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Enzyme Deficiency Protects Hepatitis C Patients from Treatment-Related Anemia
http://www.dukehealth.org/health_library/news/enzyme_deficiency_protects_hep_c_patients_from_treatment_related_anemia
By Duke Medicine News and Communications
Many people who undergo treatment for hepatitis C develop hemolytic anemia, a disorder that destroys red blood cells. In some cases, it is so severe they have to reduce their medication or stop therapy altogether.
But now, scientists in Duke University’s Institute for Genome Sciences & Policy (IGSP) have discovered two genetic alterations linked to a benign enzyme condition that keep some patients anemia-free.
They say the discovery, appearing online in the journal Nature, opens the door to treatment for patients who have never been considered candidates for therapy before and may also hold the key to new drugs that could prevent anemia from developing in the first place.
The protective mechanism is a deficiency in a gene called ITPA. “We found that patients who carried specific functional variants are strongly protected against developing anemia,” says David Goldstein, PhD, director of the Center for Human Genome Variation in the IGSP and a senior author of the study.
Previous studies had identified the genetic variants as the cause of a deficiency in the production of an enzyme, inosine triphosphatase. But it was only through a genome-wide association study that the Duke team was able to show that these same variants were protective against anemia induced by ribavirin, one of two necessary drugs in hepatitis C treatment.
About 180 million people worldwide are infected with the hepatitis C virus, and about 30 to 40 percent of them could develop some degree of treatment-related anemia, according to John McHutchison, MD, associate director for research at the Duke Clinical Research Institute and also a senior author.
“It’s a big problem. Hemolytic anemia reduces the level of hemoglobin in the blood and robs it of its ability to carry oxygen. Anything that could help us predict who is going to become anemic and who is not could help us better manage therapy and give all patients the best chance of a good outcome,” said McHutchison.
Goldstein and McHutchison, who had earlier worked together in identifying genetic variants that helped explain race-based differences in response to hepatitis C treatments, believed there was probably a gene-based solution to the anemia puzzle as well.
Working with first authors Jacques Fellay, MD; Alex Thompson, MD, PhD; and Dongliang Ge, PhD, investigators turned to a rich database already at hand: the records of 1286 individuals who had earlier taken part in the IDEAL study, a large, randomized, Duke-led clinical trial that compared leading therapies for hepatitis C.
Researchers separated the patients into three ethnic groups, (988 European Americans, 198 African Americans, and 100 Hispanic Americans) and analyzed their decline in hemoglobin levels during the first month of treatment.
The researchers conducted a genome-wide association study and found several polymorphisms -- single-letter DNA alterations -- also known as “SNPs or “snips” -- associated with reduced hemoglobin levels.
But finding an association is just a start: of more biological importance is the identification of the causal variants, the polymorphisms that directly influence hemoglobin levels.
Investigators discovered that the two variants known to cause ITPA deficiency appeared almost exclusively on chromosomes that also carried the protective version of the most associated SNP. Further statistical analysis proved that the two variants were indeed the source of protection from anemia.
McHutchison says the discovery is clinically important. “The beauty of this finding is that it may mean we could consider offering treatment to patients who have additional problems, like coronary artery disease or kidney disease. Right now, we are generally uncomfortable treating these patients because anemia could make their underlying condition worse. If a test could tell us which patients are not going to become anemic, we could consider treating them.”
“Most of us trace the birth of pharmacogenetics to a 1957 paper by Arno Moltulsky who argued that important drug responses may often depend on genetic differences among people that are invisible until an individual takes a certain drug,” says Goldstein. “These ITPA variants reflect this classic formulation of pharmacogenetics, and suggest to us that there are many other important variants that can and should be found through the careful genetic analyses of patients’ drug responses.”
Colleagues from Duke who contributed to the study include Curtis Gumbs, Thomas Urban, Kevin Shianna, Latasha Little and Andrew Muir. Other co-authors include Mark Sulkowski, from Johns Hopkins; and Ping Qiu, Arthur Bertelsen, Mark Watson, Amelia Warner, Clifford Brass and Janice Albrecht, from Schering-Plough Research Institute.
Schering-Plough Research Institute funded the study and has filed a patent application based on the findings. Ten of the study authors, including Goldstein, Thompson, Ge, Fellay, Urban, Shianna and McHutchison, are listed as inventors on the application.
By Duke Medicine News and Communications
Many people who undergo treatment for hepatitis C develop hemolytic anemia, a disorder that destroys red blood cells. In some cases, it is so severe they have to reduce their medication or stop therapy altogether.
But now, scientists in Duke University’s Institute for Genome Sciences & Policy (IGSP) have discovered two genetic alterations linked to a benign enzyme condition that keep some patients anemia-free.
They say the discovery, appearing online in the journal Nature, opens the door to treatment for patients who have never been considered candidates for therapy before and may also hold the key to new drugs that could prevent anemia from developing in the first place.
The protective mechanism is a deficiency in a gene called ITPA. “We found that patients who carried specific functional variants are strongly protected against developing anemia,” says David Goldstein, PhD, director of the Center for Human Genome Variation in the IGSP and a senior author of the study.
Previous studies had identified the genetic variants as the cause of a deficiency in the production of an enzyme, inosine triphosphatase. But it was only through a genome-wide association study that the Duke team was able to show that these same variants were protective against anemia induced by ribavirin, one of two necessary drugs in hepatitis C treatment.
About 180 million people worldwide are infected with the hepatitis C virus, and about 30 to 40 percent of them could develop some degree of treatment-related anemia, according to John McHutchison, MD, associate director for research at the Duke Clinical Research Institute and also a senior author.
“It’s a big problem. Hemolytic anemia reduces the level of hemoglobin in the blood and robs it of its ability to carry oxygen. Anything that could help us predict who is going to become anemic and who is not could help us better manage therapy and give all patients the best chance of a good outcome,” said McHutchison.
Goldstein and McHutchison, who had earlier worked together in identifying genetic variants that helped explain race-based differences in response to hepatitis C treatments, believed there was probably a gene-based solution to the anemia puzzle as well.
Working with first authors Jacques Fellay, MD; Alex Thompson, MD, PhD; and Dongliang Ge, PhD, investigators turned to a rich database already at hand: the records of 1286 individuals who had earlier taken part in the IDEAL study, a large, randomized, Duke-led clinical trial that compared leading therapies for hepatitis C.
Researchers separated the patients into three ethnic groups, (988 European Americans, 198 African Americans, and 100 Hispanic Americans) and analyzed their decline in hemoglobin levels during the first month of treatment.
The researchers conducted a genome-wide association study and found several polymorphisms -- single-letter DNA alterations -- also known as “SNPs or “snips” -- associated with reduced hemoglobin levels.
But finding an association is just a start: of more biological importance is the identification of the causal variants, the polymorphisms that directly influence hemoglobin levels.
Investigators discovered that the two variants known to cause ITPA deficiency appeared almost exclusively on chromosomes that also carried the protective version of the most associated SNP. Further statistical analysis proved that the two variants were indeed the source of protection from anemia.
McHutchison says the discovery is clinically important. “The beauty of this finding is that it may mean we could consider offering treatment to patients who have additional problems, like coronary artery disease or kidney disease. Right now, we are generally uncomfortable treating these patients because anemia could make their underlying condition worse. If a test could tell us which patients are not going to become anemic, we could consider treating them.”
“Most of us trace the birth of pharmacogenetics to a 1957 paper by Arno Moltulsky who argued that important drug responses may often depend on genetic differences among people that are invisible until an individual takes a certain drug,” says Goldstein. “These ITPA variants reflect this classic formulation of pharmacogenetics, and suggest to us that there are many other important variants that can and should be found through the careful genetic analyses of patients’ drug responses.”
Colleagues from Duke who contributed to the study include Curtis Gumbs, Thomas Urban, Kevin Shianna, Latasha Little and Andrew Muir. Other co-authors include Mark Sulkowski, from Johns Hopkins; and Ping Qiu, Arthur Bertelsen, Mark Watson, Amelia Warner, Clifford Brass and Janice Albrecht, from Schering-Plough Research Institute.
Schering-Plough Research Institute funded the study and has filed a patent application based on the findings. Ten of the study authors, including Goldstein, Thompson, Ge, Fellay, Urban, Shianna and McHutchison, are listed as inventors on the application.
also, didn't the Lindahl study show direct correlation between blood plasma levels of riba and SVR?? Meaning the amount getting INTO the body was key, not the dose given, but the amount absorbed,
This then becomes key because Inosine is made in the gut, seems to me its an adjunct of adenosine, I would think this is not only genetic because we know that intestinal process is not only gentics but reliant on the ecosystem withing the elimentary canal itself, i.e. the breakdown of chemicals is not strictly speaking our adequacy or quantities of competant intestinal villi, but also involves the entirety of the intestinal flora landscape, the dozens of bacterium varients, millions of whom produce the breakdown of all nucleotides.
Ergo I'd be hard pressed to believe one could pin everything here on genetics alone.
I'd suspect that insufficient uptake ability could be a leading cause of muscle wasting, but I'd also suspect that as inosine plays a role in both the absorption phase in the bowel cells, AND is utilized in the rebuilding and transcription of RNA, where riba also tries to do it's inhibitory work, that perhaps the virons thrive on good proteins as does the body, and that this might be a reasonable assumption based on the chemistry.
That what might help the body, proteins, might also be of use to the virons...after all, virons have to eat too.
Anyway, I still plan on eating my proteins at a different time of day than my riba, just to ensure it has a better chance of absorbing.
It seems to me there was some chatter in here a couple years ago about vegetarians SVR'ing at a higher rate...though I can't recall if any studies actually confirmed this.
mb
This then becomes key because Inosine is made in the gut, seems to me its an adjunct of adenosine, I would think this is not only genetic because we know that intestinal process is not only gentics but reliant on the ecosystem withing the elimentary canal itself, i.e. the breakdown of chemicals is not strictly speaking our adequacy or quantities of competant intestinal villi, but also involves the entirety of the intestinal flora landscape, the dozens of bacterium varients, millions of whom produce the breakdown of all nucleotides.
Ergo I'd be hard pressed to believe one could pin everything here on genetics alone.
I'd suspect that insufficient uptake ability could be a leading cause of muscle wasting, but I'd also suspect that as inosine plays a role in both the absorption phase in the bowel cells, AND is utilized in the rebuilding and transcription of RNA, where riba also tries to do it's inhibitory work, that perhaps the virons thrive on good proteins as does the body, and that this might be a reasonable assumption based on the chemistry.
That what might help the body, proteins, might also be of use to the virons...after all, virons have to eat too.
Anyway, I still plan on eating my proteins at a different time of day than my riba, just to ensure it has a better chance of absorbing.
It seems to me there was some chatter in here a couple years ago about vegetarians SVR'ing at a higher rate...though I can't recall if any studies actually confirmed this.
mb
OK, becomes but then the question becomes WHY? Why are they protected?
Inosine has been shown to inhibit the bowel cells from absorbing ribavirin. Ergo less absorption would mean less anemia.
This also means the higher the diet is in inosine, the less the riba could work, without any genetic component.
If they are saying that a genetic component prevents isonine conversions as a separate issue, that would effect how much inosine becomes available to our RNA as this is where it is utilized.
However all this does for me is confuse the issue. If Purines and inosine prevent bowel cells from absorbing the riba then I should avoid them right?
But if I am genetically predisposed to not absorb them anyway, wouldn't I still risk not doing well on tx if they are present?
This seems to me a real connundrum. inosine is supposed to be needful for nerve regeneration and even muscle movement.
I wish HR would drop by and explain how the genetics differ from the dietary concerns.
mb
how does all this relate to riba absoption being links to purine???????
http://resources.metapress.com/pdf-preview.axd?code=t37258642421271g&size=largest
Inosine has been shown to inhibit the bowel cells from absorbing ribavirin. Ergo less absorption would mean less anemia.
This also means the higher the diet is in inosine, the less the riba could work, without any genetic component.
If they are saying that a genetic component prevents isonine conversions as a separate issue, that would effect how much inosine becomes available to our RNA as this is where it is utilized.
However all this does for me is confuse the issue. If Purines and inosine prevent bowel cells from absorbing the riba then I should avoid them right?
But if I am genetically predisposed to not absorb them anyway, wouldn't I still risk not doing well on tx if they are present?
This seems to me a real connundrum. inosine is supposed to be needful for nerve regeneration and even muscle movement.
I wish HR would drop by and explain how the genetics differ from the dietary concerns.
mb
how does all this relate to riba absoption being links to purine???????
http://resources.metapress.com/pdf-preview.axd?code=t37258642421271g&size=largest
Trinity:
Somewhat in relation to your question,I have been talking to a few people in the particular study I am in and strangely enough most are Not having anemia issues,including myself.Is this just a coincidence...obviously no way to know at this point or does it say something about the inhibitor being added having that effect. That would seem odd as we are all still taking weight based riba ..but again it struck me as being noteworthy.
Lets hope that this part of it is also looked at closely...and by the time of release it will be known .
WILL
Somewhat in relation to your question,I have been talking to a few people in the particular study I am in and strangely enough most are Not having anemia issues,including myself.Is this just a coincidence...obviously no way to know at this point or does it say something about the inhibitor being added having that effect. That would seem odd as we are all still taking weight based riba ..but again it struck me as being noteworthy.
Lets hope that this part of it is also looked at closely...and by the time of release it will be known .
WILL
Wonder how much a role the anemia factor will play when the new meds come out? What we know know applies to SOC only. I have the capacity to play around with the ribavirin next go round but I do I really want to? How is my hgb going to be effected by the protease inhibitors? They are a direct acting agent on the virus and will high dose ribavirin be necessary to stifle mutation? Do I want to predose 1000 to1200 mg 3 wks in advance and then have my hgb tank 4 weeks out on treatment and be subject to dose reduction?
Trinity
Trinity
It seems that a >3g drop of HgB is desirable by week 8.
http://www.gastrojournal.org/article/S0016-5085(10)01222-9/abstract
Many of us have very different thresholds for Ribavirin and this enzyme
deficiency could be one of the reasons.
Would be great if Ribavirin dosing was more individualized , but that would require
a lot more patient care with many more HgB checks per patient.
Personally I try and keep my HgB between 10-11g (15.4 baseline) and it takes dosage adjustments at different stages of tx to accomplish that.
http://www.gastrojournal.org/article/S0016-5085(10)01222-9/abstract
Many of us have very different thresholds for Ribavirin and this enzyme
deficiency could be one of the reasons.
Would be great if Ribavirin dosing was more individualized , but that would require
a lot more patient care with many more HgB checks per patient.
Personally I try and keep my HgB between 10-11g (15.4 baseline) and it takes dosage adjustments at different stages of tx to accomplish that.
interesting stuff, thanks.
the Nature article is here:
http://www.ncbi.nlm.nih.gov/pubmed/20173735
and as evident from the 'related citations' tab there has been a flurry of similar findings. Haven't read through any of it but I think book_em asked the 64k question - so having those snps confers protection against HgB decline - but what does it say about SVR? Both Trin and Bill were in the stratospheric range of rbv mg/kg dosing, neither got anemic, but it only worked for Bill - what gives?
The other interesting twist here is that this crew( McHuchinson, Goldstein, Ge, Merck) is the same bunch that found the IL28B snps by trolling that same IDEAL data set. Some fraction of every Labcorp IL28B test may be going to offset their patent. These guys are on a roll.
the Nature article is here:
http://www.ncbi.nlm.nih.gov/pubmed/20173735
and as evident from the 'related citations' tab there has been a flurry of similar findings. Haven't read through any of it but I think book_em asked the 64k question - so having those snps confers protection against HgB decline - but what does it say about SVR? Both Trin and Bill were in the stratospheric range of rbv mg/kg dosing, neither got anemic, but it only worked for Bill - what gives?
The other interesting twist here is that this crew( McHuchinson, Goldstein, Ge, Merck) is the same bunch that found the IL28B snps by trolling that same IDEAL data set. Some fraction of every Labcorp IL28B test may be going to offset their patent. These guys are on a roll.
Interesting take you have on the information. I thought the information was more about questions then answers.
Please note that there are numerous important questions that have NOT been answered yet, at least not in this study's presented summary.
For instance, is there (or is there not) a statistically significant correlation between having such enzyme deficiency and one's probability of SVR? What good would it do to use such enzyme-deficiency information to rationalize offering treatments to the new Tx-groups (as suggested could be done with such information), if the same IDEAL study data used to find this enzyme-deficiency linkage -- more thoroughly examined -- could have also been used to show that these same non-anemia-prone people were also significantly less likely to obtain SVR in that IDEAL study (even though, through their lack of anemia, they WERE able to take the whole SOC Tx regimen, without any dosage reductions, etc)?
Remember, there is plenty of information out there suggesting that significant anemia, at least for most of us, might actually be a good sign that we might SVR [or that we are t least getting enough Ribavirin].
Notably (if memory serves), at least a few of the earlier commenters to this post had both low levels of anemia -- BUT less than desirable strengths of response to SOC Tx.
Another important question (and slightly more to the point) is: Does this enzyme deficiency actually provide its supposed anemia-protection simply by reducing ribavirin uptake? Although not a readily available test to most of us, this study could/should (and might) have directly tested (study-preserved) blood-levels of ribavirin metabolites so as to be able to answer such an important question.
Unless and until a lot more information is released about this study's methods and findings, I am inclined to lump it into the enormous pile or studies that largely failed to even give adequate thought as to what answers they should have actually been seeking as their end-point(s).
For instance, is there (or is there not) a statistically significant correlation between having such enzyme deficiency and one's probability of SVR? What good would it do to use such enzyme-deficiency information to rationalize offering treatments to the new Tx-groups (as suggested could be done with such information), if the same IDEAL study data used to find this enzyme-deficiency linkage -- more thoroughly examined -- could have also been used to show that these same non-anemia-prone people were also significantly less likely to obtain SVR in that IDEAL study (even though, through their lack of anemia, they WERE able to take the whole SOC Tx regimen, without any dosage reductions, etc)?
Remember, there is plenty of information out there suggesting that significant anemia, at least for most of us, might actually be a good sign that we might SVR [or that we are t least getting enough Ribavirin].
Notably (if memory serves), at least a few of the earlier commenters to this post had both low levels of anemia -- BUT less than desirable strengths of response to SOC Tx.
Another important question (and slightly more to the point) is: Does this enzyme deficiency actually provide its supposed anemia-protection simply by reducing ribavirin uptake? Although not a readily available test to most of us, this study could/should (and might) have directly tested (study-preserved) blood-levels of ribavirin metabolites so as to be able to answer such an important question.
Unless and until a lot more information is released about this study's methods and findings, I am inclined to lump it into the enormous pile or studies that largely failed to even give adequate thought as to what answers they should have actually been seeking as their end-point(s).
I haven"t rec"d my first trial (vl) results yet...however hgb has only dropped from 15.2 to 13.9 in 12 wk. on 1200mg...interesting
I must have been ITPA deficient too because I never developed any significant anemia either. 1000 mg riba daily for 112 lb. woman should have sent my hgb plummeting but it didn't.
It certainly makes you wonder if anemia is a true indicator or riba absorption and why anemia is such a strong indicator for possible svr.
I think this is interesting, Dave. I wonder if they intend to do ongoing research into this. As some know, I was using 2g/day ribavirin (up to 23mg/kg/day) for around 140 weeks, and never developed significant anemia as a result. I’m guessing there is a strong chance I am ITPA deficient.
Thanks for the post--
-Bill
Thanks for the post--
-Bill
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