and the levels at the end of follow-up were not different from the baseline.
These data support a connection between HCV replication and insulin resistance, and HOMA decreased when the virus was eradicated.
Besides, the incidence of diabetes type 2 is different in cured patients than in non-responders, supporting a better control of insulin resistance after hepatitis C virus clearance[13].

Thus, measure insulin resistance seems to be easier and comfortable than study steatosis in a liver biopsy. Besides, in 52 patients from UK also treated with peginterferon plus ribavirin, HOMA index was significantly higher in non-responders than patients with sustained response[37].
Thus, insulin resistance emerges as the most important host factors in the prediction of response in non-diabetic patients treated with the best available option peginterferon plus ribavirin.
Interestingly, insulin resistance has been found as a common denominator to the majority of features associated with difficult-to-treat patients:
patients with cirrhosis,
obesity,
co-infected by HIV and
Afro-American.

Unresolved question is whether insulin resistance is a marker of very difficult-to-cure or a pathogenic mechanism able to block antiviral activity of the interferon.

Peginterferons induce their antiviral activity via extracellular receptor binding. The interferon alpha signalling pathway involves the activation of Janus kinase (Jak1) and tyrosine kinase (Tyk2), initiated by the binding of peginterferon alpha-2 to the interferon heterodimeric receptor complex (IFNAR1/IFNAR2), which leads to activation of their downstream substrates, signal transducers and activators of transcription (STAT 1 and STAT2). Activated STAT then assemble as a multimeric complex and translocate into the nucleus where they bind to interferon alpha-2-stimulated response elements in the promoters of interferon alpha-2-stimulated genes[38]. Recently, in a replicon model using Huh-7 cells transfected by full length HCVRNA, interferon alpha blocks HCV replication.

However, when insulin (at doses of 128 mU/mL, similar that seen in the hyperinsulinemic state in patients with metabolic syndrome) was added to interferon, the ability to block HCV replication disappeared, and the PKR synthesis was abolished

CONCLUSIONS
In summary, hepatitis C promotes insulin resistance and insulin resistance induces interferon resistance, steatosis and fibrosis progression in a genotype-dependent manner. In genotype 1 insulin resistance decreases sustained response rate, and increase the risk for the development of steatosis and fibrosis progression, in both, coinfected HCV+/HIV+ and in hepatitis C.

However, the impact of insulin resistance in non-1 genotype seems not achieve enough importance to impair sustained response, probably due to the high sensitivity to peginterferon. The treatment of insulin resistance, decreasing hyperinsulinemia, could improve sustained response rate in genotype 1 patients with chronic hepatitis C when treated with peginterferon plus ribavirin.

Ok so the impact of IR is restricted to G1s. Well no it isn’t.
Insulin resistance and response to therapy in patients infected with chronic hepatitis C virus genotypes 2 and 3.
Journal of Hepatology 48 (2008) 28–34

Our data indicate that SVR rates of >90% are achievable in persons with low HOMA-IR values. Conversely, SVR rates drop to the levels seen with genotype 1 infection (<60%) at values above 2.

An immediate implication is that irrespective of biopsy findings (which is not mandatory in many countries), genotype 2 and 3 infection with HOMA-IR values <2 can be confidently prescribed the currently available anti-viral therapy. On the other hand, since responses in persons with HOMA-IRP 2 are similar to those achieved with genotype 1 infection, consideration should be given to enrolling these patients into clinical trials that seek to improve virological response rates.

In conclusion, the present data suggest that insulin resistance is a powerful predictor of sustained virological response rates to currently available combination therapies for genotype 2 and 3 chronic hepatitis C infection. This effect appears to be independent of fibrosis stage.

Those with a low level of insulin resistance as measured by the HOMA score can confidently be initiated on currently available therapies with a high likelihood of viral eradication.
On the other hand, treatment decisions in patients with significant insulin resistance should be more circumspect.

Hepatic Cytochrome P450 2E1 Activity in Nondiabetic Patients With Nonalcoholic Steatohepatitis

Although visceral fat strongly correlated with insulin resistance (data not shown) and HOMA strongly correlated with hepatic CYP2E1 activity.

[CockSparrow]

What about High Viral Load
http://www.medscape.com/viewarticle/570035
High Hepatitis C Viral Load is Associated With Insulin Resistance in Patients With Chronic Hepatitis C

Results: In multivariate linear regression analysis, a dose-response relationship was observed between the log10 HCV RNA level and the presence of IR. IR was positively correlated with body mass index, triglyceride, HCV RNA and alanine aminotransferase levels, but negatively correlated with adiponectin level.

Subgroup analysis stratified by HCV genotype showed that there was a trend towards a higher HOMR-IR index value and lower adiponectin levels in genotype 1 patients.

Histological analysis showed that IR was positively associated with the severity of hepatic steatosis.

What does the following have in common
Age
Age at Infection
Length of Infection

These are in a way all the same thing. Age above 40 is independently associated with IR irrespective of HCV.

Male Sex is also independently associated with diabetes.

And Yes IR activates CYP2E1 or is it the other way round.
http://www.jbc.org/cgi/content/abstract/M410310200v1
Hepatocyte CYP2E1 overexpression and steatohepatitis lead to impaired hepatic insulin signalling.

Iron Overload
High iron levels don’t seem to activate CYP2E1 but high iron in conjunction with activated CYP2E1 don’t half cause some damage.
Iron and CYP2E1-dependent oxidative stress and toxicity
Alcohol. 2003 Jun;30(2):115-20

Thus, in the presence of iron complexes, microsomes enriched in CYP2E1 are especially reactive in generation of reactive oxygen species.

High BMI
Obesity is associated with both elevated levels of CYP2E1 and Insulin Resistance.


Whats Interesting is most if not all the negative predicts have IR, Oxidative Stress and elevated CYP2E1 in common and it crosses genotype, hmmm.
Seeing as HCV activates CYP2E1 do you thing it has anything to do with this.

The physiologic role of the MEOS (CYP2E1) is to generate the sugar glucose from various precursors.
No wonder we become Insulin Resistant and therefore Interferon Resistant.

Ya think elevated levels of CYP2E1 is where all the negs start from?

CS

[lolitriqui]

Wow!!!!!!! Nice bedtime reading; read through the whole thing, didn't get bored once.

[FlGuy]

So, I've read all of it and understand some of it. And, I think some of these factors (beyond my doc's understanding) may have contributed to initial relapse. But, closer to home and in your specific case, is there something that you can take away from all this that might contribute to an effective treatment regimine? For example, overwhelming with higher doses of IFN, dealing with IR before or during treatment, or other?

[CockSparrow]

Oh i am definately going to overwhelm it with higher doses.
But yes doing something about IR first makes a lot of sense to me.
Same with Oxidative Stress really. Hense my taking HRs list of sups.

Some of the stuff Gauf is taking makes a lot more sense now than it did.
Astragalus for one. Might be taking that one during Tx myself.
He is taking quite a bit that helps reduce IR.

CS

[FlGuy]

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.

[CockSparrow]

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

[FlGuy]

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.

[zazza]

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?

[gauf]

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!

[CockSparrow]

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

[Proactive]

you mentioned age at infection and length of infection..Could you provide a link to these being predictive factors to svr chances? I've read this here before, yet have never seen any info to back the idea up..I can understand age at treatment and liver damage, but don't know if the terms are or should be used interchangably..
Pro

[Proactive]

In a sense you are saying the age of the virus itself is a predictive factor..(which maybe I could understand from a selective mutation basis..survival of the strongest virus?)

[epiphiny]

Wow, great information, thanks for posting. I am also a G3 previous non-responder and have spent hours looking for info on retreating. Like you I have realized there is nothing out there so I started reading treatment protocols for G1 non responders such as they are.

I'll admit to not understanding a lot of what you have posted and would love it to be put in to more layman's terms especially stuff about the insulin resistance.  For example what are the signs/tests we look for that indicate we would have that?  What can we do in our daily lives to help address that in a precautionary fashion?

I'm also really encouraged to see that you also think that extending treatment out for longer periods based on RVR and EVR has value as this is exactly what I am doing on this tx round and it was me that approached my doctor with the idea and he has agreed and is supporting me in this choice.  For NZ it's pretty radical as we are known to be very protocol based rather than individualizing treatment.

Anyway, it's good to know there are others out there that share these ideas as it can be a very lonely place going forward on your own with no studies and results to back you up.

Thanks again for your post Cocksparrow, most appreciated. Will look forward to hearing more.

Epi

[zazza]

This is what p!sses me off. As I understand it, being a geno 3, unless you are RVR, means you are at high risk of not getting the duration of tx you need. If you are cEVR, then you might be lucky and get 48 weeks. But if you are a geno 3 slow responder, you won't have a chance. Nobody will give you 72 weeks. Sometimes it seems geno 3 is the unlucky geno.

[FlGuy]

A liverhead put it a little more succinctly to me (G3 relapser, early cirrhosis), if not undetected by week 4, do 72. Thus, the motivation to get to und ASAP.

[CockSparrow]

Pro - you mentioned age at infection and length of infection..Could you provide a link to these being predictive factors to svr chances? I've read this here before, yet have never seen any info to back the idea up..I can understand age at treatment and liver damage, but don't know if the terms are or should be used interchangably..

From the CDC
Recommendations for Prevention and Control of Hepatitis C Virus (HCV) Infection and HCV-Related Chronic Disease

Although factors predicting severity of liver disease have not been well-defined, recent data indicate that increased alcohol intake, being aged >40 years at infection, and being male are associated with more severe liver disease

Viral hepatitis C
THE LANCET • Vol 362 • December 20/27, 2003

Factors associated with fibrosis progression in patients infected with HCV

Definitely associated
• Fibrosis stage
• Age at infection
• Duration of infection
• Age at biopsy
• Consumption of alcohol >50 g per day
• HIV coinfection
• CD4 count  40 years, and
0.20 for age  30 years, compared with  3 times, compared with 1.5–2 times the upper limit of normal).

In the analysis disregarding age at HCV infection and duration of HCV infection, older age was strongly associated with moderate to severe hepatic fibrosis (OR, 2.32 for age 36–40 years, 2.46 for age 41–50 years, 7.87 for age 51–60 years, and 7.15 for age >60 years, compared with 16–30 years).
There was no association in either analysis with sex or source of HCV infection.


So I think that Age, Age at Infection and Duration of Infection are all related.
Why because at a younger age we are less likely to be IR and have minimal Oxidative stress.
As we age we tend to put on weight which elevates CYP2E1 and we also become more Insulin Resistant. Age >40 at infection leads to faster progression, why  because we have IR.


Pro - In a sense you are saying the age of the virus itself is a predictive factor..(which maybe I could understand from a selective mutation basis..survival of the strongest virus?)

Nah not really. I don’t really believe that the virus becomes truly Interferon Resistant.
Otherwise swapping Pegs or switching to Infergen wouldn’t work.

But I do kinda agree. I think Oxidative Stress plays a part in quasi species selection which could make us harder to Treat.

If IR is one of the main reasons for non response then you would expect to see higher svr rates in those with less IR. Guess what seems to be the case with Asians.
One of the main differences between Asians and us in the West is Asians have a much lower bodyweight. Lower bodyweight = lower IR.

Here are some studies done on Asians.
A randomised study of peginterferon and ribavirin for 16 versus 24 weeks in patients with genotype 2 chronic hepatitis C
Gut 2007;56:553–559.

Results: The rate of RVR and SVR was
86% (43/50, 95% confidence interval (CI) 76% to 96%) and
94% (47/50, CI 87% to 100%), respectively, in the 16-week group, which was comparable to 87% (87/100, CI 80% to 94%) and 95% (95/100, CI 91% to 99%) in the 24-week group.

Patients with RVR had a significantly higher SVR rate than patients without RVR in both
16-week (100% vs 57%, p = 0.015) and
24-week groups (98% vs 77%, p = 0.002).

Multivariate analysis showed that RVR and age were independent factors associated with
SVR. Both treatment arms were equally well tolerated. The incidence of alopecia was significantly higher in the 24-week group (49%) than in the 16-week group (20%, p = 0.001).


A randomized trial of 24- vs. 48-week courses of PEG interferon a-2b plus ribavirin for genotype-1b-infected chronic hepatitis C patients: a pilot study in Taiwan
Liver International 2006: 26: 73–81

The rate of SVR was significantly higher in the 48-week group (80.0%, 12/15) than in the 24-week group (48.9%, 22/45, P<0.05, 95% confidence interval (CI): 1.038–16.85).

Here are some interesting bit from it
In the 48-week group, the SVR rate was 72.7% for patients with a fibrosis score of 0–2, while 100% of patients with a fibrosis score of 3–4 achieved an SVR.
However, the difference did not reach significance.

Baseline characteristics
A total of 60 patients (mean age: 45.4 +/- 10.9-year old, male/female: 39/21) were included in the final analysis.
The mean body weight was 68.4 +/- 10.6 kg.
The mean assigned initial doses of PEG–IFN 1.41 +/- 0.15 mcg/ kg and ribavirin were 15.6 +/- 1.73 mg/kg, respectively

Lower Body weight higher doses per kg than those in the west tend to have.
Ya think IR and Oxidative Stress are low in Taiwan or what.

Who says G1s are hard to Treat. They don’t seem to be in Taiwan. 80% svr rates sheesh.

So what happens when Asians are treated in the West

Impact of Asian Race on Response to Combination Therapy With Peginterferon Alfa-2a and Ribavirin in Chronic Hepatitis C

SVR occurred in
65% (34/52) of Asian patients and 45% (171/384) of white patients (P = 0.005).
When comparing the two groups by genotype, there was no racial difference observed in SVR rates among patients with genotype 2 (75% among Asians vs 77% among whites, P = 1.00) or genotype 3 (64% among Asians vs 57% among whites, P = 0.55),
but Asian patients with genotype 1 had a significantly higher response rate than their white counterparts (65% among Asians vs 36% among whites, P = 0.005). This variation in genotype 1 patients persisted even after adjusting for BMI, fibrosis, and doses of study drugs (OR 2.87, 95% CI 1.40–5.88, P = 0.03).
When stratified by genotype, the unadjusted rates of SVR show a significant difference between Asian and white patients with genotype 1 infections (65% vs 36%), a finding not seen in patients infected with genotype 2 or 3.
Response rates in Asians, in fact, were similar across the three genotypes.

Now this wouldn’t have anything to do with Insulin Resistance now would it.
CS

[Proactive]

Thanks for the info CS. I don't think their is much doubt as to insulin resistance being high negative predictor of potential svr
"Insulin resistance has been shown to impair virologic response to antiviral therapy. Hyperinsulinemia hinders the ability of PEG-IFN to inhibit HCV replication in thereplicon assay. In addition, patients with insulin resistance,as measured by the homeostasis model assessment–insulin resistance (HOMA-IR),are slightly more likely to fail HCV treatment than patients with a normal insulin index.23 These observations led some investigators to suggest thatusing an insulin-sensitizing agent along with PEG-IFN and RBV in patients with an elevated HOMA-IR score could reduce the risk of HCV treatment failure. However,it is currently unknown which of the various nonresponsepatterns could be affected by insulin resistance or if this strategy would even be effective in enhancing SVR rates.Thus, the routine use of an insulin-sensitizing agent along with PEG-IFN and RBV to treat chronic HCV infection cannot be recommended at this time."
http://74.125.95.104/search?q=cache:wdmTAMlaIMoJ:www.clinicaladvances.com/article_pdfs/gh-article-200706-sup20.pdf+dartmouth+hitchcock+insulin+resistance+study+hep+c+treatment&hl=en&ct=clnk&cd=2&gl=us

[CockSparrow]

Hi Epi
In laymans terms the HCV Core Protein Activates CYP2E1.
The HCV Core Protein also interferes with both the Insulin Signalling and Interferon Signalling pathways.

Elevated levels of CYP2E1 causes Oxidative Stress
Elevated levels of CYP2E1 causes Insulin Resistance
Oxidative Stress damages the mitochondria Anti Viral Signalling Pathway.
It also leads to Insulin Resistance in part because CYP2E1 is used to make Glucose
Insulin Resistance then activates CYP2E1.
Insulin at hyperinsulinemia levels stops interferon from working.

Insulin Resistance is associated with virtually all the negative predicts as is Oxidative Stress.

All nice and circular really aint it.
For something without a brain this virus is pretty smart. It creates an environment that protects it.

To calculate your HOMA-IR use the following formula
Insulin (mU/L) x Fasting Glucose (mmol/L) / 22.5. = HOMA-IR
If your insulin is measured in uU/mL or uIU/mL then this gives the same value as mU/L.

I think the US Units the formula is
Insulin (uIU/mL) x Fasting Glucose (mg/dl) / 405.

Gives me the same result when I convert the Glucose value.

CS

[Myown]

My hep doc did say he was testing for Insulin Resistance prior to tx, but I don't ever remember discussing the subject again. I can't just 'assume' that it must have been okay because as we know there is alot of "falling thru the cracks," with this disease and that goes on no matter where or who is txing you - its just 'human error' (I'm being nice when I say that:o)

But anyhoo, at this stage of the game, can I get an insulin resistance test (week 28 or so) to see my HOMA score and will it reflect the same score I would have had PRIOR to tx,,,,and is the name of the actual test "HOMA IR",,,or do I just do a Fasting Glucose - as with that little math formula you did........Talk to me babeeeee! ,,:o) You can answer me on forum or send me the answer in an email - either way. Thankyuh!

MO

[redrodeo]

I am 3a, was unsuccessfully treated 2x before this last go. And this last tx worked. Who knows. The first 2 tries I was wasn't able to complete the 24 wks, or I lowered the interfer dose so much that it only suppressed it. Interestly the first 2 times my starting VL's were in the 3 to 5 mil group. This last time my VL was only 13,500. How can VL flucuate so much? I started tx Dec last year and went until May 24 wks. I was undet at 3 1/2wks. But the riba so affected me that even with Procrit it was around 9-10. So we lowered the riba dose to 600mg/d. Which helped a little bit, but I was still sick. Of course all the studies say doing so lowers your SVR alot. But I had no choice. Even now after all this time I am still not back to normal. At start my Hgb was 17, now if its above 12 I'd be surprized. As far as follow-ups I was till neg at 3months(<10copies/ml)
I had a blood test for another issue about a month ago and my LFTs were still low ALT 7 and AST 14. I have my 6 month check Nov 2 and of course I am getting nervous. I don't trust any of this. So many of the long term s/e's I wasn't aware of and know one told me.
If I were u I wouldn't lose hope yet.
Chris

[CockSparrow]

Reducing Riba after you are UND has little if any impact on our svr chances.
The studies that said reducing riba was an svr no no didnt differentiate between stoppin and reducing, nor did they take into account when the reduction was done.

Going from 3- mil down to 13,500. If you work out what you did can you let me know.
That had to make suck a difference.

Having such a low hgb could not have been fun. Thats one hell of a drop.
Glad it worked for you this time.
With ALTs as low as yours i am sure you will be svr.
They are brilliant numbers

Thanks for you thoughts but I wont lose hope, I am going to beat the damn thing.
CS

[CockSparrow]

Yes My you can work it out during Tx.
Get your Glucose and Insulin tested. Then either let your Dr do the HOMA calc or do it yourself.
Glucose can be used but isnt as accurate.
Anything above 100mg/dl (5.5 mmol/L) is cause for concern.
But above 110 (6.1) aint good.

CS