Aa
Possible Action Of Ribavirin
This is fairly new information. As we know, the efficacy of IFN is dependent on the phosphorylation of PKR. I have always thought - hey, since we're bypassing our own endogenous IFN with injected IFN, why not upregulate PKR? This is part of ribavirin's job. Well, now that we know what it does, first order is to find something different that can do the same thing.
Apparently, in SOC therapy, your own body's IFN does little or nothing to help, but the whole system is bypassed altogether.
Of note:
It was once thought that IFN-generated quasispecies contributed to nonresponse. Now it seems that IFN-resistant quasispecies in genotype 1b are already in place before treatment begins. The mutation is accomplished by the virus switching amino acids. Genotype 1a responders have a lower variability of pre-treatment quasispecies than nonresponders.
Apparently, in SOC therapy, your own body's IFN does little or nothing to help, but the whole system is bypassed altogether.
Of note:
It was once thought that IFN-generated quasispecies contributed to nonresponse. Now it seems that IFN-resistant quasispecies in genotype 1b are already in place before treatment begins. The mutation is accomplished by the virus switching amino acids. Genotype 1a responders have a lower variability of pre-treatment quasispecies than nonresponders.
I agree whole-heartedly with everything you said. My own doctor helped me when I sought experimental treatment. Several years ago, he agreed to supervise me on a very high IFN dose. He kept a good eye on me and even let me come into the office without an appointment if I was having trouble. He was invloved and interested in finding out what worked, and I'm happy to learn you have two great doctors.
Insurance companies will pay if the doctor uses a chemotherapy code and not the hemolytic anemia code. That's why some doctors send their patients to see a hematologist/oncologist to prescribe the Procrit.
Co
Co
All true, but I think the problem with high-dose ribavirin (HDR) is at least in part microcosmic of the total basket of problems facing the average patient entering treatment today. That being all too often stuck with a GI (or even family doctor) who doesn't have the training or experience to implement more cutting edge strategies such as early and sensitive viral load testing, weight-based ribavirin for all genotypes, helper drugs -- and yes, HDR when indicated.
And even with a hepatologist (liver specialist) -- highly recommended IMO for anyone treating -- a little push is sometimes needed as well and probably for a complex of reasons, patient comfort and being sued no doubt somewhere on the list. That said, when I presented my desire to go HDR to two well-known hepatologists they were all too happy to oblige me, no doubt because the responsiblity shifted just a little with the idea coming from the patient, but equally because they knew it was a reasonable approach given my stats. The small molecules hopefully will make all this academic soon but I wonder just how many SVRs have been lost in the last few years for those who decided waiting was not in their best interest.
-- Jim
And even with a hepatologist (liver specialist) -- highly recommended IMO for anyone treating -- a little push is sometimes needed as well and probably for a complex of reasons, patient comfort and being sued no doubt somewhere on the list. That said, when I presented my desire to go HDR to two well-known hepatologists they were all too happy to oblige me, no doubt because the responsiblity shifted just a little with the idea coming from the patient, but equally because they knew it was a reasonable approach given my stats. The small molecules hopefully will make all this academic soon but I wonder just how many SVRs have been lost in the last few years for those who decided waiting was not in their best interest.
-- Jim
Jim -
I think a lot of ribavirin dosing is done with extreme caution. There are still doctors out there who will cut riba dosing instead of adding Procrit - which has come under more safety scrutiny lately, as I'm sure you know, and is off-label for ribavirin anemia. Some insurances won't pay for it. Some high-dose riba patients have needed transfusions to get them through therapy. I think for the most part, doctors suffer from a lack of information on the efficacy of high-dose ribavirin, as well as a powerful motivation to keep from getting sued. Add this to what you suggested - a hopeful view toward small molecule therapy, makes high-dose ribavirin a risk most doctors wouldn't want to take.
I think a lot of ribavirin dosing is done with extreme caution. There are still doctors out there who will cut riba dosing instead of adding Procrit - which has come under more safety scrutiny lately, as I'm sure you know, and is off-label for ribavirin anemia. Some insurances won't pay for it. Some high-dose riba patients have needed transfusions to get them through therapy. I think for the most part, doctors suffer from a lack of information on the efficacy of high-dose ribavirin, as well as a powerful motivation to keep from getting sued. Add this to what you suggested - a hopeful view toward small molecule therapy, makes high-dose ribavirin a risk most doctors wouldn't want to take.
CS: Now Shiffman missed the point that it is the serum concentration of RBV that is important not how much you take.
--------------------------------------
Not missing the point, just making another one -- but he was missing the boat IMO, along with his fellow cruise members who include most of our leading hepatologists here in the United States.
Serum riba levels and their role in riba dosing and SVR -- first studied by Lindahal, Bruchfeld and group -- never got the serious attention it deserved and interestingly enough hardly gets a mention in similar studies starting to pop up that suggest serum riba levels are what matters and not simply weight-based formulas.
Maybe not enough money in ribavirin to parent more studies, maybe too many side effects, maybe it's just old-school with the newer PI's making their hay -- but for those choosing SOC, proper riba dosing seems to be a well kept secret by many of the docs who should know better by now. Maybe it's different now, but two years ago when treating I found it impossible to test for serum riba levels (HPLC technology) in this country. I was about to hop a plane to Sweden to test when I hit the riba wall (ended up in the ER) and decided I probably was at my maximum dose :) HPLC testing would have been a bit more elegant!
-- Jim
-- Jim
--------------------------------------
Not missing the point, just making another one -- but he was missing the boat IMO, along with his fellow cruise members who include most of our leading hepatologists here in the United States.
Serum riba levels and their role in riba dosing and SVR -- first studied by Lindahal, Bruchfeld and group -- never got the serious attention it deserved and interestingly enough hardly gets a mention in similar studies starting to pop up that suggest serum riba levels are what matters and not simply weight-based formulas.
Maybe not enough money in ribavirin to parent more studies, maybe too many side effects, maybe it's just old-school with the newer PI's making their hay -- but for those choosing SOC, proper riba dosing seems to be a well kept secret by many of the docs who should know better by now. Maybe it's different now, but two years ago when treating I found it impossible to test for serum riba levels (HPLC technology) in this country. I was about to hop a plane to Sweden to test when I hit the riba wall (ended up in the ER) and decided I probably was at my maximum dose :) HPLC testing would have been a bit more elegant!
-- Jim
-- Jim
I dont know about you Miles but i wouldnt mind knowing what P450 genes were induced by G2a RVR. Interesting abstract.
Gene expression profiling in liver of chronic hepatitis C patients undergoing interferon therapy reveals the signaling pathway of interferon resistance
Abstract:
Objective:
Although ribavirin (Rib) and interferon (IFN) combination therapy has become a popular modality for treating patients with chronic hepatitis C virus, about 50% of patients usually relapse, particularly those with genotype1b and high viral load. It has been shown that patients in whom viremia was eliminated in the early period after staring IFN therapy showed favorable outcome. Here we investigated possible mechanisms underlying differences in sensitivities to IFN therapy.
Material and Methods:
Thirty patients who received IFN + Rib combination therapy were enrolled. Liver biopsy was performed before and two weeks after staring IFN therapy in consenting patients. Isolated RNA from biopsy samples was analyzed using the Affymetrix GeneChip system (HG-U133 Plus2.0 Array). Sliced sections were prepared from frozen liver of 12 patients, and hepatocytes and liver-infiltrated lymphocytes were separately dissected by laser capture micro dissection (LCM). Changes in serum HCV RNA before, 48hr, 2w and 24w after starting IFN were evaluated using COBAS AmpliPrep/COBAS TaqMan 48.
Results:
From the analysis results, the patients could be classified into three groups: genotype 1b with rapid viral response (1b-RVR) (n=10), genotype 1b with slow viral response (1b-nonRVR) (n=13) and genotype 2a with rapid viral response (2a-RVR) (n=7) according to viral kinetics with IFN treatment. Comparing all patients before and 2 weeks after IFN therapy, IFN-stimulated genes (IFN genes) were identified. When comparing the IFN genes between 1b-RVR and 1b-nonRVR, 1b-RVR showed a more significant induction of IFN genes than 1b-nonRVR. All patients with genotype 2a showed rapid response to IFN, although induction of IFN genes was not as high as 1b-RVR, suggesting that other factors might be involved in the IFN sensitivity of genotype 2a.
Gene expression of LCM samples demonstrated that induction of IFN genes in hepatocytes of 1b-nonRVR was severely impaired, while IFN genes in lymphocytes were fairly induced. Pathway comparison between 1b-RVR and 1b-nonRVR before IFN therapy showed that oxidative phosphorylation, apoptosis, and immune reaction were more induced in 1b-nonRVR than in 1b-RVR. When comparing 1b-nonRVR and 2a-RVR, oxidative phosphorylation was induced in 1b-nonRVR and cytochrome p450 genes were induced in 2a-RVR.
Conclusion: Impaired induction of IFN genes in hepatocytes might be directly relayed to the poor responses to IFN therapy of 1b-nonRVR patients. These responses are probably reflected by the induction of oxidative stress, apoptosis and inflammation. Other mechanisms are likely involved in a fair response to IFN in patients with genotype 2a.
CS
Gene expression profiling in liver of chronic hepatitis C patients undergoing interferon therapy reveals the signaling pathway of interferon resistance
Abstract:
Objective:
Although ribavirin (Rib) and interferon (IFN) combination therapy has become a popular modality for treating patients with chronic hepatitis C virus, about 50% of patients usually relapse, particularly those with genotype1b and high viral load. It has been shown that patients in whom viremia was eliminated in the early period after staring IFN therapy showed favorable outcome. Here we investigated possible mechanisms underlying differences in sensitivities to IFN therapy.
Material and Methods:
Thirty patients who received IFN + Rib combination therapy were enrolled. Liver biopsy was performed before and two weeks after staring IFN therapy in consenting patients. Isolated RNA from biopsy samples was analyzed using the Affymetrix GeneChip system (HG-U133 Plus2.0 Array). Sliced sections were prepared from frozen liver of 12 patients, and hepatocytes and liver-infiltrated lymphocytes were separately dissected by laser capture micro dissection (LCM). Changes in serum HCV RNA before, 48hr, 2w and 24w after starting IFN were evaluated using COBAS AmpliPrep/COBAS TaqMan 48.
Results:
From the analysis results, the patients could be classified into three groups: genotype 1b with rapid viral response (1b-RVR) (n=10), genotype 1b with slow viral response (1b-nonRVR) (n=13) and genotype 2a with rapid viral response (2a-RVR) (n=7) according to viral kinetics with IFN treatment. Comparing all patients before and 2 weeks after IFN therapy, IFN-stimulated genes (IFN genes) were identified. When comparing the IFN genes between 1b-RVR and 1b-nonRVR, 1b-RVR showed a more significant induction of IFN genes than 1b-nonRVR. All patients with genotype 2a showed rapid response to IFN, although induction of IFN genes was not as high as 1b-RVR, suggesting that other factors might be involved in the IFN sensitivity of genotype 2a.
Gene expression of LCM samples demonstrated that induction of IFN genes in hepatocytes of 1b-nonRVR was severely impaired, while IFN genes in lymphocytes were fairly induced. Pathway comparison between 1b-RVR and 1b-nonRVR before IFN therapy showed that oxidative phosphorylation, apoptosis, and immune reaction were more induced in 1b-nonRVR than in 1b-RVR. When comparing 1b-nonRVR and 2a-RVR, oxidative phosphorylation was induced in 1b-nonRVR and cytochrome p450 genes were induced in 2a-RVR.
Conclusion: Impaired induction of IFN genes in hepatocytes might be directly relayed to the poor responses to IFN therapy of 1b-nonRVR patients. These responses are probably reflected by the induction of oxidative stress, apoptosis and inflammation. Other mechanisms are likely involved in a fair response to IFN in patients with genotype 2a.
CS
Miles from Clinics in Liver Disease
Optimizing the Current Therapy for Chronic Hepatitis C Virus: Peginterferon and Ribavirin Dosing and the Utility of Growth Factors
Mitchell L. Shiffman, MD
Effect of interferon dosing on virologic response
It has long been recognized that the ability of interferon to reduce HCV RNA in serum is a dose-dependent process. Studies conducted at the author’s center longer than a decade ago demonstrated that increasing the dosage of standard interferon from 3 to 5 to 10 mU and then to 20 mU three times weekly every 3 months in those patients who remained HCV RNA positive
led to a stepwise increase in the overall percentage of patients becoming HCV RNA undetectable.
Up to 80% of patients treated with this approach eventually became HCV RNA undetectable. Increasing the dosage of peginterferon alfa-2a from 45 to 180 mg/wk or peginterferon alfa-2b from 0.5 to 1.5 mg/kg/wk also led to a stepwise increase in virologic response [18,19].
High daily dosages of consensus interferon (9–15 mg/d) and higher dosages of peginterferon, up to a peginterferon alfa-2a dose of 360 mg/wk and a peginterferon alfa-2b dose of 3.0 mg/kg/wk, respectively, have been shown to lead to a virologic response in approximately 15% to 20% of patients who previously failed to become HCV RNA undetectable after treatment with standard doses of interferon or peginterferon
Approximately 15% of patients who have genotype 1 and up to 7% of patients who have genotypes 2 and 3 have a partial response to treatment; they achieve an EVR but never become HCV RNA undetectable [1,4,10]. These patients are sensitive to the antiviral and immunologic effects of interferon and ribavirin, and two previous studies have suggested that most nonresponders who responded to higher doses of interferon or peginterferon during retreatment are those with a previous partial virologic response
Effect of ribavirin dosing on virologic response
The starting dose of ribavirin may also play a role in enhancing virologic response. In several randomized controlled clinical studies a 3% to 9% higher virologic response rate was consistently observed when the starting ribavirin dosage was increased by 200 to 400 mg/d.
It remains unclear from these studies, however, if this difference is statistically or clinically significant.
Ribavirin also helps to maintain the response and enhances the SVR by preventing breakthrough and reducing relapse. Unfortunately, the adverse events associated with ribavirin prevent higher doses of this medication from being used and, in some patients, from maintaining adequate ribavirin exposure.
Now Shiffman missed the point that it is the serum concentration of RBV that is important not how much you take.
Then there is this Abstract
Ribavirin Improves Second Phase Kinetics Through Enhanced Interferon Signaling in Genotype 1 HCV Infection
Conclusion: Ribavirin improves early viral kinetics, but only in those patients with an initial response to peginterferon. The greater induction of interferon-stimulated cytokines and the correlation with viral kinetics in ribavirin-treated patients, support the notion that the effect of ribavirin may indeed be mediated through augmentation of interferon signaling.
Do you think its possible that Riba can reduce IR and thereby improve Interferon signalling if the serum concentration is high enough. The Lindahl high dose Riba study indicates Riba does something if the concentration is high enough.
Just a thought that’s been going thru my head lately.
Maybe you high dosed the wrong drug
CS
Optimizing the Current Therapy for Chronic Hepatitis C Virus: Peginterferon and Ribavirin Dosing and the Utility of Growth Factors
Mitchell L. Shiffman, MD
Effect of interferon dosing on virologic response
It has long been recognized that the ability of interferon to reduce HCV RNA in serum is a dose-dependent process. Studies conducted at the author’s center longer than a decade ago demonstrated that increasing the dosage of standard interferon from 3 to 5 to 10 mU and then to 20 mU three times weekly every 3 months in those patients who remained HCV RNA positive
led to a stepwise increase in the overall percentage of patients becoming HCV RNA undetectable.
Up to 80% of patients treated with this approach eventually became HCV RNA undetectable. Increasing the dosage of peginterferon alfa-2a from 45 to 180 mg/wk or peginterferon alfa-2b from 0.5 to 1.5 mg/kg/wk also led to a stepwise increase in virologic response [18,19].
High daily dosages of consensus interferon (9–15 mg/d) and higher dosages of peginterferon, up to a peginterferon alfa-2a dose of 360 mg/wk and a peginterferon alfa-2b dose of 3.0 mg/kg/wk, respectively, have been shown to lead to a virologic response in approximately 15% to 20% of patients who previously failed to become HCV RNA undetectable after treatment with standard doses of interferon or peginterferon
Approximately 15% of patients who have genotype 1 and up to 7% of patients who have genotypes 2 and 3 have a partial response to treatment; they achieve an EVR but never become HCV RNA undetectable [1,4,10]. These patients are sensitive to the antiviral and immunologic effects of interferon and ribavirin, and two previous studies have suggested that most nonresponders who responded to higher doses of interferon or peginterferon during retreatment are those with a previous partial virologic response
Effect of ribavirin dosing on virologic response
The starting dose of ribavirin may also play a role in enhancing virologic response. In several randomized controlled clinical studies a 3% to 9% higher virologic response rate was consistently observed when the starting ribavirin dosage was increased by 200 to 400 mg/d.
It remains unclear from these studies, however, if this difference is statistically or clinically significant.
Ribavirin also helps to maintain the response and enhances the SVR by preventing breakthrough and reducing relapse. Unfortunately, the adverse events associated with ribavirin prevent higher doses of this medication from being used and, in some patients, from maintaining adequate ribavirin exposure.
Now Shiffman missed the point that it is the serum concentration of RBV that is important not how much you take.
Then there is this Abstract
Ribavirin Improves Second Phase Kinetics Through Enhanced Interferon Signaling in Genotype 1 HCV Infection
Conclusion: Ribavirin improves early viral kinetics, but only in those patients with an initial response to peginterferon. The greater induction of interferon-stimulated cytokines and the correlation with viral kinetics in ribavirin-treated patients, support the notion that the effect of ribavirin may indeed be mediated through augmentation of interferon signaling.
Do you think its possible that Riba can reduce IR and thereby improve Interferon signalling if the serum concentration is high enough. The Lindahl high dose Riba study indicates Riba does something if the concentration is high enough.
Just a thought that’s been going thru my head lately.
Maybe you high dosed the wrong drug
CS
My organic chemistry is pretty rusty, but if PKR can be upregulated, what about adding additional phosphate groups? Well, maybe not, but this info holds a lot of promise. I'm multiple tx 1b, always looking for a new way out.
CS - polymerase inhibitors might override the amino acid-switching problems of 1b
copyman - I am not currently blogging. I'm still working on my second novel, but I really appreciate your interest. Thanks.
copyman - I am not currently blogging. I'm still working on my second novel, but I really appreciate your interest. Thanks.
do you still have your blog up? I have not seen it for a year or two. please provide the link or address if you still have it.
MKA - As we know, the efficacy of IFN is dependent on the phosphorylation of PKR.
Yeh I am sure we all knew that Miles.
MKA - Now it seems that IFN-resistant quasispecies in genotype 1b are already in place before treatment begins.
Not a big fan of pre-existing IFN resistant mutants, or pre existing ones for that matter. Cant undo that.
If Tx resistant mutants already exist then would'nt it be better to work out what causes the mutation and stop/prevent/undo that.
CS
Yeh I am sure we all knew that Miles.
MKA - Now it seems that IFN-resistant quasispecies in genotype 1b are already in place before treatment begins.
Not a big fan of pre-existing IFN resistant mutants, or pre existing ones for that matter. Cant undo that.
If Tx resistant mutants already exist then would'nt it be better to work out what causes the mutation and stop/prevent/undo that.
CS
And of course, I posted the exact same thing twice. As usual, my brain is dysfunctional. Excuse the repeat.
Miles
Miles
Hey copyman, great to see you, too. Thanks for the hello.
comeagain: geno 1b nonresponders, or a majority of 1bs, are often the first group to be enrolled in clinical trials, because 1b is the slightly worse of the two, perhaps partly because it tends to inflict more damage to the mitochondria of liver cells. Also, nonresponse can be predicted in 1b patients who carry either of two specific switches of amino acids.
Miles
comeagain: geno 1b nonresponders, or a majority of 1bs, are often the first group to be enrolled in clinical trials, because 1b is the slightly worse of the two, perhaps partly because it tends to inflict more damage to the mitochondria of liver cells. Also, nonresponse can be predicted in 1b patients who carry either of two specific switches of amino acids.
Miles
Hey Mk, Nice to see you hear. Very interesting posts. Thanks for posting them.
comeagian: I have always read that 1b is harder to treat then 1a
comeagian: I have always read that 1b is harder to treat then 1a
I´m positiv I heard 1a is a little bit tuffer to treat.
Think we have discussed this before here at the forum, some said as you 1b and others 1a and there were studys presented dont have them but if someone have please chime in on this one.
ca
Think we have discussed this before here at the forum, some said as you 1b and others 1a and there were studys presented dont have them but if someone have please chime in on this one.
ca
Actually, I read a transcript of Dr. Schiffman testifying before the FDA about Pegasys. He stated that peginterferon does not create IFN-resistant quasispecies. Apparently, these factors are already in place before we even begin tx, especially in geno 1b. There are two 1b amino acid switches that may be predictors of nonresponse, and may be the reason why 1b is a little tougher to clear.
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