Aa
Tonight I officially start TAF - I'll put all my results here
For those that recall, I've been on the clinical trial for TDF vs. TAF. It's a double blinded study which means I do not which drug I was on. I tried asking my doctor today about this and he just smirked a little at me and said "we don't know" but I suspect he does know and opted not to tell me as per agreement/contract. However, this does not change the fact that going forward, I will now be treated with TAF for the remainder of the trial which last 9 months.
Anyway, I decided to mention to him that this new formula was going through FDA approval and he was well aware. I asked him how long would it take for it to be approved and he said about 9 months. He's very confident that it will go through without any hesitation.
Naturally, I asked him a series of questions, such as what happens if my insurance does not approve the new formula or if the FDA approves it before the trial ends or it does not get approved at all. Here were some of the answers I was given:
-If FDA Approves it before the trial ends, I will finish the trial as they want to collect as much data as they can.
-If FDA does no approve, the trial will be extended
-It's possible my insurance may not cover the new formula, especially if it ends up being significantly higher in price than the old formula. If that is the case, they can look at getting me onto the old formula or if it came down to it, switching me to entecavir.
-Price wise, they'd look at getting me a copay card to offset any of the pricing down the line. Asked about this and was told "could be a couple of hundred a month but we'll do our best to make it cheaper".
-I also asked about clinical trials down the line with them, which they said they don't have anything at the moment but I should look into the trials that are being aimed for the cure.
Overall, not only am I concerned about switching to TAF now (in case I have any reactions or symptoms come back) but what concerns me the most is the fact that they are even thinking about switching me from Tenofovir to entecavir. To me, this does not even make any since since Tenofovir works a LOT better.
Now, I did get a result back of my Ultrasound. Unfortunately, I have a cyst on my kidney that seems to be growing but my last blood test seems to be fine with kidney function. I also have a polyp on my gallblader which I have had for years now. More importantly, my liver: No abnormalities, perfectly normal.
On that note, I'll share my results going forward.. including the results from the blood being drawn today prior to TAF (which I should have in 2 weeks). For prior results, please see my old posts.
Please note, I am no doctor, I am a patient.... I know I get many questions via PM as if they are directed towards a doctor, but I can only answer so much based on my experience. Also, I have no way of getting TAF other than through this trial and do not know of any other way. Please feel free to ask anything you'd like. I'll answer my best and will give some feedback of the meds and how they are working for me down the line.
Anyway, I decided to mention to him that this new formula was going through FDA approval and he was well aware. I asked him how long would it take for it to be approved and he said about 9 months. He's very confident that it will go through without any hesitation.
Naturally, I asked him a series of questions, such as what happens if my insurance does not approve the new formula or if the FDA approves it before the trial ends or it does not get approved at all. Here were some of the answers I was given:
-If FDA Approves it before the trial ends, I will finish the trial as they want to collect as much data as they can.
-If FDA does no approve, the trial will be extended
-It's possible my insurance may not cover the new formula, especially if it ends up being significantly higher in price than the old formula. If that is the case, they can look at getting me onto the old formula or if it came down to it, switching me to entecavir.
-Price wise, they'd look at getting me a copay card to offset any of the pricing down the line. Asked about this and was told "could be a couple of hundred a month but we'll do our best to make it cheaper".
-I also asked about clinical trials down the line with them, which they said they don't have anything at the moment but I should look into the trials that are being aimed for the cure.
Overall, not only am I concerned about switching to TAF now (in case I have any reactions or symptoms come back) but what concerns me the most is the fact that they are even thinking about switching me from Tenofovir to entecavir. To me, this does not even make any since since Tenofovir works a LOT better.
Now, I did get a result back of my Ultrasound. Unfortunately, I have a cyst on my kidney that seems to be growing but my last blood test seems to be fine with kidney function. I also have a polyp on my gallblader which I have had for years now. More importantly, my liver: No abnormalities, perfectly normal.
On that note, I'll share my results going forward.. including the results from the blood being drawn today prior to TAF (which I should have in 2 weeks). For prior results, please see my old posts.
Please note, I am no doctor, I am a patient.... I know I get many questions via PM as if they are directed towards a doctor, but I can only answer so much based on my experience. Also, I have no way of getting TAF other than through this trial and do not know of any other way. Please feel free to ask anything you'd like. I'll answer my best and will give some feedback of the meds and how they are working for me down the line.
Any way to test if nad+ supplementation does it's job well or rather is damaging something ? Or one just need to observe his energy levels, recover time after workout etc ... ?
If a mitochondria obtains a point mutation by this mechanism it will typically produce a slightly altered protein with consequences varying from no relevant effect to substantial dysfunction.
if the nuclear dna obtains point mutations they can sometimes lead to a cancerous phenotype that is, through the cells inbuilt cancer defense mechanisms, frequently removed by apoptosis. But not always.
The supplement that Stef is talking about is nicotinamide riboside, it seems to be effectively uptaken intracellular in most tissues. It still needs to be converted by two consecutive enzymes into NAD+, those enzymes are available in brain and muscle in particular in the nuclear compartment where the supply of NAD is urgently needed for the function of the nuclear sirtuins , since it is consumed by their function of deacetylation, not like a coenzyme but as a depleted substrate, forming Nicotinamid in this process, which needs to be salvaged. .resynthesized..by NAMPT into NAD+.
Nicotinamid is a fairly strong inhibitor of the Sirtuin function, thus too much supply can have the opposite effect.
It is the nuclear sirtuins which will finally signal mitochondrial regeneration and improved synthesis of ATP. This is how nicotinamide riboside is expected to work. It seems that higher doses can have a negative effect likely by accumulation of competing nicotinamide, the byproduct of the critical reaction. At this time I think that 200mg per day in divided doses, ideally taken sublinqual might be optimal, but this could be quite variable depending on the individual.
if the nuclear dna obtains point mutations they can sometimes lead to a cancerous phenotype that is, through the cells inbuilt cancer defense mechanisms, frequently removed by apoptosis. But not always.
The supplement that Stef is talking about is nicotinamide riboside, it seems to be effectively uptaken intracellular in most tissues. It still needs to be converted by two consecutive enzymes into NAD+, those enzymes are available in brain and muscle in particular in the nuclear compartment where the supply of NAD is urgently needed for the function of the nuclear sirtuins , since it is consumed by their function of deacetylation, not like a coenzyme but as a depleted substrate, forming Nicotinamid in this process, which needs to be salvaged. .resynthesized..by NAMPT into NAD+.
Nicotinamid is a fairly strong inhibitor of the Sirtuin function, thus too much supply can have the opposite effect.
It is the nuclear sirtuins which will finally signal mitochondrial regeneration and improved synthesis of ATP. This is how nicotinamide riboside is expected to work. It seems that higher doses can have a negative effect likely by accumulation of competing nicotinamide, the byproduct of the critical reaction. At this time I think that 200mg per day in divided doses, ideally taken sublinqual might be optimal, but this could be quite variable depending on the individual.
Antivirals like lamuvidine or tenofovir are added to the growing DNA chain, but then, due to the lack of a hydroxyl group are terminating the further growth and you have a functionless fragment of dna, that will do no more harm. These are called obligate chain terminators, since the partial dna is terminated due to the inability to form the next chemical bond out of structural necessity.
These antivirals can also slow the production of mitochondrial dna by the mitochondria specific gamma polymerase, but no mutation is introduced into the mitochondrial dna. Upon treatment cessation, the mitochondrial genome is unchanged and can fully function again.
In contrast, entecavir and telbivudine are equipped with the necessary hydroxyl group to CONTINUE the dna growth after incorporation of the antivirals misstructured base and the result will be a mutation at this point that stays permanently upon following rounds of replication.
In needs to be pointed out that the continuation of dna chain growth after adding either of entecavir or telbivudine is a very rare event due to the distorted chemical structure..placement in space for the next nucleotide addition. ..therefore they are called NONOBLIGATE CHAIN TERMINATORS, because while they could, they will normally nevertheless terminate the chain growth for the mentioned steric reasons.
These antivirals can also slow the production of mitochondrial dna by the mitochondria specific gamma polymerase, but no mutation is introduced into the mitochondrial dna. Upon treatment cessation, the mitochondrial genome is unchanged and can fully function again.
In contrast, entecavir and telbivudine are equipped with the necessary hydroxyl group to CONTINUE the dna growth after incorporation of the antivirals misstructured base and the result will be a mutation at this point that stays permanently upon following rounds of replication.
In needs to be pointed out that the continuation of dna chain growth after adding either of entecavir or telbivudine is a very rare event due to the distorted chemical structure..placement in space for the next nucleotide addition. ..therefore they are called NONOBLIGATE CHAIN TERMINATORS, because while they could, they will normally nevertheless terminate the chain growth for the mentioned steric reasons.
1 Comments
Thank you for the explanation. So it is in the context of mtDNA. I read that
"The lack of mitochondrial toxicity was consistent with the finding that ETV-TP was not recognized by mitochondrial DNA Pol γ and failed to be incorporated into DNA or inhibit the polymerase assay at the highest levels tested, 300 μM. Combinations of ETV with each of the other HBV NRTI antivirals, adefovir, tenofovir, and lamivudine at 10 times their respective Cmax levels also failed to result in cellular or mitochondrial toxicity. In summary, cell culture and enzymatic studies yielded no evidence that would predict mitochondrial toxicity of ETV at exposure levels in excess of those expected to be achieved clinically."
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2224751/
"The lack of mitochondrial toxicity was consistent with the finding that ETV-TP was not recognized by mitochondrial DNA Pol γ and failed to be incorporated into DNA or inhibit the polymerase assay at the highest levels tested, 300 μM. Combinations of ETV with each of the other HBV NRTI antivirals, adefovir, tenofovir, and lamivudine at 10 times their respective Cmax levels also failed to result in cellular or mitochondrial toxicity. In summary, cell culture and enzymatic studies yielded no evidence that would predict mitochondrial toxicity of ETV at exposure levels in excess of those expected to be achieved clinically."
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2224751/
nad+ is anti aging supplement which improves mitochondria' function so better energy transport inside all body cells. I'm sure studyforhope can explain it better.
If Entecavir may incorporate into cells' dna (any cells or only liver cells ?) won't those cells sooner or later removed by regular apostosis after stopping treatment ?
Yes he could take half of the pill, since the vl is very very small now, this should work just fine. The high dose is meant to treat patients in the billions down to und, there is a large chance to develop adaptive mutations on the way despite the fact that there are no known resistance mutations to tenofovir.
Entecavir might have a similar issue, not much is really known about that. The tissue culture studies to determine mitochondrial damage are done on cell lines that might behave quite different than muscle tissue in vivo.
Entecavir has the unpleasant issue of the theoretical possibility of incorporation into the growing dna chain, leading to permanent mutations incurable after stopping the drug. This has not yet been shown in direct studies, but the carcinoma problems in the animal studies point in that direction.
the entecavir sister drug lobucavir was halted in mid trial by the fda, since parallel mouse studies showed such a huge rate of carcinomas. The nucleoside portion was the same, only the side tail to attach better to the polymerase is different.
Entecavir might have a similar issue, not much is really known about that. The tissue culture studies to determine mitochondrial damage are done on cell lines that might behave quite different than muscle tissue in vivo.
Entecavir has the unpleasant issue of the theoretical possibility of incorporation into the growing dna chain, leading to permanent mutations incurable after stopping the drug. This has not yet been shown in direct studies, but the carcinoma problems in the animal studies point in that direction.
the entecavir sister drug lobucavir was halted in mid trial by the fda, since parallel mouse studies showed such a huge rate of carcinomas. The nucleoside portion was the same, only the side tail to attach better to the polymerase is different.
2 Comments
Well, you make my day worst with this reply. I am on etv....i thought it s a bit safer.
To Studyforhope.
"Incorporation into the growing dna chain" - isn't this the mechanism behind Entecavir (and Lamivudine) to thereby terminate reverse transcription of pgRNA to HBV DNA? Also, human cells do not replicate by growing dna but rather by mitosis?
Or are you talking in a different context? Do pardon me if my questions are silly.
"Incorporation into the growing dna chain" - isn't this the mechanism behind Entecavir (and Lamivudine) to thereby terminate reverse transcription of pgRNA to HBV DNA? Also, human cells do not replicate by growing dna but rather by mitosis?
Or are you talking in a different context? Do pardon me if my questions are silly.
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