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?)
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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 :-(