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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


66 Responses
Avatar universal
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

Avatar universal
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.
Avatar universal
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
451988 tn?1209915425
Wow!!!!!!! Nice bedtime reading; read through the whole thing, didn't get bored once.
96938 tn?1189803458
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?
Avatar universal
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
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