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Avatar universal

Tx round 3 an Update

For those who don’t know, I am a G3 two time non responder.
Yet to experience the joy of Relapse, never quite managed to get to Undetectable.
So much for being an easy to treat genotype.

Just before Christmas I had a Gastroscopy and Endoscopy done.
Waste of time and money really No H.Pylori or anything else much wrong.
Basically if I wasn’t sick I'd be healthy.
Now you would think turning up on time and at the right hospital would be fairly straight forward.
Well not for me it wasn’t, I turned up at the wrong Hospital didn’t I.
Now I was supposed to be at the Hospital at 6:40. I was even half an hour early.
When I arrived the Hospital section I was supposed to go to was basically empty.
OK I am early I thought. So I waited around till about 7:00 and still nothing no one about.
Then a Nurse wandered thru and asked what I was doing. So I told her.
She said we don’t do those on Mondays we are closed. Sh!t I thought, what now.
She knew who my Dr was and rang thru to another Hospital and sure enough he was there.
So I was sent to the wrong Hospital. Hey it wasn’t my fault I was given the wrong forms.
It could only happen to me. Pretty funny really in hindsight.

Now before I was top and tailed, hopefully with different scopes, and properly sterilized ones at that. I gave my Mr Dr a letter on how I wanted to treat, 13 pages detailing exactly how I wanted to treat and why.
I was going to post this letter but it was 13 pages so I didn’t.
However Gauf has posted much of it in his journal.

Below is the Tx plan I asked my Dr for.
• PegIntron 120mg twice a week for 4 weeks, followed by PegIntron 120mg weekly.  
Taper down for 1-2 months at EOT.
• Ribavirin 1200mg daily (weight based).  
Predose for 2 - 4 weeks.
• Alinia - Nitazoxanide 500mg BID.  
Predose for 4 weeks.  Ideally Alinia should be taken up to complete Tx end.
With 48 weeks this would require 51 weeks worth of Alinia.
• SAMe 1600mg BID and TMG 5 grams BID
• Insulin Sensitizer such as Metformin.

PCR tests will be done at
PreDose Baseline
2 weeks
4 weeks

Now curiosity may get the better of me here as I wouldn’t mind knowing what my VL is before my first IFN shot and at the end of week one. But I’ll have to pay for those. Still might get these PCR tests though.

I saw My Dr again in early January and much to my surprise he agreed to everything I wanted to do.
He even agreed to me taking Metformin. I went to a lot of trouble justifying Metformin only to discover I didn’t need it. I had managed to get my HOMA-IR score down to 1.2 with some of HR’s supplements.
Well something I did worked, I was also loosely following the South Beach Diet for a couple of months.
Although my glucose is still a little higher than I would like at 5.6 mmol (101mg/dl), but I am really happy with my insulin which is 5 mU/L (5 uU/dl).

Alinia in Australia is an Orphan drug. What this means is you can get it but Dr’s cant prescribe it without getting approval from the TGA (Aust version of the FDA more or less).
So my Dr agreed to do this and sent the details off to the TGA.
Well Shite, they actually approved it, I half expected them not to, seeing as I appear to be the first person in Aust to take Alinia for HepC.

Now while My Dr agreed to me tapering IFN he had concerns about sterility.
Well I hadn’t thought of that had I. So I looked into it.
Now tapering with Pegasys is dead easy.
You just get another needle and syringe and withdraw half of what in the syringe each time. How hard is that.
Well with Pegintron d@mn near impossible. You see when pegintron is mixed it only lasts 24 hours when stored in the fridge. Using it after 24 hours risks bacterial infection.
So unless I am prepared to waste a truck load of IFN then Tapering with PegIntron is not an option.
Pity really because I quite like the idea. But I just cant bring myself to throwing out Interferon.

During my latest visit Monday 9th, we discussed modifying the IFN Dosing.
Instead of taking Peg-Intron twice a week I am going to
DoubleDose the first shot, Although I didn’t tell him this bit.
Then have another shot 3 days later.
Then move the shots out to every 4 days for two weeks
Then every 5 days for two more weeks
Then every 6 days
Finally get back to weekly dosing at week 8
So I intend to have my first shot on Tuesday March 3rd which will mean the weekly shots will end up being on a Friday from week 8.

We then faxed off the approval letter to the Company that supplies Alinia and ticked the box to deliver to Patient.

Also got a script for Peg-Intron.
Now he asked for 168 Rebetol pills but for some reason I ended up with 140 pills. Not sure why. Doesn’t matter much as 1000 is what I should be taking but I want the extra Pill.
So gave me a bottle of Copegus.
Now I didn’t care that he gave me Copegus and I was going to be taking Rebetol, H3ll they the same drug. But I have been advised that I shouldn’t mix Copegus with Rebetol.

From the RebetolPI
The safety and efficacy of REBETOL Capsules with interferons other than INTRON A or
PEG-INTRON products have not been established.

So maybe I shouldn’t mix them.
As Copegus are pink pills and Rebetol has blue stripes on the capsule then I kinda saw them as boy/girl pills.
I was hoping that if you mixed them together that they will bread.
Instead it looks like they might fight. Bugg3r. Not much in the way of studies to go on.
Just as well I am Double Dosing and actually have an extra box of Rebetol because of that.

As of today I have 6 bottles of Alinia and a Pegatron Pack, and will order another next week.
I will start predosing Riba and Alinia on Tuesday.
First IFN shot will be on March 3rd
So Round 3 is about to begin. See if I can go from NR to RVR.

Now for why I want to treat this way.

DoubleDose Peg-Intron
My reason for high dosing Peg is based on Viral Kinetic studies which show that the first phase decline is dose dependant.

Ribavirin
I Intend on taking 200mg above my normal weight based dosing for as long as my reds hold up.
The extra RBV should help with the viral kinetics.

Alinia
Alinia is the only drug other than Interferon that has cured HCV on its own.
OK you need LVL and the rates aren’t that high but neither was IFN monotherapy rates.
While the mechanism of action of Alinia is largely unknown, what is known is that it activates PKR (Protein Kinase R) and also interferes with protein folding.
It is also a powerful anti bacterial amongst others things.
Seem to kill almost everything, eg H. Pylori, Giardia, Cryptosporidium etc.
But best of all if it doesn’t work then Alinia doesn’t make me even more resistant, unlike the PIs

SAMe & TMG
Now this may surprise many but Alinia is not the key to this SAMe is.

Here is why, just don’t ask me to explain it.
The Addition of SAMe prevents STAT1 from hypomethylating which prevents it from binding to PIAS1.
This improves Interferon Signaling.
Viperin another ISG (IFN Signaling Gene) also requires SAMe as it is a SAMe radical.
Viperin has shown anti viral activity against HCV.

Continued
85 Responses
Avatar universal
Some Info on Interferon Signaling
The expression of HCV proteins induces an ER stress response.
The consequence of prolonged ER stress is the release of Ca2+ from the ER into the cytosol. Cytosolic Ca2+-transients activate Ca2+ dependent kinases, which phosphorylate the transcription factor CREB.
Phosphorylated CREB binds to the CRE-element in the PP2Ac promoter and induces transcription.
Elevated PP2Ac level inhibits the enzymatic activity of PRMT1.
Two consequences of reduced PRMT1 activity are the
• hypomethylation of STAT 1 and
• the hypomethylation of NS3 helicase.

Hypomethylated STAT1 shows increased association with PIAS1 and decreased binding to IFNa-target genes upon IFNa treatment.
The consequence of the inhibited IFNa-signaling is a reduced antiviral response, which contributes to the development of chronic liver infection, which later on can progress to liver cirrhosis and HCC.

On the other hand, the unwinding activity of hypomethylated NS3 is increased compared to methylated NS3.
The higher unwinding activty of NS3 causes an increase in viral replication.

Therefore the upregulation of PP2Ac has two advantages for the virus:
• reduced cellular antiviral response and
• increased viral replication.


Many viruses have evolved strategies to protect themselves against the IFN system2. Viruses can interfere with the IFN system by blocking IFN synthesis, by inhibiting IFN signaling or by inhibiting the functions of IFN-induced proteins such as dsRNA-dependent protein kinase (PKR).

The most important signal transduction pathway for IFNs is the Jak-STAT pathway3. IFNa and IFN (3 activate STAT1, STAT2 and often STAT3. Signal transducers and activators of transcription (STAT) proteins are activated by members of the Jak kinase family through the phosphorylation of a single tyrosine residue4. Activated STATs form dimers, translocate into the nucleus and bind specific DNA elements in the promoters of target genes.

This activation cycle is terminated by tyrosine dephosphorylation in the nucleus, followed by the decay of dimers and the nuclear export of STATs.

Negative regulators of this signal transduction pathway have been found at three levels.

First, the suppressor of cytolcine signaling (SOCS) family members SOCS 1 and SOCS3 prevent phosphorylation and activation of IFN induced STATs by inhibiting the IFN receptor associated Jak kinases.

Second, downstream of STAT activation by tyrosine phosphorylation, IFN induced gene transcription can be inhibited by protein inhibitor of activated STAT1 (PIAS1). PIAS1 inhibits binding of STAT1 dimers to the response elements in the promoters of target genes. The binding of PIAS 1 to STAT1 is regulated by methylation of STAT1 by protein arginine methyl-transferase PRMT1 l T.
Arginine methylation inhibits binding of PIAS1 to STAT1, whereas demethylation of STAT1 enhances its association with PIAS 1.

A third step of negative regulation occurs through dephosphorylation and deactivation of STATs in the nucleus. Recently, the 45 lcDa isoform of protein tyrosine phosphatase TC-PTP was identified as the nuclear STAT1 phosphatase.

The inventors have found that the catalytic subunit of protein phosphatase 2A (PP2Ac) was overexpressed in liver extracts of HCV transgenic mice. Interestingly, expression of an N-terminally modified catalytic subunit of PP2A in the human hepatoma cell line Huh7 resulted in hypomethylation of STAT1 leading to inhibition of STAT1- DNA binding through increased binding to PIAS 1. The relevance of these findings for the human disease was confirmed in liver biopsies from patients with chronic hepatitis C.

Moreover, the inventors have found that treatment with a methyl group donor can restore IFN signaling. S-adenosyl-L-methionine (SAMe, also called AdoMet or S- Adenosylmethionine) is a methyl group donor produced naturally in all living organisms.

Under normal circumstances, it is produced in the cells by the transfer of an adenosyl group (derived from ATP) to methionine by the enzyme methionin adenosyl transferase.

After enzymatic transfer of its methyl group, SAMe is metabolized to homocysteine, a potential toxic substance. Homocysteine can by recycled to SAMe by transfer of a methyl group from betaine by betaine-homocysteine methyltransferase (BHMT). By using a combination of SAMe and betaine, the inventors found a significant increase in the induction of interferon stimulated genes by IFNa.

The inventors have found that treatment of cultured cells with SAMe increases the methylation of STAT1 and increases IFN signaling. Since methylated STAT1 can not be bound by its inhibitor PIAS1, it is a better IFN signal transducer.

If you want to read more on this here are some links

(WO/2005/071101) TREATMENT OF HEPATITIS C INFECTION BY INCREASING STAT1 METHYLATION
http://www.wipo.int/pctdb/en/wo.jsp?wo=2005071101&IA=IB2005000158&DISPLAY=DESC

Interferon alpha Signaling in Viral Hepatitis
http://pages.unibas.ch/diss/2008/DissB_8424.pdf

Molecular Mechanisms of Insulin Resistance in Chronic Liver Disease
http://pages.unibas.ch/diss/2008/DissB_8384.pdf
Avatar universal
Should have also mention I will also be taking the following Supplements and dosage
Mainly to reduce Tx Insulin Resistance and Oxidative Stress

SAMe..................: 1600mg BID
TMG (Betaine)......: 5 grams BID

R-ALA..................: 600 mg BID
NAC.....................: 2 grams BID
CoQ10..................: 200mg
Taurine.................: 1000mg BID
Vitamin C
Vitamin E
Vitamin D3
Vitamin B12
Vitamin B6
Folic Acid
Multi Vitamin – no Iron)
Magnesium
Probiotic

CS
Avatar universal
Sounds like a great plan!
3rd time's a charm
I wish you minimal sx's and SVR!!!
enigma
Avatar universal
Looks like you have done all the research and passed it by your doctor and was given the green light, “outside the box” and good to go. Hope you keep a journal through the journey and hope to see UND early and SVR at the end. I am sure the doc is going to monitor you through out, Good Luck!

jasper
Avatar universal
Best of luck to you CS...I am glad you are apparently looking at this tx as it relates to bi/tri-phasic viral decline based on viral kinetic studies..My feeling is, you should be open to dosage/tx adjustments based on these studies...but that will (IMO) require many pcr's during the phasic declines to actually chart the results...again, best of luck
pro
Avatar universal
I wish you success CS.  Sounds like a terrific plan and all the very best to you.  You've put a tremedous amount of time and energy into your plan and your efforts will pay off.
Trin
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