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

[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

[Myown]

Thanks so much!  I answered the other too.
seeya!
MO

[CoWriter]

I agree with you that the impact of IR is not restricted to G1s.  Both the core protein of genotypes 3a and 1b interfere with the insulin signaling pathway....


"The hepatitis C virus core protein of genotypes 3a and 1b downregulates insulin receptor substrate 1 through genotype-specific mechanisms.

Both molecular and clinical evidence support a link between HCV infection and insulin resistance. We examined the in vitro interaction between the HCV core protein of genotypes 3a and 1b with the insulin-signaling pathway. We measured the expression levels of insulin receptor substrate 1 (IRS-1), IRS-2, and other factors involved in the insulin signal pathway in a human hepatoma cell line (Huh-7) transiently expressing the HCV core protein of genotypes 3a or 1b by molecular biology and biochemical techniques. The IRS-1 (but not IRS-2) protein level was significantly reduced in Huh-7 expressing the core protein of both genotypes 3a and 1b, as compared to cells transfected with the empty vector. However, while the core protein of genotype 3a promoted IRS-1 degradation through the downregulation of peroxisome proliferator-activated receptor gamma (PPARgamma) and by upregulating the suppressor of cytokine signal 7 (SOCS-7), the core protein of genotype 1b activated the mammalian target of rapamycin (mTOR). We confirmed these findings by using agonists for PPARgamma (rosiglitazone) or short interfering RNAs for SOCS-7. Conclusion: Despite the small sequence divergence of the HCV core proteins of genotypes 3a and 1b, the 2 proteins appear to interfere with the insulin signaling pathway using genotype-specific mechanisms. (HEPATOLOGY 2007;45:1164-1171.).  "



Re:  Insulin resistance....

It isn't the IR per se that causes some of the problems but the compensatory hyperinsulinemia.  In other words, when somebody is insensitive to insulin (IR), their body produces more insulin....resulting in hyperinsulinemia.


Hyperinsulinemia causes an increase in hepatic P450 1A2 activity.....

In addition to insulin's effect on CYP1A, it has also been shown to increase CYP2E1....

http://dmd.aspetjournals.org/cgi/content/full/27/6/695


(By the way, CYP2E1 and CYP1A2 activity is HIGHER in MALES than females)


The hyperglycemic state, hyperinsulinemia, obesity, and FASTING all cause an increase in the expression of CYP2E1....and induction of CYP2E1 promotes liver injury.

It's interesting that FASTING increases CYP2E1....my guess is that it happens because during periods of fasting, the liver releases glucose, creating a hyperglycemic state and the resulting hyperinsulinemia.....which of course induce CYP2E1.

[CoWriter]

"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."


So you mean to tell me that you've spent all those weeks doing research on non-response and I've spent hours teaching you about insulin resistance so you would come to the conclusion that the answer is to HIGH DOSE?

What about all those people who high dosed and still failed?  How about the added risk from high dosing?

Let me make it really simple for you.....

The past predicts the future.  When somebody treats and gets depressed....and they treat a second time, they will most likely get depressed again.  The past predicts the future.

That means that if you were insulin resistant the first time you treated (and YOU KNOW YOU WERE), you will probably be insulin resistant the second time you treat.  Hell...you're probably insulin resistant NOW.  

So do something about it NOW!  Because the longer you go with untreated insulin resistance, the more insulin resistant you'll become and the more damage to beta cells you'll have.  

If you get rid of the insulin resistance, you'll be able to stop the vicious circle and posssibly DECREASE your VIRAL LOAD so you'll have a better chance next time you treat.

And I don't mean treat the insulin resistance with supplements.  I mean treat it with real medicine like Metformin and keep an eye on the HOMA reading.

And learn about diet.

[CoWriter]

"So once again it appears to be the quantity of alcohol not just alcohol per se. "

But alcohol also has an additive effect....and it's an immuno-suppressant.


"Additive effect of ethanol and HCV subgenomic replicon expression on COX-2 protein levels and activity.

ABSTRACT
Summary. The mechanisms by which alcohol exacerbates liver injury in patients with hepatitis C are unknown. We used the hepatitis C virus (HCV) subgenomic replicon cell system to evaluate the effect of ethanol on HCV replication and viral protein synthesis. Our results demonstrate that alcohol stimulates HCV replicon expression at both HCV-RNA and protein levels. Furthermore, we observed that ethanol treatment showed an additive effect in cyclooxygenase-2 (COX-2) protein expression and activity already induced by HCV viral proteins, and in turn increased HCV viral expression. Our results suggest that COX-2 activity is involved in ethanol-induced HCV-RNA and NS5A protein expression, because acetylsalicylic acid (ASA), a COX-1/2 inhibitor, blocked this induction and downregulated COX-2 protein expression and activity. Therefore, we suggest that ethanol increases HCV replication expression, at least in part, by upregulating a key cellular regulator of oxidative stress pathway known as COX-2 or its products."

[mickythenose]

Impressive body of research. The problem still remains that there are non-responders.  Myself being one of them. Twice. I'm Genotype 4. Not many of us in this part of the world.

Anyway it becomes evident that Interferon isn't an effective way of dealing with HCV infection. Costly with many side effects.

There are some other things on the front though that may prove to be across the board effective. In recent years a group of scientist in the US have come up with a way to kill the virus using low power visible light laser. Star Trek stuff. In test it has an 80% kill rate.

Here is an interesting article that explains the plan.

http://technology.newscientist.com/article/dn12368-visible-light-pulses-knock-out-viruses-in-blood.html

Here is an abstract from a paper titled "Inactivation of viruses with a very low power visible femtosecond laser"

We demonstrate for the first time that, by using a visible femtosecond laser, it
is effective to inactivate viruses such as bacteriophage M13 through impulsive
stimulated Raman scattering. By using a very low power visible femtosecond
laser having a wavelength of 425 nm and a pulse width of 100 fs, we show that
M13 phages were inactivated when the laser power density was greater than
or equal to 50 MW cm−2. The inactivation of M13 phages was determined by
plaque counts and depended on the pulse width as well as power density of the
excitation laser.

Another paper that has interest concerns rats. But that is the way of research. The paper is titled "LED ENHANCEMENT IN MITOCHONDRIAL OXIDATIVE
PHOSPHORYLATION FOR HEPATECTOMIZED RATS"

Here is the discussion.
"Previous studies from our laboratory have shown
an increase in the energy capacity and hepatic
regeneration of hepatic remnants illuminated with low
intensity laser light at all wavelengths used.5,10 Laser
light is a coherent light with a specific wavelength that
effectively stimulates mitochondrial function.2,5,10 In the
present study we investigated the effect of low intensity
LED light on mitochondrial function through the
oxidative phosphorylation index. LEDs and lasers both
produce radiation at specific wavelength. Nevertheless,
LEDs are neither coherent nor collimated and they are
broader in emission when compared with lasers. These
properties can cause higher penetration in many cases.
    We have used a special home-made LED device
that employs an array of emitting centers, with
wavelength centered at 630 nm. The overall emitted
powers over a full hemisphere is about 500 mW, given
an energy density that depends on the distance between
device and target. Intensities as 20 to 50 mW/cm2 are
obtained with this device.
   In the present study we noted an effective
interaction between LED light and hepatic
mitochondria, with an increased phosphorylation rate
for the latter. This increase occurred at levels similar
to those induced by laser light, indicating a possible
effect of hepatic regeneration induction, an energydependent
process.
   The ADP:O ratio was similar in the three groups
studied, showing that LED light did not have a damaging
effect on the mitochondrial membrane.11 Thus, the light
induced an increase in oxidative phosphorylation
without damaging the mitochondrial membrane. Further
studies are currently underway in our laboratory for a
better understanding of the interaction between LED
light and hepatic cells and organelles for clinical
application to hepatology in the near future."

Near Infrared (NIR) light from LEDs can penetrate the the body up to 25cm. That is almost 10in. The point is that there are things on the horizon that will be more effective and cost efficient than pharmacology has been able to provide.

For more research I would suggest Google K. T. Tsen. Also Quantum Devices. They make the LED arrays for NASA and have a large section on research covering a variety of things. Some of interest to us.

The work of K. T. Tsen is being "fast tracked". The HIV community is very organized. We need to push for fast tracking this for the HVC community.

Best to all.

[CockSparrow]

The hepatitis C virus core protein of genotypes 3a and 1b downregulates insulin receptor substrate 1 through genotype-specific mechanisms.
Saw a presentation on that at the conference I was at.

So you mean to tell me that you've spent all those weeks doing research on non-response and I've spent hours teaching you about insulin resistance so you would come to the conclusion that the answer is to HIGH DOSE

No its the fall back position.
There is not a single high dose study ever done that has not produced a higher on Tx response rates.
The current doseage regime isnt based on maximizing hcv killing. Its about compromise.
An an interferon level that produces the lowest dropout rate with the maximum svr rate.

Apart from that you are better off killing as many early on as as you can. High doing does that. It still has an appeal. And yes i know it doesnt work for everyone.

If you get rid of the insulin resistance, you'll be able to stop the vicious circle and posssibly DECREASE your VIRAL LOAD so you'll have a better chance next time you treat.

"And I don't mean treat the insulin resistance with supplements.  I mean treat it with real medicine like Metformin and keep an eye on the HOMA reading"

Yep but we can get supplements and modify our diet.
Wheres the study that shows Meformin makes any difference.

CS

[CockSparrow]

LEDs can penetrate up to 10 ins. I work in IT and never knew that.
Moving away from the computer now.

I'll look into it, thanks.
CS

[mickythenose]

I was surprised at the level of penetration as I do some electronics work and use LEDs.

Here is something from the 'Introduction" on a paper titled "Effect of Light Emitting Diode Irradiation on Proliferation of Human Bone Marrow Mesenchymal Stem Cells"

"Low level light therapy, such as low-intensity laser and LEDs (Light emitting diodes) irradiation, is widely used in pain reduction, treatment of edema, eczema, dermatitis, persisting ulcers, burns, arthritis and arthrosis, and in veterinary medicine, sports medicine, and rehabilitation centers [1]. The biological effects are directly caused by very low light intensity irradiation on the tissue, not by heating in which the range of temperature increased is from 0.1 to 5oC. The most effective irradiation is in the red and near infrared range of the spectrum for the fact that hemoglobin does not absorb in this region and light can penetrate deep into the living tissue. Most of the light photons at wavelengths between 630-800 nm travel 23 cm through the surface tissue and muscle between input and exit at the photon detector [2]. Previous studies showed that low level laser irradiation provides low energy stimulation to tissues, which results in increased cellular activity during wound healing, increased proliferation rate of fibroblasts and keratinocytes, as well as enhancement of growth factor synthesis, collagen production and angiogenesis [3]. Low level laser irradiation can also trigger increase in mitochondrial membrane potential and stimulate c-fos expression [4]. Previous experiments revealed concentration of cytokines , including IL-1α,TNFα,IL-2 and interferon-γ, increased in culture supernatant of human peripheral blood mononuclear cells; IL-1αand IL-8 in culture supernatant of keratinocytes, after He-Ne Laser irradiation [5, 6].
Light emitting diode (LED) is a special diode semi-conductor element that emits light by applying electricity to arouse the movement of electrons in semiconductor material. Compared to lasers, LEDs are light-weight and cost –effective. LEDs can be made to produce multiple wavelengths, and can be arranged in large, flat arrays allowing treatment of a large area [3]. LED-technology developed for NASA (U.S.A.) plant growth experiments in space shows promising results for delivering light deep into tissues to promote wound healing and human tissue growth. The use of light with NASA LEDs in human trials has been approved by U.S. Food and Drug Administration [2-3]. Although the mechanism of action of
LEDs in nonablative light therapy is not fully elucidated, it is
believed that specific LED light parameters modulate certain
cellular and subcellular photoreceptors. Thus, tissue effects
may be achieved through up-regulation or down-regulation of
intracellular signaling cascades [7]. Comparison of the
therapeutic effect of a laser (coherent) and a LEDs
(noncoherent) source showed no significant difference at the
same wavelengths, intensities, and radiation times [1, 8]. In
addition to promotion of tissue growth, LEDs have been used
in photodynamic therapy for oral cancer patients [9, 10]. Ohara
et al. demonstrated that blue light from LEDs array exerted
cytostatic effects on B16 melanoma cells [11]. It was found
that photomodulaton with red light from GaAlAs LEDs array
(670 nm, bandwidth 25-30 nm, energy density of 4 J/cm2)
might enhance neuronal viability and restoration of neural
function following retinal injury [12]. Therefore, LEDs offer an
effective alternative to lasers for photodynamic therapy and
photostimulation."

One thing that I found interesting is that the laser treatment showed an increase in Interferon among other things. The LEDs seem to do the same thing. Something to consider.

[CoWriter]

"Wheres the study that shows Meformin makes any difference."

You just don't want to admit I'm right....but you know I am. ; )

[CockSparrow]

LMAO

[GoodByeHepC]

This is by far one of the most interesting and informative threads I've seen

Thanks, Cocksparrow for your tenacity and taking the time to make these contributions.

You may or may not remember but I'm another G3 "non responder". I always felt that my peg-intron dosage was low. My body weight was right on the cusp of the recommended dosage 167-170 lbs and my Dr prescribed that I take only 96mcg of Pegintron when I probably should have been taking the entire 120mcg. Especially considering that I was throwing away the rest.

When I was not RVR by week 8 I begged him to consider a dosage increase and he refused. I was relatively uninformed back then so I blindly followed his advice.

Toward the middle of my treatment I began increasing the dose myself because it was clear that the virus was not being overcome. But it was too late and he recommended that I discontinue treatment after a 21 week blood test. I finished the pegintron and have some Riba left over.

Knowing what I know now I'm furious that he did not afford me a better opportunity to clear the virus and now I'm just another Lab Rat lost in the sea of statistics.

Another thing that I'd like to offer is that I was undergoing Phlebotomy twice a month to decrease Iron. I had to fight for this even though my iron levels were elevated and I was diagnosed with heterozygous hemochromotosis (single mutated gene causing iron overload). I explained to him that my iron levels had always been very high throughout my life.

Personally I think iron overload should be taken just a s seriously as drinking alcohol.

When I did my baseline blood tests before starting treatment my VL was only around 700,000. I instinctively feel that the phlebotomy not only decreased my iron load but also decreased my Viral Load as well. Now that I've discontinued treatment and Phlebotomy my VL is over 2 million, the highest it's ever been in my life.

My Dr. was apathetic to the point of being robotic. It was clear to me that he was just going through the motions and was not deviating one inch from the textbook. He's clearly doing this for way too long and for the wrong reasons.

In retrospect I'm pretty convinced that much of the data that's spoon fed to potential patients is not accurate or complete - especially in the case of Geno 3s. I think that many decisions made about our treatment has more to do with the insurance companies bottom line.

Now I'm afraid my status as a G3  "non Responder" will have a negative impact on my eligibility for future re-treatment.

Now that I have that off my chest...

What is cEVR and pEVR?

Thanks

g

[alagirl]

and I was diagnosed with heterozygous hemochromotosis (single mutated gene causing iron overload
--------------------------------------------------------------------------------------------------------------------------
I have the same thing.  But I thought only the homozygous folks could actually get hemachromatosis due to the genetic mutation?  I've had issues with iron overload twice, but my issues are thought to be from actual IV iron and blood transfusions.  

[alagirl]

Sorry, that last was for you.  Forgot to address it.

[epiphiny]

"Now I'm afraid my status as a G3  "non Responder" will have a negative impact on my eligibility for future re-treatment. "

I was also given that label after being woefully under treated the first time round so I know how you feel!  However, drug companies, doctors and the FDA now recognize that there  is a high percentage of "difficult to treat" people across the genotypes and there is a great gap in treatment options that needs to be addressed;  drugs are being fast tracked and more trials are now being geared toward that category.  I have just done a trial for a PI for G3, G2 non-responders with good success thus far.

I also agree that treatment protocols  are often motivated by the mighty dollar but I think there is more hope around than there was 5 years ago when I first treated and things are changing constantly, albeit not as fast as we would like.

Keep positive, keep searching and keep fighting.  We are going to get there!!!

Epi :)

[merryBe]

hey I'm just gonna throw this out and see what sticks to the wall.

1. my viral load went up not down in 3rd month of tx.

only 2 things might have accounted for this that I could ferret out.

1. I was eating high fiber meals not knowing this could interfer with Riba absorption until jmjm told me that month.

2. I was taking PPC as per HR's instructions.

my solution was to eliminate the only possible causes. So no more fiber, no extra lipids.
I know the lipid thing is controversial, due to it's benefit to fibrotic reduction, but I reasoned it also adds to the lipid shell which is how virions are thought to protect themselves so well from the tx drugs.  
I therefore reasoned my fiber could be eaten at other times than with Riba, and reducing my fat intake from all sources healthy or otherwise might also give my virions more vunerability.

wish I could tell you which method helped the most, but I went to UND in record time after making these 2 changes and have stayed there ever since.

mb

[epiphiny]

Ok, I am now sooooo confused about whether or not to add any extra fat (lipids) to my diet.  Between this and the thread about thyroid probs and SVR I feel I have a whole set of 'what ifs' to obsess over.  Just when I thought it was safe.

[CockSparrow]

"GoodByeHepC - I was diagnosed with heterozygous hemochromotosis (single mutated gene causing iron overload)."

My HFE Blood test had the following written on it
C282Y Mutation not Detected
H63D Heterozygous Mutation Detected

Carrier of a single low-risk HFE mutation.
Development of hemochromatosis unlikely.

Its unlikely your High Ferritin is caused by this mutation. Blame the virus.

“GoodByeHepC - What is cEVR and pEVR? “
cEVR = Complete EVR (UND @Week 12)
pEVR = Partial EVR (2 or more  Log Drop @Week 12 but not UND)

"GoodByeHepC - My Dr. was apathetic to the point of being robotic. It was clear to me that he was just going through the motions and was not deviating one inch from the textbook."

Sometimes it feels like the way we are treated is designed so that we fail ay.

"GoodByeHepC - Now I'm afraid my status as a G3  "non Responder" will have a negative impact on my eligibility for future re-treatment."

No the opposite is the case G2s & G3s have excellent svr rates when retreated.
Even when failing previous Peg treatments.

In the Epic3 study G2/3s had a 58% svr rate.
That extra 24 weeks makes a lot of difference for us.
But if not UND at weeks 12, 0% svr.

Also the lower your Fibrosis the better.
Below is Epic3 combined genotype svr stats by Fibrosis level.
The same step down effect will apply to G3s. It does for naives.
F2 = 30%
F3 = 25%
F4 = 17%

You will beat it next time.
All the Best
CS

[CockSparrow]

“Ok, I am now sooooo confused about whether or not to add any extra fat (lipids) to my diet.”
If the drugs are working don’t change a thing.

Wish you Well
CS

[CockSparrow]

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

[epiphiny]

Thank you for your encouragement :)

[merryBe]

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 (diabetes) 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

[hippygem]

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

[CoWriter]

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

[CoWriter]

"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.

[merryBe]

I love the idea in theory that an oral med could reduce insulin resistance and increase EVR.  However, I was interested in this prior to treatment and told by my endocrinologist, GP, and hepatologist that these were all very hard on the liver and should not be considered for liver diseased patients.

Fortunately I had discovered on my own that I had every symptom of pituitary  dysfunction which was subsequently confirmed as working at 10-20% of normal output.
this is common in HCV people by the way, somehow the virus causes Pituitary changes and shutdown.

My therapy was controvercial, I went on HGH injections to return my pituitary to normal levels of human growth hormone for my age. This in turn returned my IGF=1 to normal levels, (insulin growth factor).  This in turn returned me to normal AC1  (4.6) from highs of 6.9-7.2)
Even though the literature suggests HGH and INF can both cause insulin resistance and/or diebetes (diabetes), this has not been my experience.  In fact the addition of HGH returned my cells to normal metabolism and compensated for the damage that HCV (or something else) had done to my pituitary.  This is important in that getting to the root cause or the missing hormone most likely to be the culprit in causing diebetes (diabetes) makes more sense than insulin replacement, at least in my mind because it spares all the fluctuations and possible complications that both hyper and hypoinsulemia can cause.

I will say I also watched my diet rather arduously for the first few months, but I did an experiment at chistmas, and an increase in sugars caused not one bump in my BS levels. So I'm fairly convinced insulin resistance has more than one possible way of being corrected. The question now is how to convince the medical community that one therapy may be superior and less toxic than another.  At this point HGH is as expensive as insulin injections, but several companies are working on an oral secretouge which should bring the cost and benefit to a whole new generation of sufferers.

mb

[hippygem]

Cowriter and CS and HR

I spoke to specialist and GP, both say that I dont have Insulin Resistance.
The specialist wont do HOMA-IG, says its meaningless.

I decided to go on the supplements CS is taking, and delay treatment for a couple of months, April.

Here are my blood test done in November.

Any info or comments would be appreciated.

*Haemoglobin= 157g/L (115-155)*
Platelets= 263x10/L (159-400)

AFP= 3 (<7) - AFP is of use in the diagnosis and monitoring of hepatocellular carcinoma and germ cell tumors.
RBC=5.13x10 (3.80-5.20)
*PCV=0.46L/L (0.35-0.45)*
MCV=90.4 fl (80.0-98.0)
MCH=30.6 pg (27.0-33.0)
MCHC= 338 g/L (3315-355)
RDW= 12.8% (11.5-15.5)

White Cell Count= 8.44x10/L (4.00-11.0)

Neutrophils= 57.4% 4.84x10/L (1.80-7.50)
Lymphocytes= 34.1% 2.88x10/L (1.00-3.50)
Monocytes=5.2% 0.44x10/L (0.20-0.80)
Eosinophils=3.1% 0.26x10/L (0.02-0.50)
Basophils=0.2% 0.02x10/L (0..00-0.10)

*Glucose= 6.6 (3.8-5.5)fasting.* - IR test in Dec=6.8, glucose=6.3

ALT=77 (0-55)

*Total Triglycerides= 2.7 (0.3-2.0)

Total Cholesterol=4.8 (<5.5) desirable
HDL Cholesterol=1.4 (1.0-2.2)

[hippygem]

Not sure what happening with the test in Dec, all I knew about was the IR test, which was a fasting blood test = 6.8.
Dont know where the specialist got the 6.3 as I didnt have any GGT done that day.

[CockSparrow]

You need to get a copy of the test results
Without that its all a bit of a guess.

CS

[susan400]

I appreciate all your research you've done.  As far as my using any kind of diabetes medications with my next treatment, that's going to have to be left up to my doctors.  My internal medicine doctor has had my A1C done numerous times and I'll be getting another one in Feb.  He's pretty much stayed on top of things with it because my sister had Type II and sero-converted into Type 1, but she's very obese and does not closely control her diet, nor exercise as much as she should.  My Dad had Type II and aggressively followed his diet and exercise and lost a bunch of weight.  He did so well that his doctor told him that he was no longer diabetic and took him off of all his diabetic medicine.  I exercise just about every day of the week.  My weight is in the perfect range as far as my BMI. My past 2 biopsies showed no steatosis, even though I do have the bridging fibrosis.  My triglycerides are not real high, not to the degree even where they would give me medications for them.  My cholesterol has been within normal limits.  My liver doctor told me point blank that he doesn't think that I fit the profile for insulin resistance.  So, I'm at a loss there.  If neither of the 2 doctors seems to be going there, I don't know that there's much more that I can do.  When you go into clinical trials, they are very specific on what you can take and what you can't so, if my next treatment is in a clinical trial, I don't see that I'd be able to use Metformin or any insulin.  If my A1C gets into the high range then, I think that they would probably be more inclined to further investigate this theory.  I do agree that my fasting blood sugar is slightly high...  As I said, I am listening to your words of advice but, since I'm now into an HMO and have to use the doctors that accept my insurance, financially speaking, I can't really go several different doctors to find one who will pursue this, you know?  At least now, I finally have prescription drug coverage.  Susan400

[CockSparrow]

http://care.diabetesjournals.org/cgi/reprint/32/Supplement_1/S62

Diagnosis of diabetes
Current criteria for the diagnosis of diabetes in nonpregnant adults are shown in Table 2.
Three ways to diagnose diabetes are recommended at the time of this statement, and each must be confirmed on a subsequent day unless unequivocal symptoms of hyperglycemia are present.

Although the 75-g oral glucose tolerance test (OGTT) is more sensitive and modestly more specific than the fasting plasma glucose (FPG) to diagnose diabetes, it is poorly reproducible and difficult to perform in practice.
Its boring but I wouldn’t say its difficult to perform.
It’s the waiting around for 2 or 3 hours that’s the main issue with it. Bring something to read.

Because of ease of use, acceptability to patients, and lower cost, the FPG has been the preferred diagnostic test.
Though FPG is less sensitive than the OGTT, the vast majority of people who do not meet diagnostic criteria for diabetes by FPG but would by OGTT will have an A1C value well under 7.0% (6).
Vast Majority is not everyone. You might be able to use this.

Though the OGTT is not recommended for routine clinical use, it may be useful for further evaluation of patients in whom diabetes is still strongly suspected but who have normal FPG or IFG (see Section I.C).


http://care.diabetesjournals.org/cgi/reprint/32/Supplement_1/S13

CLASSIFICATION AND DIAGNOSIS
Patients with IFG and/or IGT are now referred to as having “pre-diabetes” indicating the relatively high risk for development of diabetes in these patients. In the absence of pregnancy, IFG and IGT are not clinical entities in their own right but rather risk factors for future diabetes as well as cardiovascular disease.
They can be observed as intermediate stages in any of the disease processes listed in Table 1. IFG and IGT are associated with the metabolic syndrome, which includes obesity (especially abdominal or visceral obesity), dyslipidemia of the high-triglyceride and/or low-HDL type, and hypertension.


Now you don’t have Metabolic Syndrome, which is why your Dr’s don’t see you as having a problem. But you need to understand we are not trying to diagnose Diabetes here.
What we need to know is how Insulin Resistant we are so we know what our IFN response is likely to be.
Once you know you are IR then you can do something about it. Now you are already doing the classical things such as diet and exercise and they aren’t doing much.
Why because it’s the virus that is causing your IR.
You can reduce this by taking the following supplements
Resveratrol, ALA, NAC, Tarine. Astragalus and Stevia would also be good.
Most of HR’s other sups would be a good idea as well. But not PPC it goes off to easy.

Now you need an Insulin test done.
I have no idea why Insulin tests are so hard to get but they are.
Its going to be up to you to convince your Dr’s that you need this.
Actively manage your own care, so to speak.
Try and get them to give you an Oral Glucose Tolerance Test (OGTT).
And make sure insulin is being done with it.
This is used to diagnose Diabetes but will give us useful information, as well.
Your FPG is high enough to make this a worthwhile test.
It is more accurate than FPG but more expensive and time consuming.

Remember your Doctor is trying to diagnose Diabetes we are not.
CS

[CockSparrow]

Susan
http://care.diabetesjournals.org/cgi/reprint/32/Supplement_1/S62

Diagnosis of diabetes
Current criteria for the diagnosis of diabetes in nonpregnant adults are shown in Table 2.
Three ways to diagnose diabetes are recommended at the time of this statement, and each must be confirmed on a subsequent day unless unequivocal symptoms of hyperglycemia are present.

Although the 75-g oral glucose tolerance test (OGTT) is more sensitive and modestly more specific than the fasting plasma glucose (FPG) to diagnose diabetes, it is poorly reproducible and difficult to perform in practice.
Its boring but I wouldn’t say its difficult to perform.
It’s the waiting around for 2 or 3 hours that’s the main issue with it. Bring something to read.

Because of ease of use, acceptability to patients, and lower cost, the FPG has been the preferred diagnostic test.
Though FPG is less sensitive than the OGTT, the vast majority of people who do not meet diagnostic criteria for diabetes by FPG but would by OGTT will have an A1C value well under 7.0% (6).
Vast Majority is not everyone. You might be able to use this.

Though the OGTT is not recommended for routine clinical use, it may be useful for further evaluation of patients in whom diabetes is still strongly suspected but who have normal FPG or IFG (see Section I.C).


http://care.diabetesjournals.org/cgi/reprint/32/Supplement_1/S13

CLASSIFICATION AND DIAGNOSIS
Patients with IFG and/or IGT are now referred to as having “pre-diabetes” indicating the relatively high risk for development of diabetes in these patients. In the absence of pregnancy, IFG and IGT are not clinical entities in their own right but rather risk factors for future diabetes as well as cardiovascular disease.
They can be observed as intermediate stages in any of the disease processes listed in Table 1. IFG and IGT are associated with the metabolic syndrome, which includes obesity (especially abdominal or visceral obesity), dyslipidemia of the high-triglyceride and/or low-HDL type, and hypertension.


Now you don’t have Metabolic Syndrome, which is why your Dr’s don’t see you as having a problem. But you need to understand we are not trying to diagnose Diabetes here.
What we need to know is how Insulin Resistant we are so we know what our IFN response is likely to be.
Once you know you are IR then you can do something about it. Now you are already doing the classical things such as diet and exercise and they aren’t doing much.
Why because it’s the virus that is causing your IR.
You can reduce this by taking the following supplements
Resveratrol, ALA, NAC, Tarine. Astragalus and Stevia would also be good.
Most of HR’s other sups would be a good idea as well. But not PPC it goes off to easy.

Now you need an Insulin test done.
I have no idea why Insulin tests are so hard to get but they are.
Its going to be up to you to convince your Dr’s that you need this.
Actively manage your own care, so to speak.
Try and get them to give you an Oral Glucose Tolerance Test (OGTT).
And make sure insulin is being done with it.
This is used to diagnose Diabetes but will give us useful information, as well.
Your FPG is high enough to make this a worthwhile test.
It is more accurate than FPG but more expensive and time consuming.

Remember your Doctor is trying to diagnose Diabetes we are not.
CS

[CockSparrow]

Susan
http://care.diabetesjournals.org/cgi/reprint/32/Supplement_1/S62

Diagnosis of diabetes
Current criteria for the diagnosis of diabetes in nonpregnant adults are shown in Table 2.
Three ways to diagnose diabetes are recommended at the time of this statement, and each must be confirmed on a subsequent day unless unequivocal symptoms of hyperglycemia are present.

Although the 75-g oral glucose tolerance test (OGTT) is more sensitive and modestly more specific than the fasting plasma glucose (FPG) to diagnose diabetes, it is poorly reproducible and difficult to perform in practice.
Its boring but I wouldn’t say its difficult to perform.
It’s the waiting around for 2 or 3 hours that’s the main issue with it. Bring something to read.

Because of ease of use, acceptability to patients, and lower cost, the FPG has been the preferred diagnostic test.
Though FPG is less sensitive than the OGTT, the vast majority of people who do not meet diagnostic criteria for diabetes by FPG but would by OGTT will have an A1C value well under 7.0% (6).
Vast Majority is not everyone. You might be able to use this.

Though the OGTT is not recommended for routine clinical use, it may be useful for further evaluation of patients in whom diabetes is still strongly suspected but who have normal FPG or IFG (see Section I.C).


http://care.diabetesjournals.org/cgi/reprint/32/Supplement_1/S13

CLASSIFICATION AND DIAGNOSIS
Patients with IFG and/or IGT are now referred to as having “pre-diabetes” indicating the relatively high risk for development of diabetes in these patients. In the absence of pregnancy, IFG and IGT are not clinical entities in their own right but rather risk factors for future diabetes as well as cardiovascular disease.
They can be observed as intermediate stages in any of the disease processes listed in Table 1. IFG and IGT are associated with the metabolic syndrome, which includes obesity (especially abdominal or visceral obesity), dyslipidemia of the high-triglyceride and/or low-HDL type, and hypertension.


Now you don’t have Metabolic Syndrome, which is why your Dr’s don’t see you as having a problem. But you need to understand we are not trying to diagnose Diabetes here.
What we need to know is how Insulin Resistant we are so we know what our IFN response is likely to be.
Once you know you are IR then you can do something about it. Now you are already doing the classical things such as diet and exercise and they aren’t doing much.
Why because it’s the virus that is causing your IR.
You can reduce this by taking the following supplements
Resveratrol, ALA, NAC, Tarine. Astragalus and Stevia would also be good.
Most of HR’s other sups would be a good idea as well. But not PPC it goes off to easy.

Now you need an Insulin test done.
I have no idea why Insulin tests are so hard to get but they are.
Its going to be up to you to convince your Dr’s that you need this.
Actively manage your own care, so to speak.
Try and get them to give you an Oral Glucose Tolerance Test (OGTT).
And make sure insulin is being done with it.
This is used to diagnose Diabetes but will give us useful information, as well.
Your FPG is high enough to make this a worthwhile test.
It is more accurate than FPG but more expensive and time consuming.

Remember your Doctor is trying to diagnose Diabetes we are not.
CS

[CockSparrow]

Dont you just hate Double Posts
CS

[CockSparrow]

Susan
Some info for you from the American Diabetes Association.

Standards of Medical Care in Diabetes—2009
American Diabetes Association
http://care.diabetesjournals.org/cgi/reprint/32/Supplement_1/S13

Diagnosis of pre-diabetes
Hyperglycemia not sufficient to meet the diagnostic criteria for diabetes is categorized as either
(IFG) impaired fasting glucose  
(IGT), impaired glucose tolerance
depending on whether it is identified through the FPG or the OGTT:

● IFG = FPG 100 mg/dl (5.6 mmol/l) to 125 mg/dl (6.9 mmol/l)
● IGT = 2-h plasma glucose 140 mg/dl (7.8 mmol/l) to 199 mg/dl (11.0 mmol/l)

IFG and IGT have been officially termed “pre-diabetes.”
Both categories of prediabetes are risk factors for future diabetes and for cardiovascular disease (CVD) (7).

Insulin Resistance and Pre-Diabetes
http://diabetes.niddk.nih.gov/DM/pubs/insulinresistance/

How are insulin resistance and pre-diabetes diagnosed?
Health care providers use blood tests to determine whether a person has pre-diabetes but do not usually test for insulin resistance. Insulin resistance can be assessed by measuring the level of insulin in the blood. However, the test that most accurately measures insulin resistance, called the euglycemic clamp, is too costly and complicated to be used in most doctors' offices. The clamp is a research tool used by scientists to learn more about glucose metabolism.

If tests indicate pre-diabetes or metabolic syndrome, insulin resistance most likely is present.

Diabetes and pre-diabetes can be detected with one of the following tests:

• Fasting glucose test. This test measures blood glucose in people who have not eaten anything for at least 8 hours. This test is most reliable when done in the morning.

Fasting glucose levels of 100 to 125 mg/dL are above normal but not high enough to be called diabetes.
This condition is called pre-diabetes or IFG.
People with IFG often have had insulin resistance for some time.
They are much more likely to develop diabetes than people with normal blood glucose levels.

• Glucose tolerance test. This test measures blood glucose after people fast for at least 8 hours and 2 hours after they drink a sweet liquid provided by a doctor or laboratory.
A blood glucose level between 140 and 199 mg/dL means glucose tolerance is not normal but is not high enough for a diagnosis of diabetes.
This form of pre-diabetes is called IGT and, like IFG, it points toward a history of insulin resistance and a risk for developing diabetes.



Frequently Asked Questions about Pre-Diabetes
American Diabetes Association
http://www.diabetes.org/pre-diabetes/faq.jsp

Q: How does the FPG test define diabetes and pre-diabetes?
A Normal fasting blood glucose is below 100 mg/dl. A person with pre-diabetes has a fasting blood glucose level between 100 and 125 mg/dl. If the blood glucose level rises to 126 mg/dl or above, a person has diabetes.

Q: How do I know if I have pre-diabetes?
A: Doctors can use either the fasting plasma glucose test (FPG) or the oral glucose tolerance test (OGTT) to detect pre-diabetes. Both require a person to fast overnight. In the FPG test, a person's blood glucose is measured first thing in the morning before eating.

Q: Which test is better?
A: According to the expert panel, either test is appropriate to identify pre-diabetes.

Risk factors for diabetes or pre-diabetes.
These include:
high blood pressure,
low HDL cholesterol and high triglycerides,
a family history of diabetes,
a history of gestational diabetes or giving birth to a baby weighing more than 9 pounds, or belonging to an ethnic or minority group at high risk for diabetes.

CS

[willing]

have to confess I haven't been following the insulin vs non-response issue at all, so this may not be applicable. However, if you haven't already seen this, you may want to take a look of the new Roche/Pharmasset press release

http://investor.pharmasset.com/releasedetail.cfm?ReleaseID=358626

R7128 is *finally* moving to phase IIb. The trial, as was the case for phase I, will enroll previous non-responders but only G2/G3s. IMHO, R7128 is the most promising PI candidate out there. The RVR stats speak for themselves (90% RVR among G2/G3 non-responders in phase I).

[CoWriter]

"R7128 is *finally* moving to phase IIb. The trial, as was the case for phase I, will enroll previous non-responders but only G2/G3s"
----------------

It says the trial will enroll naive Genotypes 1 and 4.....

"The phase 2b trial is anticipated to enroll about 400 treatment naive, genotype-1 or genotype 4 HCV-infected patients."

Co

[CoWriter]

"I love the idea in theory that an oral med could reduce insulin resistance and increase EVR.  However, I was interested in this prior to treatment and told by my endocrinologist, GP, and hepatologist that these were all very hard on the liver and should not be considered for liver diseased patients."
----------------------

Actually, some studies have shown that insulin sensitizers are safe for HCV patients (but Metformin is not recommended for patients with HIV because of the risk of lactic acidosis).  From AASLD Nov 2008......


Assessing Hepatotoxicity of Thiazolidinediones (TZDs), Metformin, and/or Statin Therapy in Chronic Hepatitis C (HCV) Patients

H. Han, A.S. Boxer, M. Adler, J.L. Matloff, D.C. Carriero, M. Vachon, D.T. Dieterich, , Mount Sinai Medical Center, New York, NY;

Purpose: Patients over the age of 40 with Hepatitis C (HCV) have a three-fold higher prevalence of Type 2 diabetes (T2DM) than those without HCV. In addition, glucose abnormalities are associated with a poorer virologic response in chronic HCV patients. Attempts to improve insulin sensitivity prior to or during combination pegylated interferon and ribavirin therapy may result in a higher rate of viral response to HCV treatment. The aim of the study is to assess hepatic safety of insulin sensitizers such as TZDs and metformin, and/or cholesterol lowering agents like statins when used in patients with chronic HCV, prior to HCV treatment. Methods: IRB-approved, retrospective chart review from 2002 to 2007 of patients at a liver clinic in our center with chronic HCV treated with at least one of the study medications. We examined variations in ALT, AST, GGT, HDL, LDL and total cholesterol, triglycerides (TG), HbA1C, and calculated HOMA-IR at baseline and after 3 to 6 months of therapy. The Student T-Test was used to compare pre-treatment and post-treatment parameters. Results: Fifty-two patients (73% males, ages 36-68), of which 32 were on TZDs, 14 on metformin, and 6 on statins, were included for analysis. Compared to the pre-treatment, the post-treatment group evidenced a decreased trend in all biochemical parameters except for TG and HDL cholesterol. There was a statistically significant (p<0.05) decrease in calculated HOMA-IR from 7.37 (8.28) to 2.40 (0.87) after 3 to 6 months of treatment, and HbA1C declined from 5.44 (1.11) to 5.29 (0.82) %. ALT, AST, and GGT levels improved from 83.56 (82.47) to 65.92 (46.04) IU/L, 78.44 (66.76) to 65.77 (42.11) IU/L, and 139.48 (132.60) to 136.84 (202.38) IU/L, respectively. Total and LDL cholesterol also showed a trend downwards from pre-treatment (167.63 [37.69] and 82.65 [29.73] mg/dL, respectively) to post-treatment (162.55 [35.16] and 77.86 [27.21] mg/dL, respectively). TG and HDL values trended up from 163.85 (97.52) to 171.04 (127.99) mg/dL and from 49.59 (17.91) to 49.93 (19.99) mg/dL, respectively. There was no significant change in BMI from pre-treatment, 28.38 [5.72], to post-treatment, 28.04 [4.24] kg/m^2. No patients discontinued medications because of liver-related side effects. Conclusions: The decreasing trends in ALT, AST, GGT, and total cholesterol with the use of TZDs, metformin, and/or statins demonstrate the relative safety of these agents in HCV patients. The significant decrease in calculated HOMA-IR with insulin sensitizers given before HCV therapy may indicate a role for them in improving treatment response in HCV patients. A randomized study is underway.


"This is important in that getting to the root cause or the missing hormone most likely to be the culprit in causing diebetes (diabetes) makes more sense than insulin replacement"
------------------------

Untreated GH deficiency is associated with insulin resistance....but short-term (<6 months) GH replacement can decrease insulin sensitivity further.

GH replacement therapy increases lipolysis, thereby increasing circulating free fatty acid (FFA) concentrations. These increased FFA concentrations may decrease the uptake of glucose in skeletal muscle.

Therefore, the increased lipolysis induced by GH replacement therapy seems to be a sword with two edges in terms of insulin sensitivity. The short-term effect, with increased lipid oxidation and increased circulating free fatty acid levels, deteriorates insulin sensitivity. The long-term effect, with a reduction in body fat, is beneficial for insulin sensitivity.

"Growth Hormone Replacement Therapy and Insulin Sensitivity"

http://jcem.endojournals.org/cgi/content/full/88/4/1453

You know....the same fatty acids used by the Hepatitis C virus to make its outer coating.

In cellular metabolism, glucose (sugar) can be converted into fatty acids. Many viruses use these fatty acids to build their viral envelopes, or outer coatings, which help the viruses penetrate and infect human cells.

When the Hepatitis C virus gets into your body, it tries to increase your metabolism so that it can reproduce more quickly by using fatty acids to build protective outer coatings which will help it penetrate and infect your liver cells.

And one of the ways to create more glucose that can be converted into fatty acids, is by making you insulin resistant and eventually turning you into a diabetic.

BTW, you don't treat insulin resistance with insulin.  Insulin resistance leads to hyperinsulinemia ...too much insulin (which makes interferon ineffectve).  The last thing you would want to do is increase the insulin even more.      

  
"I will say I also watched my diet rather arduously for the first few months, but I did an experiment at chistmas, and an increase in sugars caused not one bump in my BS levels."
-----------------------  

When the Hepatitis C virus makes you insensitive to insulin, the pancreas has to produce larger amounts of insulin to keep your blood sugar under control (and sometimes, it makes too much, that's why some people have transient hypoglycemia) ....and you end up with hyperinsulinemia.....TOO MUCH insulin.....and having too much insulin, makes interferon ineffective

The problem isn't really the sugar you eat but the large amounts of insulin that are produced every time you eat all that sugar.  So don't do that again.


So I'm fairly convinced insulin resistance has more than one possible way of being corrected. The question now is how to convince the medical community that one therapy may be superior and less toxic than another.
----------------------
  
First we have to convince them to test people to see if they have insulin resistance, and so far we're not doing well with that.  And as I'm sure Jim would say, diet and exercise are not toxic...LOL and they should be the first measures used to improve insulin resistance.

Co

[CoWriter]

Regarding your white brain spots.....

White spots found on MRI in the brain's myelinated neurons, similar but smaller than those on the brains of multiple sclerosis patients....are also found on Polio survivors and Chronic Fatigue Syndrome patients.....and are related to Growth Hormone deficiency.

Co


http://books.google.com/books?id=t8i4e_q3Gj0C&pg=PA289&lpg=PA289&dq=growth+hormone+deficiency+and+white+brain+spots&source=web&ots=i22g7qnk1C&sig=h432hU-84L35IisVrq1-lyhcYSA&hl=en&sa=X&oi=book_result&resnum=2&ct=result

[willing]

The clinicaltrials.gov entry for r7128 specifies the following eligibility criteria

"Genotype 1 Patients who are HCV treatment-naive, with no history of exposure to interferon, ribavirin, or direct antivirals; OR Genoytpe 2 or 3 patients who have previously been treated with interferon."

since this is marked as phase II and "recruiting" I had assumed it covers the new IIb trial as well but perhaps not - it's worth checking with them.  

Overall, if ifn isn't effective, a tx regime that relies on it as little as possible seems advisable. One of the pleasant surprises from the NS3a trials was they showed improvement even among non-responders - that is even a poor ifn response was sufficient to deal with escape mutations. For r7128 that situation will improve further because of the lower level of evasion.

[merryBe]

this reminds me of the rife machine crowd material.
Infra red has been used for years in physical therapy, the benefit of penetrating heat can be helpful for certain conditions.

However, the rub on LED's is 2 fold,

1. they lose half their strength in the first 30 days of use, all Leds do, and they continue to decline from there so the benefit if any is short lived unless diodes are replaced monthly....
2 they are being marketed to people who are desparate, trying to suck several thousand each out of people with advanced diseases who haven't been helped or cured by modern medicine is the mark of a scam.
Don't beleive me? Go search for home LED light therapy machines and see what they cost. Then try to find even any lisenced medical professionals (beside chiropractors which don't count as they'll push anything) who will even use them, much less try finding a legit doc who will tell you they'll cure HCV. (When you do find the one nut out there, ask him for his research and then double check with each publication to see if it was ever even published.  I've been there done that...Get back to me, I'm dying to hear your results.

mb

[merryBe]

wow, I really appreciate you putting this altogether, and think what with CW chiming in it's turned into a great thread.  My only concern is regarding the tapering in of INF.

I've read a bit on tapering, most of the studies were done before Riba was even available, and the benefit on tapering in or while on was proven to lower rates of SVR. In fact the study I read no one SVR'd.  Of course INF being the only drug back then, the results may not apply as well now, yet still they are telling.

The verdict on tapering off INF at treatments end has a different set of issues and may be of great benefit, as outlined in the discussion Headed up by HR in another thread in Medhelp.
http://www.medhelp.org/posts/show/393732

if you are tapering in could you share your thinking or research on that please?

mb

[merryBe]

thanks for all those great answers. Your case for metformin is formidable, my only question is do you know which oral med would be less taxing on the liver, P450 and so forth?  It would seem wisdom to have approached my tx this way is view of the stats, but maybe at stage 3/4 the docs were weighing benefit vs. risk, I don't have HIV, but stage 3/4 is pretty late to start tx.. Don't know, but it did take me forever to get UND.

thanks for the GH article too. They did ease me very slowly up to a therapeutic dose, and my diet as I said was arduous. Both of these were attempts to reverse my IR and they seem to have worked.

Fatty acids and lions and bears, oh my. Well, yes, but we can get overly concerned here if we forget the liver will make it's own cholesterol if we don't eat enough. So any way we slice it there are going to be fatty acids to contend with. To lipid or not to lipid,,,that is the question.

I', not sure my GH results are optimum here as I have been so anemic that I'm viturally frozen in space and time. The procrit is only just keeping me at 10,, and so excercise is hanging up 5 blouses, and then collapsing. Hence I've lost no weight in spite of limiting calories because I'm unable to move more than 20 ft without becoming breathless. Hopefully this will get better after tx.

The thought that HCV has crossed the blood brain barrier has been around, and worrying me since my MRI. Unfortuantely my doc never even diagnosed me with anything all the years I complained. So my first guess was chronic fatique, second guess fibromyalgia, 3rd pituitary dysfunction. The latter 2 were confirmed but the first oas a real as real gets. Who knows what all can cause demylinazation....for that matter, pituitary dysfunction itself could cause such a domino throughout the body could it not?
I mean, I have neuropathy elsewhere, maybe failure to repair tissue brough on by GH deficiency causes all these changes. Maybe HCV or polio, or another virus would be the trigger, but in the end the cure needs to be kill the virus AND replace or return the gladular secretions to normal. Right?  
However my HGH got down to 20% of normal we do know if cells are not replaced with healthy new cells as they need to be that eventually complete shutdown, multiple gland and organ failure, and death will follow.
It will be interesting to see if in a few years they'll have a special brain cocktail taylored to each individuals faulty signal pathways, thus rewiring via chemical pathways around the whole disease processes. Won't that be a breathe of fresh air.

it's not the getting old that's ever bothers me, it's the getting helpless and sick that nobody wants. It'll be fun to see that go by the wayside. I hope our children at least will live to see it, and get to be productive for twice as long as we've been.

You know, I read about shaken baby, whiplash, and even radiation (I grew up near the Nevada test site) causing pituitary failures, but that article was the first one to suggest viral origins.  For that matter...who is to say they won't yet discover MS starts with a yet to be discovered virus.

Well, now at least when I break into Scarecrow mode...singing "If I only had a brain" we'll all know why, ain't it the truth!!  LOL

thanks for the good imput!!  me want imput......(short circuit loves stephanies)

mb