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Drug interactions in the liver 101

Sep 21, 2011 - 12 comments
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drug interactions

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p 450

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cytochromes

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protease inhibitor warning

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PROTEASE INHIBITOR





Drug interactions in the Liver 101.    

What you need to know.

My clinic has postponed treating any patients with triple therapy until their software is updated to include all of the newest information regarding P450 interactions.  Therefore I’m NOT the only person realizing just how crucial and important this all has become.  Ergo I’ve decided to regroup my thoughts and explain the basics.


The people most in need of this information are late stage liver patients, and those taking anti-rejection, or HIV drugs, or who are medicating for any other serious medical condition. Especially if these groups plan on treating their Hepatitis, this information could prove invaluable. Actually anyone doing triple therapy really does need to pay attention here.

Many of you have written privately asking me to filter my knowledge base down to it’s essence on my favorite topics.  I’m sorry for my long delay, but here is at least a first attempt on one topic.
For further clarity one may reference my 2 past threads on P 450 drug interactions in this forum..


The key words here are cytochromes, P 450, hepatoxicity, inhibitors and inducers

PAUSING TO MARVEL-The liver’s job is to break down drugs, make them usable, soluable, removing their hydrophobia and preparing them for the body, and for excretion as well. The liver is the most phenomenal organ in the human body, performing millions of complex chemical conversions everyday, and replacing tired worker cells 5 times faster than elsewhere in the body. If we had to represent the liver’s daily workload by having chemists standing by to achieve in test tubes what the liver does so effortlessly, we would have to fill several hundred Costco warehouses full of chemists, and they would still be hard pressed to do for you what this little organ does!! And how does it know what to do with each atom, each molecule? Why does it prioritize and try to remove toxins (like alcohol etc.) first?  How does it detect what is lifethreatening, and where is it’s database, that each cell can know just what should be done with the thousands of compounds showing up each day?
The amount and complexity of the work done each day by this organ is truly staggering.

Back to work:

Here is a good primer on hepatoxicity.

http://en.wikipedia.org/wiki/Hepatotoxicity

OK, so now we’ve covered the basics. Did you notice acetaminophen (Tylenol, Paracetamol) is now considered the most hepatoxic of all OTC drugs? That of course, remains a hot topic of debate with some, but I myself am entirely convinced Tylenol and later stage liver disease should be mutually exclusive items. It’s not just the drug itself, it’s the number of other drugs that cause a build up that is the issue, and also it’s a travesty that so many OTC products contain it, but that the public doesn’t always realize that they are double or triple dosing themselves when they add one or two cold/flu remedies to their daily regime. Pain control is a serious issue, and must be addressed, but there are safer ways to control pain or fever that are not as damaging to the liver. However there is a whole generation who grew up with, and were medically trained to believe that tylenol could do no wrong, so I won’t debate the topic, I’ll simply mention that the research and current chemistry is converting more docs to a cautionary stance with every passing day. OK, enough of that, we aren’t here to debate Tylenol, we are here to understand how the liver deals with drugs.

So, let’s begin.

Here is my favorite P 450 Chart.   http://medicine.iupui.edu/clinpharm/ddis/table.aspx

Although this chart is not as up to date as some others I have found, this one at least color codes the most dangerous drugs, which I found very helpful.

So what is a P 450 cytochrome and why should we care?

Put simply it’s a protein whose enzymes help break down drug metabolites into forms our bodies can use, and also into forms we can later eliminate from our bodies. A cytochrome is an iron based structure, (cytochrome means cell enzyme, cytochromes are specialist, they have in common, regardless of which substrate they belong to, that they all depend on iron for their function ) …they reside primarily in the liver and help us deal with certain chemicals. Without them, many more substances would be toxic, and few if any would help us.
Think of the substrates as just mechanics in a garage, one guy does your brakes, another guy does tranny, another does engines, Same with substrates, it simple means that certain cells specialize in certain drugs.  Sometimes more than one substrate participates. Like one chemical process occurs first and then it gets passed to the next cytochrome for a different process.
Like with your car, maybe you go for brakes and tires, and one guy does his job first, then the other process will follow.
The reason which substrate a drug uses is important is because there are only so many of each cytochrome, so in order not to overwhelm the system the thought occurred to me to switch my other meds away from CYP3a (the one the tx drugs use) as much as possible.

Most of the articles and explanations I’ve read concerning  cytochromes and drug (P 450) interactions are highly technical.
This post will attempt to speak to the layman for that reason, to bring some small clarity perhaps.

A good synopsis might be just to say that certain proteins within special cells have been identified as responsible for the metabolism of drugs within the body. Most exist within the liver, but they are found throughout other parts of the body as well. Where ever they are found, they do the same job.
The important thing for a liver patient is to make sure their doctor tailors their treatment to the other conditions for which they must medicate.
This is important at all times, but especially if undergoing chemotherapy for hepatitis or liver cancer, any kind of chemo therapy really.

Especially true in later stages of liver disease, where the amounts of healthy liver tissue have been reduced, it becomes important to create as few conflicts as possible within the drug profile of a patient.
It also becomes important that a patient remain PATIENT with their doctor.
Especially true while on chemotherapy we will sometimes be desirous of instant relief.
Often a patient may have side effects and be tempted to take an EXTRA dose of something to alleviate some of their suffering, or to use OTC products without their doctor’s knowledge.
These actions must be avoided or taken with a goodly dose of trepidation. This is one time when if one is good, two could be deadly, not better.

Increases in dosage of helper drugs should be allowed only if the effects, sides, and the blood work all indicate the patient is tolerating the additional drug without marked elevations of liver enzymes. Additonal to toleration one must bear in mind competition means one drugs uptake will inhibit another drugs uptake. Ergo even well tolerated things can and do reduce the amount of chemotherapy drugs that will be metabolized, and, as plasma builds of the non utilized drug, the toxic metabolites not broken down (since no cell can get to it) are also building. Think of this like the IRS at tax time…there’s only so many folks to shuffle all that paper…and as the paper stacks up,  the fire hazard also increases exponentially.
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Since some chemo drugs are strong inhibitors and/or inducers (they can increase or effect the strength of other regular meds and drugs). Therefore any new drug must be introduced slowly and watched cautiously. The cautions are for our benefit, because the understandings of all these interactions are still in their infancies this cautionary is needful. Especially where the new Protease Inhibitors are concerned, both those for HCV and those for HIV, some of these new antiviral drugs have marked effects on all other drugs being utilized.


It may help to pause here to explain inducers and inhibitors.  They do what the word describes.

1. An inhibitor  competes with other drugs. It inhibits them and changes how they perform. It’s sort of a bully trying to take over so to speak.
2.  An inhibitor can also increase the plasma levels of other drugs, making them many times more potent, and inhibiting them from clearing the body in a timely manor. This then leads to build ups, toxic levels of one or multiple drugs competing for that cytochrome.
3. An inhibitor can stop another important drug from working because the inhibitor competes for the same few cells to be “metabolized”.  Therefore a strong inhibitor can prevent another weaker drug using that same cytochrome from working at all. It’s rather akin to there being just so many seats in the theatre, once the theatre is booked, no more can get in; and, should you let more in, and create a “standing room only situation” then the meds become so tightly packed like sardines that when it comes time to exit, no one can get out!! They are crammed too tightly to move at all. This may be a poor analogy but it’s all that comes to mind just now.


On Dr. Flockhart’s charts (link above) one will observe certain drugs have been marked in red, orange and so forth…this is to alert you to their strengths as an inhibitor or inducer.  A red or orange drug needs to be treated with a lot of respect. They are the atom bombs so to speak of the drug world, and can do a lot of good, but a lot of harm as well, when it comes to interactions.

Here they are listed as follows:

A strong inhibitor is one which raises a drugs plasma AUC value > 5-fold or more, or causes an 80% drop in clearance rate. (that means 4/5 of the drug that should leave the body will not leave when it should. This then leads to a potentially deadly hepatoxicity very quickly.

A moderate inhibitor is one that causes a > 2-fold increase in the plasma AUC values or 50-80% decrease in clearance.

A Weak inhibitor is one that causes a > 1.25-fold but < 2-fold increase in the plasma AUC values or 20-50% decrease in clearance.

Even moderate or weak inhibitors need to be respected. If you must be on a medication, you will need to half your dose in order to adjust for the 2 fold increase a moderate inhibitor would cause.
This should not effect your health then, because the lowering will still leave you with the same amount in your body as previous to beginning chemo therapy.  Of course, you will still be monitored for signs of build up, and when chemo is over, you will no doubt be returning to your former dose.

Please don’t be scared by all of this, just try to understand that your doctors now have tools to help them navigate through these mine fields, and they and you would be remiss in not using them. For many years the reason that some folks made it through chemo therapies just fine, while for others it proved fatal was not well understood. However not that the chemistry and role of the various cytochromes has come to light, many more positive outcomes will become possible.

Other drugs listed on Dr. Flockhart’s charts are simple inhibitors, and they will not compete for room to be metabolized by the available cytochromes, they will instead enhance or Induce a stronger response and more enzyme activity. Whenever a drug or food stimulates the synthesis of more enzyme protein,9 enhancing the enzyme's metabolizing capacity, it is known as an inducer. It is however difficult to predict the time of any enzyme induction because many factors exist, amongst them are enzyme turnover, drug half-life etc. In other words, it’s extremely difficult to time an inducer to induce, which is why there are no drugs yet for HCV that are prescribed to do it.

WARNINGS

With INHIBITORS: The fact that they are not classified as strong, moderate or weak, does not mean they are problem free. Any drug utilizing the same cytochrome will still compete for available space to metabolize. Doses of each drug must therefore be adjusted to compensate for this and/or watched carefully through blood work.
  
SIDEBAR, the one that STEAMS me was that barbequed items are on the list…it’s going to hard to forego my favorite cooking method, but for what it’s worth we can’t live without a liver….so for a few months I’ll do without it, especially important if I have to go on Cipro again.

With INDUCERS, we have another issue, that the inducer will effect the strength of the other drugs using that cytochrome. Inducers make other things stronger, apart from clearance issues, this can be problematic. Foods can also be inducers. The temptation will always exist to use an inducer to create a stronger presence of a drug not readily absorbed. I’m reminded of some folks who thought they should add a grapefruit derivative to their regime years ago for this purpose. The dangers however far outweighs the benefit.
We only have one body, turning it into a test tube with unproven and potentially unsafe adjuncts is not wisdom.
Make sure whatever you add to your regime is added with your doctor and pharmacists knowledge and approval!!

Whether one speaks of natural substances such a St. John’s Wort, or certain drugs that are known to induce, the fact remains that the predictability of response has not been established and therefore the possible complications are a real and present danger.  Since the discovery of inducers much research has been and continues to be done on certain pro-drug transporters in an attempt to find inducers that will benefit other drugs, create a more therapeutic or quicker absorption rate without overshooting and creating hepotoxicity. Here is where a portion of the Hippocratic oath must be observed, “First, do no harm”…and this applies to the patients private attempts especially,( it should be we, not just our doctors who adhere to first, do no harm.).

Of course, no matter how simple one tries to make all of this, it does get complicated. If you take antacids or proton pump inhibitors this will effect the treatment drugs and how absorbable they will be, if you take antidepressants you may have to be switched to a safer one than the one you take. This is because an SSRI using the same substate could result in serotonin overload and poisoning, a serious issue.  AGAIN, I share this in the hope that we as patients will take seriously our need for due diligence and for including a good medical team in all our decisions going forward.

Back to inducers, many folks have thought hey, why not take something to make the other things I take stronger..now that we know what the inducers are.  You would not be the first to have thought of this. To date however, very few inducers have proven safe, though some are in clinical trials every year….they are known as pro-transporters. Yet to date there has been limited success for obvious reasons.  Since time, foods, other drugs, fat content of meals, stomach acids, bile salts, colon bacterium, and dozens of other things factor into drug absorption rates, it is easy to shoot past a goal when trying to create an instant effect with an inducer. Since every patients profile is different, their metabolisms differ, they drugs they take differ….so the complexity of helping vs. killing them is very real. Since some inducers have been observed creating 100 fold increases in plasma levels, it is imperative that the patient NOT attempt to improve the synergy of any drug without the knowledge and approval of his or her physician.

BOOZE_ A common inducer we should mention here is alcohol, it is responsible for more overdoses than all other inducers combined. Alcohol creates sufficient increases in bioavailablity across all substrates of so many substances that it could be classified as the number 1 killer, if we were to reclassify drug overdoses as what they more often really are, alcohol related drug overdoses.  Alcohol’s effects are not only due to cytochrome use, but due to it’s solvent nature, rapidly altering myriad drugs on every substrate. It is responsible for a great deal of the aspirin and acetaminophen poisonings since it increases their levels so severely, and with barbiturates and alcohol taken together we see countless deaths.

POT_Tetracannibinol (marijuana) is also an dangerous inducer, and has been shown to cause a 7 fold increase in liver fibrosis comparative to alcohol. Perhaps because the greater the inducing, the greater the toxicity then of other drugs, and hence the greater the inflammation as a result of the toxicity. Inflammation of course, is considered to have the greatest influence on fibrosis and scar formations. In other words the cascading effects of certain substances has been well documented.
I trust that sometime in the near future enough will be known for medicine to gingerly enter the world of pro-transporters, especially for those drugs hard to absorb. To date however, I think the most hopeful research comes rather from a process known as electroporation, currently being tested by Inovio and other firms in regards to HCV treatments. This method allows instant penetration into the cell, if it ever makes it to market it will undoubtedly close the gap by achieving therapeutic levels of all treatment drugs in hours, not weeks, and hence reduce the chance of mutations to zero.  Of course prior to this treatment adjustment to current medications would be wisdom to avoid all that has been mentioned here.

CONCLUSIONS:  About 30% of all the drugs we take are metabolized by the CYP 3a, and so are the Protease inhibitors. The interferon is an inhibitor also (in fact, the reason many hepatitis patients need stronger doses prior to and during tx, of many meds is because of natural interferon, (any viral infection raises interferon levels,) inhibiting the way all drugs are then metabolized. The Interferon making the system more sluggish as it concerns other activities. However, one study did observe improvements even in the presense of treatment drugs once one month had ensued, http://www.ncbi.nlm.nih.gov/pubmed/1695539?dopt=Abstract), (and assuming a drop in VL no doubt) Finally ribavirin metabolism involves several cytochromes.  but primarily 2D6 and  3a. Here I would focus on the cyp 3a, because the telaprevir or boceprevir are also reliant on this cytochrome. Meaning this cytochrome will have plenty to do while you are treating.

My SUGGESTIONS to the patients, and the high risk or late stage patients especially would be
1. to try to find drugs that metabolize on cytochromes that are not being used for the chemo drugs, or better yet,
2. choose drugs or find things that are dealt with chiefly by the kidneys, as some drugs are able to bypass the liver, not dependant on that organ as they do not have to be conjugated, changed into a different metabolite to be useful), so choose these rather than the liver dependant drugs whenever possible (of course this is not always possible, but it doe not hurt to ask, or do a search for example, google “ medcication metabolized by kidneys for ________(your disease). This is of course ONLY good advise if your kidneys are healthy and in good shape.
3. involve your physician and report every item you are taking accurately including vitamins, minerals, herbs, protein drinks, etc etc.
4. involve your pharmacist and give them the same complete list, and make sure they are alerted to your chemotherapy even if you receive your chemo drugs from a specialty pharmacy make sure you have a local pharmacist that is aware you are on the chemo drugs, and who will keep an eye on every new addition.
5. Remember the average pharmacist has had 6 YEARS of training exclusively drugs and chemistry, whereas the average specialist had one year of training…so whom may be more savvy is hard to say…1 year….vs.  6 years….hmmm.
6. get all your meds, as much as possible from ONE primary pharmacy the better to eliminate information loss or half engaged providers. Form a rapport with said pharmacist.If you are undergoing chemotherapy I would strongly advise against using mail order pharmacies simply because with the volume they do, and the distance, there is not as much chance of them catching
7. try to get a CBC within a week of starting any new drug so you can see and head off any build up. Watch Alt/ast and bilurubin especially. Do not settle for a monthly CBC if you are adding helper drugs twice monthly should be a minimum, or weekly would be better when on multiple meds and chemo. If you are a distance from your clinic, arrange for a closer clinic to do the labs and forward them to your hepatologist. Don’t postpone any labs. (at my clinic missed labs is grounds to be removed from treatment…it’s that crucial to your health, so don’t treat this lightly)
8. try natural methods before resorting to drugs wherever possible. Example: before taking an oral anti-itch RX, try tepid showers, olive oil rubs and silk sheets. Then try a toical cream and only lastly resort to a systemic RX, and if you must because the itching is unbearable, then allow your liver doctor to prescribe you one, do NOT use benydryl, it cheap yes, but more hepotoxic than the one they will give you if you ask. But again, try natural methods first…. If you can get by without the additional drugs it will be far better for your liver.

9. try half or quarter doses for side effect helper drugs. (not epo or neupo those you must take full dose), and not your regular meds like heart or BP meds etc…those reduce only with doctor approval…but for the things more minor such as itch or nerves or sleep. You may find that you can get enough relief from a lesser dose (partly due to the inhibitor buildup effect) than what your doctor prescribed. The smaller the dose that you can get by on, the better your chemo drugs will work, remember most will compete for the same few cytochromes that your chemo drugs are trying to use. Get a good pill cutter. Half or quarter non-time-release drugs and experiment with less.
10. If you have iron overload already, or liver cancer, you will want to avoid drugs needing to use Cyp1a2 as this cytochrome is where much oxidative stress occurs. If you can find a drug using a different substrate with these conditions, it might be wisdom in order to lower your oxidative stress.
11. Nevertheless do not discontinue any medicine without doctor approval.

OF COURSE, THESE HINTS won’t work for everyone in every circumstance, but even switching one or two medications to a similar medication that happens to utilize a different cytochrome might help

  A. make your chemotherapy more successful, and

B. help it to be less toxic simultaneously.  

PS….remember I’ve mentioned all chemicals are drugs so to speak. Even vitamins are a type of drug. Even if natural they are concentrated chemicals and must thought of as chemicals and be used judiciously.
Even though many are friendly and helpful, one needs to do some real research before assuming everything touted as good for really is.
An example would be one I mentioned recently on my PURINE thread….that brewers yeast greatly interferes with ribavirin absorption. Therefore you should not take a multi, or a B vitamin with your riba meal. Anything derived from Yeast will interfere with the treatment drugs.  This is a whole other topic, so I’ll stop here.

SIDEBAR: Please note, my clinic, and many others as well, are adding patients slowly to their rosters. This is because the alarm bell about the protese inhibitors being so incredibly interactive has finally gone out. No patient wants to wait in a line to treat this disease, but because of the complexity of the treatment landscape the docs cannot add everyone waiting at once. They need to take the sickest first, and get them well established, and then add more each month as they are able.  AIDS patients in particular will need special care and possible changes to their current regimes. We need to recognize that if they can treat ten or 20 a month well, it’ll be a better outcome than if they try to treat 100 at once. In which case either standard of care suffers or docs get zero sleep…both really. So if you’ve been waiting to treat, then you are learning why we are called “patients”.
Since most clinics only have a handful of docs truly familiar with this disease I feel the wait is well justified.
If some of you are stage 2, and are asked to wait an extra few months to begin treatment, be glad.  It would be better to wait for the specialists that to go to some GI guy who has never treated with the PI on board and doesn’t have the information, training and staff to really deal with the issues that may emerge. If you want to be safe in treating, wait your turn patiently for a specialist and the reward will be that those professionals will be able to help you more and keep you safe from harm. (just my opinion)



I realize this is a lot of information, and apologize in advance for those not wishing to have to think about any of it.
Let’s just hope that our doctors are all thinking it thoroughly through for us.
Meanwhile, some few of us do wish to be informed, this was for us.

Good luck to us all.

mb

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Comments
Post a Comment
317787_tn?1373214989
by Dee1956, Oct 05, 2011
Dear Merry, just read this and wanted to thank you very much for all of your research time and commitment to the above information.  I am 6 weeks into Incivek Peg and Riba and I can tell where some of my medicines have been "enhanced" so I cut back a small bit
Not really feeling well today but wanted to thank you
Dee
p.s. when I was first told I would be on Pegintron it scared me as at the time I would have preferred Pegasys since many people say the sides are better.  Since then I read somewhere that the Pegintron is processed through the kidneys vs Pegasys processed through the liver.  Have you heard anything like that?  I am now thinking that perhaps that is why, when faced with 2 choices my doc picked Pegintron for me.  It may just be a coincidence (I previously relapsed after Pegasys)  Had my 4 week blood drawn don't have the results yet, gosh I hate to wait. :)
Thanks again
D

233616_tn?1312790796
by merryBe, Oct 05, 2011
I'm not sure that I'm keen on repeating with either form of peg due to the end of week fall off (roughly 24 hrs with no INF on board each week, this is not common knowledge).  The virus takes no breaks, so I'm not sure our treatment plans should.
My GPN said its a day of rest for us...but the viron can better mutate in an INF free environment. So not again, live and learn...No sabbaths for my bugs, thanks but no thanks, these bugs need a constant beating to be beaten IMHO.

For most folks, pegs will be the choice, the compliance is better since we only have to take a shot once a week.
It's going to be difficult to make yourself sick every day with multiple shots per day, and very important not to miss ANY.
However, that will be my choice, concensus Infergen...or at least thats the plan, assuming I can maintain my glutton for punishment stance once tx ensues.

as far as one peg vs the other, pegasus faired better in most studies, it kind of became a wash when you got to relaspe time however, meaning even though more SVR'd on the pegasus, the main issue is staying virus free, and there the differences were negligable.  Sometimes docs pick one over the other due to just wanting the patient to have more hope, or depending on their raport with a particular drug compnay. In any case, I think you'll do fine with either.  I'm only doing the Infergen because I'm determined to give this virus NO quarter this time around.

here's some of the studies and stats on the 2 pegs:

Is One Type of Pegylated Interferon More Effective for Treating Chronic Hepatitis C?


SUMMARY: A pair of Italian studies in the January 2010 issue of Gastroenterology comparing the 2 marketed brands of pegylated interferon -- Pegasys (pegylated interferon alpha-2a) and PegIntron (pegylated interferon alpha-2b) -- both indicated that Pegasys produces a higher rate of sustained virological response in patients with chronic hepatitis C virus (HCV) infection. An accompanying editorial suggested that the goal now is to determine how well the 2 formulations will work with the directly-targeted HCV drugs now in development.



By Liz Highleyman

Pegylated interferon plus weight-adjusted ribavirin is standard therapy for chronic hepatitis C, but there has not been consensus about the relative benefits of Pegasys (Roche/Genentech) and PegInton (Schering-Plough). Past research has produced conflicting findings, and data have not always been strictly comparable due to regimen differences such as varying doses of ribavirin, which helps prevent relapse after the end of therapy.

Interferon alpha used for hepatitis C treatment is a genetically engineered version of a natural human cytokine (chemical messenger). It works by enhancing immune system responses against HCV. Pegylated interferon is attached to polyethylene glycol (PEG), which makes it last longer in the body (allowing injections once instead of 3 times weekly). Pegasys and PegIntron have different shapes and sizes (40 kDa vs 12 kDa molecular weight), which influences their pharmacokinetic properties and may affect how well they work.

Study 1

In the first new study, Maria Grazia Rumi from Università degli Studi in Milan and colleagues compared the safety and efficacy of the 2 pegylated interferons in treatment-naive chronic hepatitis C patients stratified by HCV genotype.

The study included 431 participants. About half had hard-to-treat HCV genotypes 1 or 4, and about 19% had liver cirrhosis, another characteristic associated with poorer treatment response.

Participants were randomly assigned (1:1) to receive 180 mcg/week Pegasys or 1.5 mcg/kg/week PegIntron for 24 weeks (genotypes 2 or 3) or 48 weeks (genotypes 1 or 4). In accordance with the drugs' differing prescribing instructions, genotype 1 and 4 Pegasys recipients received 1000-1200 mg/day weight-adjusted ribavirin and genotype 2 and 3 Pegasys recipients received a fixed dose of 800 mg/day; in contrast, all PegIntron recipients received 800-1200 mg/day weight-adjusted ribavirin regardless of genotype.

Results
In an intent-to-treat analysis, the overall sustained virological response (SVR) rate 24 weeks after completing treatment was significantly higher in the Pegasys group compared with the PegIntron group (66% vs 54%, respectively; P = 0.02).
Among the 222 patients with HCV genotypes 1 or 4, the corresponding SVR rates were 48% vs 32%, respectively (P = 0.02).
Among the 143 patients with genotype 2, the SVR rates were 96% vs 82%, respectively (P = 0.01) (there were too few genotype 3 patients to permit a separate analysis).
The Pegasys and PegIntron groups had similar rates of treatment-related serious adverse events (1% in both) and discontinuation due to adverse events (7% vs 6%, respectively).
In a logistic regression analysis, use of Pegasys was an independent predictor of SVR (odds ratio 1.88).

Based on these findings, the study authors concluded, "Although the 2 regimens showed a similar safety profile, the [pegylated interferon alpha-2a]-based treatment yielded significantly more SVR than [pegylated interferon alpha-2b]."

Study 2

In the second study, Antonio Ascione from Cardarelli Hospital in Naples and colleagues compared the safety and efficacy of Pegasys versus PegIntron in 320 previously untreated chronic hepatitis C patients.

About 18% of participants had cirrhosis at baseline, and about 55% had high HCV RNA viral load (> 500,000 IU/mL).

Again, participants were randomly assigned (1:1) to receive 180 mcg/week Pegasys or 1.5 mcg/kg/week PegIntron for 24 weeks (genotypes 2 or 3) or 48 weeks (genotypes 1 or 4). In this study, however, all participants -- regardless of genotype -- received ribavirin at doses 1000 mg/day if they weighed < 75 kg (about 165 lb) or 1200 mg/day if heavier.

Results
In an intent-to-treat analysis, more patients overall achieved SVR in the Pegasys group compared with the PegIntron group (68.8% vs 54.4%; P = 0.008).
Among genotype 1 or 4 patients, the corresponding SVR rates were 54.8% vs 39.8%, respectively (P = 0.04).
Among genotype 2 or 3 patients, the SVR rates were 88.1% vs 74.6%, respectively (P = 0.046).
Among participants without cirrhosis (all genotypes combined), SVR rates were 75.6% with Pegasys vs 55.9% with PegIntron (P = 0.005).
Among patients with cirrhosis, however, SVR rates were statistically similar (42.4% vs 46.1%, respectively; P = 0.774).
Among patients with high baseline HCV RNA, SVR rates were again higher in the Pegasys compared with the PegIntron group (75.6% vs 55.9%; P = 0.005).
Among patients with low baseline viral load, SVR rates did not statistically differ (68.4% vs 65.7%, respectively; P = 0.727).

"In patients with chronic HCV infection, treatment with peginterferon alfa-2a plus ribavirin produced a significantly higher SVR rate than treatment with peginterferon alfa-2b plus ribavirin," the investigators concluded.

Editorial

In an accompanying editorial Stefan Zeuzem from J.W. Goethe University Hospital in Frankfurt, Germany, offered a perspective on the findings from these 2 trials in the context of prior research.

"Owing to greater variations in peak-to-trough ratios for peginterferon alfa-2b than peginterferon alfa-2a, HCV RNA levels tend to fluctuate more (at least within the initial 4 weeks of therapy) in patients treated with peginterferon alfa-2b than in those treated with peginterferon alfa-2a," he noted.

One previous large study, the IDEAL trial sponsored by Schering-Plough, included more than 3000 HCV genotype 1 patients treated with Pegasys or PegIntron according to the drugs' respective label directions (i.e., the ribavirin dose was not consistent). In that study, Pegasys recipients had a higher end-of-treatment response rate (64.4% Pegasys vs 53.2% PegIntron) but PegIntron recipients had a lower relapse rate (31.5% Pegasus vs 23.5% PegIntron) so the sustained response rates ended up being statistically similar (40.9% Pegasys vs 39.8% PegIntron).

A recent systematic review by the Cochrane Collaboration of randomized clinical trials comparing the 2 pegylated interferons, which included a meta-analysis of SVR rates in 8 trials with a total of 4293 participants, found that Pegasys was slightly but significantly more effective than PegIntron (relative risk 1.10; P = 0.004), with similar results for all subgroups; adverse event profiles were similar.

"Taken together, since the publication of the pivotal phase 3 trials for peginterferon alfa-2a and alfa-2b in combination with ribavirin, it took another 8 years to characterize the pharmacodynamic differences between the 2 drugs in detail," Zeuzem wrote. "At the dawn of new direct antiviral drugs against HCV we need now to investigate how important the observed differences between the peginterferons (and other long-acting interferons such as albumin interferon) are in combination with HCV NS3/4A protease and NS5B polymerase inhibitors."

It also remains to be determined whether one form of pegylated interferon works better than the other in HIV/HCV coinfected patients, who tend to respond less well to interferon-based therapy than people with HCV alone.

Study 1: A.M. Migliavacca Center for Liver Disease, Fondazione IRCCS Maggiore Hospital, Mangiagalli e Regina Elena, Università degli Studi di Milano, Milan, Italy; Unit of Epidemiology and Biostatistics, San Carlo Borromeo Hospital, Milan, Italy.

Study 2: Department of Gastroenterology, Liver Unit and Pathology Units, Cardarelli Hospital, Napoli, Italy; Department of Medicine, Centre for Liver Disease, Fatebenefratelli Hospital, Napoli, Italy; Gastroenterology Unit, IRCSS de Bellis, Castellana Grotte, Italy.

2/12/10

References

M Rumi, A Aghemo, GM Prati, and others. Randomized Study of Peginterferon-alpha2a Plus Ribavirin vs Peginterferon-alpha2b Plus Ribavirin in Chronic Hepatitis C. Gastroenterology 138(1): 108-115 (Abstract). January 2010.

A Ascione, MD Luca, MT Tartaglione, and others. Peginterferon Alphalfa-2a Plus Ribavirin Is More Effective Than Peginterferon Alphalfa-2b Plus Ribavirin for Treating Chronic Hepatitis C Virus Infection. Gastroenterology 138(1): 116-122 (Abstract). January 2010.

S Zeuzem. Do Differences in Pegylation of Interferon Alfa Matter? (Editorial). Gastroenterology 138(1): 34-36 (Free full text). January 2010.

good luck with your labs Deb..the waiting is the hardest part.


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by mikesimon, Oct 06, 2011
J Hepatol. 2011 Jul 11. [Epub ahead of print]

Hyporesponsiveness to pegifnα2b plus ribavirin in patients with hepatitis C-related advanced fibrosis.
Prati GM, Aghemo A, Rumi MG, D'Ambrosio R, Nicola SD, Donato MF, Degasperi E, Colombo M.
Source

A.M. Migliavacca Center for Liver Disease, 1st Division of Gastroenterology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan.
Abstract
BACKGROUND & AIM:

The success of pegylated-interferon (PegIFN) / ribavirin (Rbv) therapy of chronic hepatitis C is compromised by liver fibrosis. Whether fibrosis equally affects the two PegIFNα-based therapies is unknown. To assess the response to the two PegIFN regimens in patients with different degree of liver fibrosis.
METHODS:

A sub-analysis of the MIST study: 431 consecutive naïve patients randomly assigned, based on HCV genotype, to receive either PegIFNα2a 180 μg/wk plus daily Rbv 800-1200mg (A) or PegIFNα2b 1.5 μg/kg/week plus daily Rbv 800-1200mg (B), were stratified according to Ishak staging (S) into mild (S0-S2) or moderate (S3,S4) fibrosis and cirrhosis (S5,S6).
RESULTS:

In A the sustained virological response (SVR) rates were not significantly influenced by fibrosis stage (71% in S0-S2, 66% in S3,S4, 53% in S5,S6, p=0.12), compared to B where the SVR rates differed according to fibrosis stage (65%, 46% and 38%, p=0.004, respectively). This was even more so in HCV-1/4 patients treated with PegIFNα2b where the SVR rates were twice as many in S0-S2 vs S⩾3 (44% vs 22%, p=0.02), while in A the SVR rates were similar between the two fibrosis subgroups (S0-S2: 47% vs S⩾3: 48%, p=0.8). By logistic regression analysis genotype 1/4 and lack of rapid virological response were independent predictors of treatment failure in both treatment groups, while S⩾3 fibrosis was associated to PegIFNα2b treatment failure, only (OR 2.83, 95%CI 1.4 - 5.68, p=0.004).
CONCLUSION:

Liver fibrosis was an independent moderator of treatment outcome in patients receiving PegIFNα2b, not in those receiving PegIFNα2a.

http://www.ncbi.nlm.nih.gov/pubmed/21756847

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by merryBe, Oct 07, 2011
yes, that's a good point Mike.  I don't recall what stage Deb is, but she could switch to the pegasus if she is stage 4, it might give her more peace of mind if nothing else.  The only reason reason some docs condsider it a wash is because the relaspe rate it wiping out any gains the pegasus shows over the pegitron, as referenced by the above study and below

>>>>>>>One previous large study, the IDEAL trial sponsored by Schering-Plough, included more than 3000 HCV genotype 1 patients treated with Pegasys or PegIntron according to the drugs' respective label directions (i.e., the ribavirin dose was not consistent). In that study, Pegasys recipients had a higher end-of-treatment response rate (64.4% Pegasys vs 53.2% PegIntron) but PegIntron recipients had a lower relapse rate (31.5% Pegasus vs 23.5% PegIntron) so the sustained response rates ended up being statistically similar (40.9% Pegasys vs 39.8% PegIntron).

One percentile is considered a wash and statistically irrelavant, within the margin of error or related to other patient and/or study anomalies.

However, you have to take into account the drug companies doing the study are trying to prove their product works as well..

If I were choosing a peg to go with this time around, I would definitely choose the pegasus, even though it is a statistical dead heat as to relaspe rate.  Reason being, the higher SVR as evidenced in all the studies still indicate that the pegasus is working better during tx.
It might mean that the time releasing agent is a factor, and perhaps one is staying in the system longer.
That's only a guess.  Whatever the reason, I'd go with the drug with the highest stats, just for the additional peace of mind if nothing else.

If she wanted to go a different route, based on the studies, it shouldn't be too difficult to get a doc to go along with a switch.  Yet as I said, at days end, both drugs cure identical numbers, so it's somewhat a non-issue in my mind, assuming one wants to use the time released, which is still the best bet for most patients.

If she is stage 4. as I am, she might want to look at the gamma INF...Infergen.
My reasoning, confirmed in your study again, is that the more scar tissue, the more aggressive the INF needs to be to get at the little buggers. I think they burrow into the fibrous tissue, and survive better in these little burrows, much like animals that burrow into dens or coral reefs that survive being eaten and scavenged better than those that are out in the open. This is only a guess, but there's no other logical reason I can think of, for the scarring having such an effect on SVR rates.
Since the gamma seems to be stronger, (at least according to most patients) and since it can be maintained without the 7th day off issue, I'm hoping it will work marginally better at penetrating and ferreting out these crafty virons. It certainly can make folks sicker, let's hope that means it's got a more aggresive component..

The issue with the gamma is always going to be compliance, which is the same for every form of INF and especially for those injected daily.
Unfortunately, studies don't  take into account compliance when they run their statistics on how many SVR, but it has always been an issue, and is why the pegs came into existance in the first place.
I'm pretty certain that if compliance could honestly be assessed, we would see higher SVR's for those that did comply than with the pegs.  

My method for overcoming compliance issues was to buy a watch with 12 alarms.
It will beep and say "Infergen shot"  or "riba time"  or whatever I care to program it to say.

The watch is called a CADEX 12 alarm, and can be worn on the wrist or as a pendant.

Without this device, it would be a lot harder to remember, especially if you having a rough day and sleeping,
but with this watch I think anybody could pull it off....except someone who shuts off their beeper without doing the deed.

mb

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by lynda607, Oct 07, 2011
Good luck with the Infergen and Incivek, you're going to need it the first twelve weeks.  Doubt you'll be posting that the side effects are tolerable.  If you'll notice by all the posts, people are having a difficult time on triple.  Incivek can present with quite severe side effects and daily Infergen will most assuredly compound that.  Infergen also knocks down blood values very quickly and Incivek can also induce anemia much quicker so it would be wise to have checks and balances in place at all times.  One must do what one feels is necessary and hope you truly understand what you're getting yourself into.  Not a treatment protocol I would recommend to the general population. You may be cured but you may never fully recover from that wild ride at the rodeo.  


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by merryBe, Oct 07, 2011
Lynda, thank you very much for your concern. I am well aware of the sides, and not looking forward at all to this protocol, however, I relaspsed after 88 weeks of riba/peg, and was UND for over a year, yet still relasped, so my only rational option at this point is to add the PI.

The infergen we know is stronger as well. The chance I might lessen sides there by spreading out my shot, 3 times a day rather than once, may reduced fever/chills somewhat, and also keep plasma level more even.
(infergen has 4 hr half life). My body works well with INF (IL28b showed the right alleles) so we will be able to dial back if necessary and still get some punch there.  Had my alleles not been optimal, I would not be subjecting myself to more INF of any type, but since they are, I should get a good result. I'm hopeful that the INfergen will settle down, many folks said after a few days their bodies adjusted (except Magnum who took way more than normal).
Since the peg gives you steady state more, the way to keep the sides lower by doing 5IU shots 3x daily instead of one 15iu shot makes sense don't you think?? It mimics the peg more this way...and doesn't spike the body so badly.  I can see why a mg shot would give chills/heaves/etc.  but I don't see why 3 shots would solve for this.

Besdies which, one has to take the Telaprevir every 8 hours EXACTLY (they are being very emphatic about this at my clinic)...so it just makes sense to go ahead and take the shots 3 times as well.
anyway, that's the plan.  We'll see if it's doable ;o.

Beyond that, I will not be doing stronger dosing, as Magnum did (God forbid) and we will put Epo etc on board as soon as tanks occur.
Side effects weren't good last time, but I'm as prepared as one can be, having gone through 2 years already.

The main issues I believe effected my last treatment are being addressed. They were NOT addressed last time, because my clinic didn't know, didn't tell their patients.  Through this forum, and my own research I have learned what 5  major things were done wrong that contributed to a bad result.

these were as follows....and I must tell you my clinic was remiss in not knowing and informing concerning all this:

1. I was not told about eating fat to help riba absorb (until in month 4 a forum member mentioned it)
2. I wasn't told too much fiber could push riba through too quickly to absorb (again a forum member informed)
3. I wan't told proteins (purines) could greatly interfere w/ riba absorption...I found this in my own researching
4. I wasn't told about the crucial role Insulin resistance played, until a forum member informed us at my EOT.
5. I wasn't told the pegasus doesn't work on the last day of the week, I discovered this, and then my clinic admitted it to me.

By dealing with all these issues, I feel I will have a better chance this time around and am hoping for a stellar log drop, God willing.
You are right about recovery, I am 2 years beyond tx, and just lately feeling somewhat recovered, the first year after tx barely felt that way.
Still, I am positive, one more shot to try to cream this virus, and hopefully in half the time, might leave me time to raise my grandkids and enjoy some golden years, and that'll make it worth it.


Avatar_m_tn
by lynda607, Oct 07, 2011
You can't discount the eRVR's that have been posted on the board and it's being done with Pegasys and PegIntron.  I really think your minimizing how powerful the DAA's are.  People with cirrhosis, people who have failed treatment multiple times, high viral load, diabetes -  many many are UND at wk 4 so whatever you think Pegasys is supposedly not doing on the 7th day does not seem to be having any impact on viral clearance.  With a DAA, you're dealing with a whole different concept, the response is not the same as it is with SOC alone.  The DAA's make insulin resistance, body mass, viral load, even advanced fibrosis much less of an issue and they do their best work within the first week, maybe two.  Don't know if you plan on doing 48 weeks regardless, but with eRVR treatment duration can be cut in half.  With eRVR, the chances of SVR for relapsers is around 92 percent and that's with 24 weeks of treatment.

I know a number of people who did Infergen by the book after relapse with pegylated interferon, some even less than 15 IU  and still said it was extremely difficult and many didn't SVR.  I would hate to be your stomach or thighs by the end of a month after injecting 3 X daily and that's not counting helper drugs if needed.  At the end of each day you'll have taken as much Infergen as if you injected one time daily and I cannot see the 3 x daily technique as beneficial.  Incivek is a very powerful drug, and few if any are unaffected.  Nausea, vomiting, rash, rectal discomfort just to name a few and you must take the Incivek with 20 grams of fat and you're going to have some added nausea with daily Infergen.  You obviously have your mind made up, I wish you the best and hope you have a contingency plan in place if things do not turn out as you anticipate.  

Would hate to see multiple posts from you on the long term side effects thread years from now.  :)





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by merryBe, Oct 09, 2011
Hi Lynda again. You made some very good points and I don't discount any of them.

My hope is indeed the ERVR, and hopefully since I won't be eating purines when I take my riba, I may get better response.  Plus I'll be doing the FAT and the IR control from the get go.

I also believe my doc was remiss in telling me to have 3 BM's a day. He was telling me to eat lot of fiber, but the problem is the riba needs time in the gut to absorb...and 3x a day means things are moving too quickly for optimal absorption. The doc had answered my query as to what was best for my liver, but I don't think he was taking into account what it takes to absorb that riba, as he didn't tell anyone about fat or purines...I had to bring that research to him.

You may want to check out my Purines thread. It seems that the studies done indicted a 30% to 100% reduction in riba absorption in the presense of purines.  Since my docs told me to eat proteins throughout the day, I'm assuming I had at least a 30% reduction as in the human studies, and possibly a lot more than that.

That means that though I was taking 1200 mg riba, in all liklihood I was getting 800 at best, and probably considering my constant protein diet maybe half of that, maybe only 400 mg!!

This is part of why I believe my response was so poor...the tx was almost as bad as the old INF monotherapy IMHO.
Not being informed was the biggest issue as had I known, (and the minute I found out I altered to comply), I certainly would have complied from the get go.

I do have a fall back plan if the Infergen is too intense, first to dial back slightly, then to switch to pegasus after going UND.  
My rational for the heavy punch to start with is based on the studies showing the mutants that survive form in the first week, and that the harder the puch, and more pronged the approach early on, the less chance of viable mutant survirors.

Please note, last time around I didn't go UND until week 20.  I will not even go there again.
If I don't get a ERVR, OR at leat a RVR I probably will quit and not beat a dead horse. The deck is stacked aginst me ( IR, high BMI, stage 4, cirrohsis,
so unless I use the most drastic means, and get results early, I believe my odds will not justify a year of this...for the very reasons you gave, the long term damage for a 10-15% chance of cure won't be warranted.

So I thank you so much, and appreciate what you have said, and have thought this through and read extensively.

Yet again, I treated for almost 2 years, which is a VERY long time on these drugs.

So I only am going to get one more shot at this with INF on board.
The odds of mutaions if one doesn't get UND quick are a real concern, and the chances of retreating any time soon go down with the PI on board, so unless this combo really mops the deck, I will cut my losses and live to fight another day.  I was foolish in clinging to hope based on just a couple of studies last time, the real truth is even if one does everything right, this is still just a c.r.a.p. shoot and the odds are stacked againt all but the early responders. The best chance of beating it is the ERVR result, I do know that, and will act accordingly. In fact the whole point of doing the regime I'll be doing is to get that coveted status.

Thanks again for your concern, and please keep in touch. It sounds like you've done your share of research and I always value the views of those who have.

mb

opps, almost forgot.  The reasoning behind 3 shots is simple, INF stays around 8 hrs in the system, it clears quickly, has a 4 hr half life.
Naturally, if we take 15 mg at once of course we are going to get a big punch but also a big bowl of nausea, chills etc.
the sides you mentioned, however, we are also going to have very little in the system for 16 hrs of each day.
Neither of these ideas made sense to me.
If I break the dose into thirds, and take 5 mg each time I should achieve 2 goals, one is less severe sides than if I take 15 mg all at once...(especially important with a stage 4 liver that has limited processing abilities left)...and secondly, I will have some INF on board at all times of the day and night, which is not true of one shot per day.
In any case, this seems a reasonable approach to me, and I did give it some thought.

Avatar_m_tn
by can-do-man, Oct 09, 2011
Have you gave any thought to doing a lead- in? Some of the experts think this is a wise choice even when doing the Incivek.

Virologic response to a 4-week pegIFN/RBV lead-in is a predictor of the likelihood of SVR after completing boceprevir- or telaprevir-based therapy. The use of a lead-in phase is mandated in all patients treated with boceprevir in the prescribing information. A lead-in phase is not included in the telaprevir prescribing information. Some experts would consider using a lead-in phase for patients who would be treated with telaprevir, when the results might influence a decision on whether to continue therapy or how long to treat, such as previous null responders or treatment-experienced patients whose previous response category is unclear, or in some patients with advanced fibrosis or cirrhosis.



http://www.clinicaloptions.com/Hepatitis/Treatment%20Updates/HCV%20New%20Agents/Module/Practical_Guide/Pages/Page%203.aspx

cando



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by Dee1956, Oct 21, 2011
Merrybe, MikeSimon, thank you so much, I really appreciate the two of you taking the time to provide me with this information
At the beginning of this I thought I was going to be on Pegays, like before.  I guess we talked so much about Incivek the thought did not occur to me.  I did later ask if I could use the Pegasys but the administrator said she would have to start all approvals again and I had already waited two months
When I ask the doc why he gave chose pegintron over pegasys he said he often does that if someone has relapsed on one as I did.  I still wish that I had been able to take the Pegasys, this treatment seems a lot harder though the doc says it is the Incivek and since I only have 6 more weeks I will feel better.  I hope so.  I feel like a wimp for not insisting on Pegasys but maybe he chose for specific reason back in August which he can't remember now :)  I just have to trust him.  He said this tx would be hard and it is  I am itching so badly right now and have tried benedryl, pills, lotions and am about to scratch the skin off my body  
I am going to ask my doc about atarax today.  If anyone has a suggestion I would be very grateful. Finally the benedryl knocked me out :)  I pray it does not come back today.
Dee

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by Dee1956, Oct 21, 2011
Merry, if you have a chance could you tell me where there is a list of inhibitor/inducers for Incivek?  Of course I gave my doc all my meds I take but no one mentioned anything about food that might inhibit or incude
Yesterday I read that yu should not eat Oatmeal with Incivek triple tx and I was floored.  Of course I was also surprised when, after the first tx I was told I needed to take fat with the riba.  I had an idiot for a trial doc and in fact when Roche audited him he was fired.  Sorry, too much information :)

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by Dee1956, Jan 02, 2012
Merrybe, thank you again, I did not know about fat with Riba the first time, did not know about IR, I have diabetes though when on tx my sugar goes really low so I wonder if I have liver diabetes.
Incivek is very hard and after I started tx it turned out that I was on medications that needed to be modified or changed.  It is too late for me since I did not find out till the first week in December when I started to suffer from the medications.  I did not know what to do.  Incivek stays in the body a long time, I finished on Nov 27th
Dee
Thanks again
Dee

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