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W.A.R (War Against Resistance): with 3 weeks combo Oxymatrine + SOC then Oxymatrine mono for 6 months?

I am considering the following strategy to start just in a two weeks time:

    Oxymatrine + "induction" SOC  for only 3 weeks, then
    Oxymatrine as mono-Tx  6 Months.

[SOC, Standard of Care: Peg-IFN (PEGASYS) + Ribavirin]

I am GT 1b; got infected with HCV and HBV simultaniously probably due a series of  blood transfusions shortly after birth for 48 ys.  I am a 4-time nonresponder with HCV, 2 times to full-time SOC, (once Pegintron once Pegasys; the first attempts were 6 months IFN mono tx-s; the response curve was similar over all Txs: slow but marked decline to up to log 4 VL reduction, but never achieved UND.) HBV status is neg, but HBcAG is positive indicating past HBV-clearance.

I have the stuff now. I have discussed it with my hepatologist - but I would appreciate your opinion and suggestions very much before starting.

Should I do it ???

thanks ... Skepsis
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Avatar universal
Dear Kalio, Jim, memremeet, GoofyDad, Copyman!

Thank you for your support.

(This post landed 2 times in nirvana, possibly because some formatted links included. I had to reconstruct it... Has someone ever experienced such a loss of posts?)

Well, it was somewhat misleading to call the planned introductory combo in the starting 3 weeks interval as SOC: for many of us the word "SOC" designates obviously the combination PEGIFN + Ribavirin with standard doses AND standard time of therapy.

I know some of - by HR cited - results about Oxymatrine from not public sources, but the final result distinguishes not very much from that what you can already know from the internet - you have just more confidence when rely on more detailed information. What seems interesting especially for my case is the assumed and promising non specific activitiy against both HCV and HCV along with its attributed generic hepatotprotective effect.

Beneficial effects of Oxymatrin with HCV and HBV (No VL improvement was stated or examined): http://www.wjgnet.com/1007-9327/10/3269.asp

There will be a short review in the coming February issue of "Liver International" about herbal products and HCV, among them oxymatrine (no free access, I assume).
***
Two main factors could support my short term, only 3 week long introductory combination:

1. My "resistance calculation" above: the bigger part of chance for resistance should have been eliminated very early (by week 2).

2. I want to minimize all the negative effects of IFN and Ribavirin. (Long term and remaining sides, bone marrow depression, and give the immune system the chance for rapid recovery from side effects.)

I am sitting in a small European country (Hungary), which is somewhat limiting my treatment options. This is partly why I take the initiative in designing my own strategies. (I could change this situation however by moving to neighboring Austria or Germany where health care standard and funding is one of the highest worldwide - but with family it is not that easy step as it sounds.)

It is a big gamble to go or not to go with any present therapies - even with well established therapy options. As a non-resonder I have no more than 15-20% chances (to be very optimistic) with ANY IFN-Ribavirin combinations, including the pegged or non pegged forms of consensus and natural IFNs.

Another consideration for extremely short term initial IFN+riba only is that clinical trial designs have some obvious bias and tend to explore long term potential of drugs - a small correction built in in my decision making. (Once I read about an intermittent dosing trial, but I can't find it now - but the risks with intermittent short time therapies are nothing new either: previous IFN-based therapies before the PEG era were nothing else than very short time intermittent therapies and if we sum up the primary success rate with the relative high response rate of a follow-up combo therapy with PEG-IFN of non-responders to previous Combo with plain IFNs we get about the same efficacy than with the new PEG-SOC alone - one proof again for low rate of true resistance against SOC ...)

Nonetheless I will consider to take your advise to wait, Jim. With past HBV infection I have some additional reason to move forward actively (to live with HCV and significant liver damage cirrhosis)a past HBV infections makes a 10-15 times higher risk for HCC: http://www.natap.org/2006/AASLD/AASLD_58.htm
)

By the way my gastroscopy today was negative, helicobacter negative, no esophagus varices, ultrasound also negative (for 2 years it used to be light enlarged spleen and liver, by now all normal! Could it be the beneficial effect of last one-year SOC last year, and/or the fact that I changed my blood pressure medication to losartan for 4 months? Losartan has been attributed two beneficial effects besides lowering BP: lowering Uric acid and the supported antibibrotic effect in kidney and liver, latter supported by one small study

Antifibrotic effects of losartan with HCV: http://www.wjgnet.com/1007-9327/11/7560.pdf

but other clinical trials with losartan and irbesartan are ongoing, both losartan and irbesartan are ARB-class meds(Angiotensic Reseptor Blocker).
==================================================
Facit: I don't want to drop my plan altogether, but I'll "allow it more time to ripe". I'll make a fresh quantitative PCR, reconsider a new biopsy for the sake of better documentation of oxy performance and I'll go to the Nationalbibliothek and medical library in Vienna to do some further research about Oxymatrine. I'll let you know, if I have found out something.

Greetings:

Skepsis
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Avatar universal
Oxy as monotherapy is not a good idea due to the risk of the virus mutating around it, that is why it is recommended that it be taken in addition to SOC and not without SOC, you need the interferon to "protect" against mutation is the way I understand it.

Taking oxy while you are not on interferon could render the oxy useless as a tool in your arsenal to fight the virus, and that gives you one less tool to work with. We have very few tools available.
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Avatar universal
i think anything is worth a try. Oxymatrine has proven anti-viral qualities so who knows. there have been studies where it was used alone and knocked down the virus so i think it can benifit as a mono therapy. please keep us informed if you try it. thanks
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Avatar universal
OK. Just read Skep's analysis, above. (I just started the Zone diet so brain a little disconnected at moment) but still not convinced the Oxy could sustain a negative viral load, assuming induction plus oxy got him negative in three weeks.

I suppose if one were going to try this approach, then strict stop rules probably should be in place with very sensitive weekly viral load tests. First, you'd probably want to stop if SOC induction plus Oxy doesn't get you to non-detectible, although I'd probably give it 4-6 weeks as opposed to 3. Then you'd want to monitor viral load weekly and stop right away in the event of a viral breakthrough.

But frankly, I just don't see anything out there to suggest that Oxy Mono will sustain a negative viral load after a short course of induction. If this works, we have a breakthrough in HCV treatment, but I just don't think so.

-- Jim
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Avatar universal
Skep: Oxymatrine + "induction" SOC for only 3 weeks, then
Oxymatrine as mono-Tx 6 Months.

[SOC, Standard of Care: Peg-IFN (PEGASYS) + Ribavirin]
-------------------------------------------------
Goof, Think you're correct, I may have confused Skep's definition (above) of SOC as a second stage of treatment.

Assuming, he only does oxy plus induction SOC for 3 weeks and then oxy mono, my question would be what is he basing this approach on? You can't just pull drugs off a shelf and combine them any which way. Also, I think HR said Oxy mono wasn't good but not sure if that's still relevant after oxy plus sOC induction. Unchartered waters sounds like to this sailor.

On the other hand, if someone has compelling data on such or a similar approach, a different story. Still think the Vertex trial for non-responders might be a better choice. As to the amount of liver damage, Skepsiss mentioned Knodell which is different from Metavir and then described his condition as "not very threatening". Actually, I thought Knodell -- as opposed to Metavir -- only has one score. Maybe Skeptis wants to post the actual biopsy report which will detail the amount of fibrosis.

Be well,

-- Jim
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92903 tn?1309904711
Looks to me like he's not talking long term IFN. Also not insignificant liver damage. It's a tough spot to be in. Good wishes to you Skepsis.
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Avatar universal
To condense the above a little -- the main problem with your plan is that this would be the fifth time your committing yourself to a long term treatment with interferon. Even if oxymatrine proves beneficial, that benefit  will come with the serious downside of another full course of interferon therapy.

-- Jim
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Avatar universal
You've treated four times with interferons and did not respond.

Since you still do not have significant liver damage, I think it's time to consider calling it a day with long course interferon, induction or not.

As to Oxymatrine, my understanding is that it's one of those *potentially* good antivirals without any kind of track record. Do you really want to hang your SVR and another exposure to interferon on that?

If it were me, I'd sit back and wait for results of the Vertex trials. Preliminary SVR results should be in within weeks and more definitive numbers by the end of the year. At least this is a drug in trial with a treatment base to compare to.

Not sure if you qualify, but Prove 3 is taking non-responders. While it's still SOC, the potential of turning non-responders into RVRs would interest me a lot more than induction plus SOC plus Oxymatrine.

How much independent research have you done on Oxymatrine. HR has stated that you can't adaquately research it on the internet and you need to go to a medical library and dig up the original sources, then organize and bring them to a doctor. Even so, I don't think you will come up with anything as mature as what will be developing with Vertex over the next year.

And even if Vertex doesn't pan out, I think after 4 treatments you might still sit back, concentrate on liver-healthy living, possibly even some more bening anti-fibrotic meds/herbs, while monitoring your liver. A better treatment is due sooner or later. You've already given SOC all that any reasonable person could ask.

All the best,

-- Jim
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Avatar universal
Im hangin' in there. How about yourself? It does drag on and on. I just try to remember that eventually this will end. The oxymatrine seems to be going fine, my only "side effect" has been an increase in energy. Who knows if it will help, there won't be any way to gauge it's impact because I was on tx and already UND, but I feel good about taking it. It makes a lot of sense to me to add another antiviral to the med regimen.  
I also added Green Defense to insure I have my bases covered on the colorful vegetable front. Hard to eat all the veggies I should daily so Im hoping that will fill any gaps. You know how weird your appetite is on this stuff. I hope the time goes by fast for you!

Dointime..
It's nice to see you again. So you are in the group that is taking VX950 and Interferon but no Riba? I didn't know that was happening here, are you in Europe? Maybe Im just mixed up, that could definately be the case.
I can't wait to see your VL results! That would be great if the riba wasn't needed. It would allow many more to be able to treat. We still need a non interferon solution for others, but it's a start!
Hope you are doing ok, treatment is hard enough by itself but to deal with all the issues that go along with being in a trial must be a real challenge.
My deepest thanks to too you and all you guys on trials who are true pioneers.
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Avatar universal
You have probably already sen this but just in case you haven't, here is a study about retreating in your situation that discusses the various issues and scenarios ( raising doses, changing interferons, etc) we are discussing.

http://www.lib.okayama-u.ac.jp/www/acta/pdf/57_3_151.pdf.



Best of luck with your scope tomorrow, let us know how you do.
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Avatar universal
Thanx, both of You, these are well founded thoughts for a good decision support.

For the motivation to try the concept with Oxymtarine and an extreme short combo induction with SOC:

I had HAI 2 and stage 3-4 on last biopsy before last therapy for 2 years, not a very threatening picture, but I AM very symptomatic all the time (general fatigue, polyarthritis, cryoglobulinemia, heavy maldigestion, corneal problem).  My present job as an IT-freelancer is very demanding and my family is depending heavily on it existentially. I cannot imagine a longer and much heavier SOC for the moment for all that sx. On tx I exhibited a very slow decline, too, it is very improbable to get an RVR after all.

As I understand your standpoint reflects mainly the previous discussion about resistance in the thread:

http://www.medhelp.org/forums/hepatitis/messages/44784.html

But some oder considerations exist which eventually led me to this approach.

A hypothetical thinking model is valid for ALL antiviral therapies:

- Chronic HCV infection does maintain a pool of genetical variants or strains of HCV virus family.
- This pool of strains is dynamic: new strains will be added by new mutations.

Why should be the very first phase of Tx so critical when mutations can occur during the whole course of therapy?

Two thresholds can be defined for each individual viral strain to be able to thrive successfully, if (and only if) the viral strain surpasses that critical mass, then it can thrive:

Threshold_Nat is for natural course, threshold_tx  under therapy (this is a dependent on the specific therapy).

Always true: Thresh_Tx >= Thresh_Nat. Criteria of SVR can be formuleted as:

VL < Thresh_Nat  (a viral amount of smaller than Thresh_Nat has to be achieved by the end of therapy.

By VL is not meant Viral Load measured in serum but rather in each HCV-hosting body compartment -  particular threshold values may be varying for each tissue, the above relation between them should nevertheless be maintained for each body compartment at the end point of therapy to achieve SVR!). To achieve this goal an appropriate VL decline curve (or rather curves, for each body compartments) has to be maintained during therapy.

The implication of this depends on which one of the following 2 hypothesises is true.

- Hypothesis "A" : Resistance is due to pre-existing strains (wild type) becoming predominant only under specific selectional pressure imposed by therapy.

- Hypothesis "B" : Some new therapy-resistant mutations are becoming the pre-dominant strain under therapy. This mechanism would imply the very negative consequence of future resistance, that some particular HCV subpopulation of this newly breeds within an individual will very probably be remaining alive long term and would not be susceptible anymore to future attempts of the same antiviral agents.

Regarding SOC I am declined towards Hypothesis A (pre-existing wild type is responsible for resistance - albeit resistance pattern can depend on the particular therapy). The observation that relapsers generally exhibit a very similar response pattern during repeated therapies and that SVR chances of relapsers is significantly higher than that of NON-Responders is contradicting hypothesis B. That would mean, that we don't have to fear so much future resistance which we are breeding with each therapy failure.

Ribavirin is attributed a certain mutagenic action mechanism: Ribavirin is a nucleoside analogue meaning that this molecule has the potential to incorporate into the (preferrably only the viral-but very probably not) genome in place of the corresponding real nucleoside. Ribavirin acts also on a competitive way (competition with the nucleoside which it replaces), that is the very reason why ribavirin should have a certain concentration to be effective. Nonetheless the mutagenic effect of ribavirin on the virus might function in such a specific a way that no fit strains will be benefitted at all, e.g. when the transcriptase process will completely be disrupted with originating viral parts that cannot be used for replication but dissolve.

Nevertheless, we can state some implications for the case if "B" were true. (As a matter of fact "B" can prove to be very true with some emerging monotherapies.) Mutation rates depend on replication count at a given time and can be best expressed as [mutation count]/[replication count] - a measure which is constant throughout therapy. Furthermore, we can expect that replication rate is roughly a linear function of the replicon count and thereby of VL (again to be seen for each separate body compartment playing a role in HCV-Replication!) A greater than log2 reduction seen typically with a succesful SOC within the first 4 weeks means that with a relative steep response curve more chances of resisting mutations can be ruled out in these very first 1 to 2 weeks than after that time during the whole remaining therapy course altogether! (The time point where AUC_begin = AUC_rest is at about 2 weeks. [AUC=Area Under the Curve] - is proportional to calculated chance for a specific mutation to a given time point.)

On the contrary, assuming hypothesis "A" (that preexistent wild type strains are becoming predominant under tx pressure) we have to deal with a concept of general shift between strains in viral population toward the dominance of resistant ones. Viral strains are competing for resources with each other all the time (receptors for entry a cell, constituent nucleotides in citoplasm or ribosomes in endoplasmic reticulum to be able to transcript within the cell - the latter once relevant only if it is a common event that multiple virions of different quasispecies are entering simultanously a single cell). Once such a shift has occured, one resistant strain can get a real boost by loosing the evolutonary pressure  previously exerted by competing strains of the HCV virus family itself. If the pressure on these strains from ongoing therapy is too week to compensate for their boosting within the whole HCV-population, we have to do with a viral breakthrough. After a while the immune response and therapeutic effect together are so overwhelmed, that even originally dominant but meanwhile under therapy diminished strain can manage a second breakthrough, restoring or approaching the old kind of mixture of viral genotype.

There has been a model widely discussed for viral kinetics during (succeful) SOC:

IFN might inhibit foremost the infection of new cells. This might explain why the full course of 48 or even 72 weeks is necessary: life expectation of infected hepatic cells can be as long as a half to one year - when therapy is maintained this long after achieving UND, by this time all infected cells should have died out and SVR is achieved. (The recently suggested option to reduce SOC to 24 Weeks for RVR patients with GT 1 seems supporting this model.) It would mean the addition of SOC to ANY agent could be beneficial because of new infection and thereby new mutations could widely be broken down to evolve (with hypothesis "B") or despite the shift towards it the resistant strains cannot reach that critical mass to thrive (hypotheses "A").

Some more remarks to Hypothesis "B":
1.) even if "B" was true for the first-time-therapy we have to deal with "A" definitely later during follow-up therapies ...

2.) "B" implies an implicitly that resistant mutations (fit enough to thrive) must occur infrequently - if  resistant mutations occured in large numbers, that would mean hypotheses "A" automatically will be enforced...

3.) I could gather some information about mixed genotypes with following resulting picture:

Mixed GT is relatively rare, because GT 1 outperforms other GTs in co-infected patients. If I have understood correctly it could be a challenge for labs to detect mixed GTs when one GT is in the minority. (I just wonder how much more this would be the case when seeking for minor genetic variants such as minor resistant strains?)
================================================
I concluded shortly that I could have a positive chance to get a response from Oxymatrine while having minimal risks of provoking long lasting resistance and due to the short time IFN-Riba I can avoid much of the sx.s of SOC. And one more benefit: with an abrupt end of therapy you are left with a tormented immune system, killed down bone marrow.  It takes time to recover to produce sufficient levels of natural Interferons - this could be one cause of some relapses. Short therapy duration may minimize this risk, too.

Skepsis

PS. I am going to bed now, here in Europe we have midnight - Tomorrow at 8 a.m. gastroscopy :-(  
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Avatar universal
One consideration might be to start off this tx with "induction" therapy. Doubling up the doses in the beginning of treatment. I doubled both for the first month, I also doubled up the Riba, neither of which am I suggesting anyone else do, but that is what I did.I have not needed had to use rescue drugs or reduce med doses so far.  Since I had already failed therapy I wanted to start off with a bang. It worked for me and I think FL also did the same thing and we were both UND by week 4. The tale of our SVR is yet to be told but from what I read, my chances of success would improve if I started out with a higher dose.










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Avatar universal
Kalio how has your treatment been going? Haven't seen you around much. We've been chatting a bit lately about oxymatrine lately. I was wondering how you're treatment was going? Anything interesting to report?

Skepsis unless you have significant liver damage, than I'm not sure I'd do another round of IFN right now. The more I learn about the various antivirals (which might include oxymatrine if the Chinese claims are legit), the more I think of them as very precious "silver bullets". They mustn't be squandered or used in a thoughtless manner. Not that what you suggested was throughtless, it's just that if oxymatrine turns out to be a dud, you'll be setting yourself for yet another drug resistant breeding session by such a short course of IFN/riba. If you've got minimal fibrosis, I might wait out some of the PI's (like telaprevir). You've already demonstrated relatively poor response to IFN in the past, and considering that your accumulated IFN exposure is getting up there, I'd be careful about inducing undesirable long term side effects. I'd try to wait until the time is truly ripe to strike - and then strike with a VENGEANCE. For instance, when the first PI comes available, combine that PI with IFN and possibly riba induction dosing for ~2 months and then follow up with another 4-8 months (or whatever the PI SVR stats dictate at that time). Maybe add oxymatrine into the mix too, but I'm reluctant to say that because of how little I know about oxymatrine and how it may interfere with a PI or maybe even IFN/riba (although I doubt it would).

Otherwise, if you do have significant liver damage and time is truly of the essence, then I'd agree that another round might be warranted. As you said, I'd start with induction therapy with IFN/riba and oxymatrine, but I would not discontinue the IFN/riba after the induction period (after which hopefully you would be UND). I would simply back off on the dosage to normal levels and also continue with the oxymatrine. I'd go at least a year, and perhaps longer. Just my $0.02...
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Avatar universal
The way I understand it, the antiviral (oxymatrine) should be taken only while on Interferon, if taken without the "protection" from mutation you gain from interferon, you risk rendering the oxy useless. I'd start the oxymatrine once you start the tx.

Best of luck with starting tx! I hope it goes smoothly for you and you have few side effects!
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