Measurement of VL in first 12 wks of treatment

[Trish77]

I would like to know how important it is to all of you to know your exact VL during treatment at 4 and 8 weeks.  If you have a PCR that measures down to <50IU/ml, are you content with a Pass/Fail until that week 12?

This is the scenario I'm in for and I'm not happy about it, I want to know my exact VL count at 4 weeks and 8 weeks if I fail, as in I'm above <50IU/ml.  Is this reasonable or am I getting uptight for nothing?  I'm thinking if I know at 4 weeks that I'm not doing so well, I can ask the doctor to alter my treatment to increase my odds.  Then I can measure again at 8 weeks how it's going.  A pass/fail doesn't give me enough information, I'm thinking.  Am I off-base there?  Hard to know if I'm letting emotions get in the way of clear thinking at the moment.

(I posted all my questions in one post on the other side..but way too much to slog through I'm thinking so I'm breaking it out individual posts for the questions that are on my mind.)

[Trish77]

Well.  I am stunned.  I finally spoke to the Public Health Lab to see what would be involved in getting my own quant PCR at my own cost, at least to establish my baseline VL.  As I've said ad nauseum before, I'm at 1.3mil IU/ml, the upper limit of the assay used.  The information they gave me today is that there are only two places in Canada that do these PCR's and that this IS the upper limit of the assay available to them. There IS no higher limit than that.  My poor Dr.  THAT is what he was trying to tell me.  The woman told me that they will soon begin to start using a test that tests 10 to the 7th instead of 10 to the 6th (I don't know the correct notation for that, simply repeating word for word her terminology) and that will test up to 10 million IU/ml.  

I am stunned.  They consider anything above 800,000IU/ml to be "treatable" so that is why my doctor said that I'm already at 1.3mil IU/ml so it doesn't matter.  However...it still matters to ME.  I simply understand now what he said when he said...there isn't anything higher.

I'm just going to take awhile to digest that.   Whether I get in the drug trial or not determines how far I take this and in what direction....but...wow.  I guess to some you'll be saying "what's the big deal?" but...I don't know...an accurate baseline seems really important to me.  

  

[jmjm530]

Prev: .5 hour to dissolve because of outer coating
1 .5 hours to work it way into digestive system
    3 hours to reach total absorption and distribution in blood plasma depending
      on person variable 3 or 4 hours but I used the 3 hours in the equation.
    5 hours total x2 = 10 hour front end and back end
168 hours from intake to elimination
-10 5 front end and 5 back end
158 divided by 2 = 79
---------------------------------------------------
It appears that the most important PharmaKinetics of ribavirin have been omitted.

2 days until you need sleep aids. (16 divided by 8 hours sleep)

4 days until you need an AD. (20 divided by 5 days of week)

7 days until you need a divorce (70 divided by the average number fights per hour (10))

[willing]

as best I can tell  changes absorption, concentration, clearance, etc. in pharmacokinetics are all modelled by simple, time-dependent, differential equations (eg as a function of time, the change in the amount of  drug in "compartment" A  equals some transfer constant times the amount in "compartment" B).

That Preston'99 paper cited as reference 79 in Lindal's dissertation,
http://www.ncbi.nlm.nih.gov/pubmed/10508023
sets out the nine differential equations they used to model rbv's flow through the body. As you posted earlier, the term "half life" applies to any phenomenon where some quantity decreases with tiime, so as rbv moves from compartment to compartment  through the body, the term half-life applies to any compartment that rbv is diffusing out of, not just final elimination.

The quality of any model  comes down to how  realistically it describes what's really happening. Even with 9 ordinary differential equations (ODEs) the Preston model is a simple-minded, three compartment,  description of how a single rbv dose breaks down and as emphasized by that 79 vs 298 difference doesn't do a good job of describing the "multi-dose" regimen on tx (there likely are more sophisticated models out there that handle multiple dosing;  this is probably the sort of stuff pharmacology students are tortured with).

The 4-week to steady state claim seems long and may be another area where that review is a bit dated (since it came out shortly after rbv was fda-approved for hcv in '98  it probably uses many of the same studies submitted  for fda approval and that are now part of the med insert fine-print).  There's a good graph of plasma concentration at start of tx with std rbv dosage in  various patients in Figure 1 of
http://www.ncbi.nlm.nih.gov/pubmed/17494069

things look pretty stable after 14 days.

[geterdone]

What is the total time from intake to elimination? Could be wrong am most of the time here but this is how I see it given your question. Any other takers to Zazza’s question if wrong and would like to know myself.

jasper

   .5 hour to dissolve because of outer coating
1 .5 hours to work it way into digestive system
    3 hours to reach total absorption and distribution in blood plasma depending
      on person variable 3 or 4 hours but I used the 3 hours in the equation.
    5 hours total x2 = 10 hour front end and back end
168 hours from intake to elimination
-10 5 front end and 5 back end
158 divided by 2 = 79

Jasper

[geterdone]

Actually it should have been an error rate of .385 not 1.385.

jasper

[zazza]

LOL! Hey, guys, I just figured out I should never have become a drug junkie, I should have become a hep doctor with a math major instead!

[geterdone]

79x2=158+.5=158.5+1.5+160+4=164+.5=164.5+3.73=168.23 divided 2=84.115-.5=84.615-3.73=80.885-.5=80.385 subtract 1.385 error rate of absorption between 3 and 4 hours =79 hours of half life for a single dose from intake until total elimination of the body. I think?

jasper

[zazza]

I don't quite understand what "single-dose half-lives of absorption, distribution" means. My pharmacist said that absorption starts at 0.05 hours after oral intake and that the ribavirin is distributed throughout the body by 3 - 4 hours. What does half-life mean in this context?

[zazza]

The figures in Mr Liver's article above "The Clinical Pharmacology of Ribavirin" seem to be the same as those my pharmacist gave to me as information directly from Schering-Plough.

"Ribavirin is rapidly absorbed following oral administration (mean time to maximum concentration [Tmax] = 1.5 hours), followed by rapid distribution and prolonged elimination phases (single-dose half-lives of absorption, distribution, and elimination are 0.05, 3.73, and 79 hours, respectively)."

I find the differentiation in the article between duration of half-life for single dose and multiple dosing interesting: 79 hours vs 298 hours. 298 hours equals 12 days and 10 hours. (Kcmike mentioned a half life of 21 days in another thread. Was that incorrect?) 298 hours would explain why many seem to be feeling better 2 weeks post tx.

Notice also the mention of approximately 4 weeks to reach steady-state ribavirin concentration. In other contexts here on Medhelp 5 months have been mentioned. Which is correct?

And lastly notice the mention of approximately 15 half-lives (6 months) to ensure no effect on fetus.

"During multiple dosing, ribavirin accumulates extensively in plasma, with a ratio of multiple-dose to single-dose AUC at 12 hours (AUC12hr) of 6.[17] Following dosing with 600 mg twice daily, steady-state ribavirin concentration was reached by approximately 4 weeks, with mean steady-state plasma concentrations of 2,200 ng/mL. After discontinuation of dosing there was a washout half-life of 298 hours.[17] The extended washout period likely reflects slow elimination from nonplasma compartments (Figure 5). The fact that the multiple-dose ribavirin half-life (298 hours) is considerably longer than the single-dose half-life (79 hours) means that it is not possible to predict (ie, model) multiple-dose ribavirin pharmacokinetic parameters based on single-dose parameters."

"The extensive accumulation of ribavirin nucleotides and their slow dephosphorylation contribute to the long half-life following multiple dosing (approximately 300 hours). To prevent potential teratogenic effects, we have estimated that 6 months (approximately 15 half-lives) is required to ensure a complete washout following cessation of dosing."

[Lady Lauri]

..........I keep trying to tell them that it's not covered and I want to PAY for it.  They don't know how to deal with out of the box ...............

Glad you got the 'script', now hope you get it done!
I had a woman Dr. for years, loved her! She left and went to another office, they don't take my (crummy) insurance. I tried to see her and to pay CASH! They don't take CASH??? (self pay!) I said "okay, so if I had 20 million bucks and want to pay CASH for everything, I can't?" .....'No mam, we don't take cash, self pay'! I haven't been able to get past them just to talk to her! Sending her a letter as she will be amazed what has come of all the 'other' office's mistakes, and want her opinion on some things! She was the kind of Dr. that when she ordered a test for you and you didn't go, she'd call you herself and say "WHY haven't you done this? Get over there and do this!"
  Pretty bad when cash doesn't work!

LL

[geterdone]

I don’t know if this has been posted before but may shed some light on the European medical community’s thoughts on the 4, 8, 12 pcr testing and shorter tx duration for the geno 1’s
jasper
"This study shows that in HCV genotype 1, treatment duration should be tailored to the 12-week on-treatment virologic response," Dr. Mangia and colleagues write. "HCV RNA should be monitored qualitatively at week 4 to identify patients with the highest likelihood of response, and at weeks 8 and 12 to determine if extended duration may be required," they conclude.
Individualized Treatment Duration for HCV Meets With Success

NEW YORK (Reuters Health) Jan 15 - In patients with hepatitis C virus (HCV), individualizing the duration of peginterferon/ribavirin treatment yields success rates similar to standard 48-week treatment, thus sparing unnecessary costs and side effects, according to results of two randomized controlled studies published in the January issue of Hepatology.
In one study, Dr. Alessandra Mangia from "Casa Sollievo della Sofferenza" Hospital, San Giovanni Rotondo, Italy, and colleagues treated 696 patients with HCV genotype 1 with peginterferon alfa-2a (180 g/week) or peginterferon alfa-2b (1.5 g/kg/week), plus ribavirin (1,000 to 1,200 mg/day). Patients were randomized to treatment for 48 weeks (the standard treatment group; n = 237) or for 24, 48 or 72 weeks if HCV-RNA was undetectable at 4, 8, or 12 weeks, respectively (the variable treatment group; n = 459).
According to the investigators, results showed "equivalent rates of lasting viral clearance after therapy administered for the standard 48-week length or a variable duration tailored on the first undetectable HCV RNA during the initial 12 weeks of therapy."
Nearly 49% of patients receiving variable treatment based on detectable HCV RNA achieved a sustained virologic response, compared with 45% of patients in the standard treatment group (p = 0.37), Dr. Mangia and colleagues report.
"This study shows that in HCV genotype 1, treatment duration should be tailored to the 12-week on-treatment virologic response," Dr. Mangia and colleagues write. "HCV RNA should be monitored qualitatively at week 4 to identify patients with the highest likelihood of response, and at weeks 8 and 12 to determine if extended duration may be required," they conclude.
Meanwhile, in a study of 428 patients with HCV genotype 2 or 3, researchers from Norway randomly assigned patients who achieved a virologic response after 4 weeks peginterferon alfa-2b (1.5 g/kg) weekly and ribavirin (800 to 1,400 mg/day) to complete either 14 weeks or 24 weeks of treatment.
In intention-to-treat analysis, Dr. Olav Dalgard from Ulleval University Hospital, Oslo and colleagues found that 81.1% of patients in the 14-week treatment arm and 90.7% in the 24-week arm achieved a sustained viral response.
Among patients with an HCV RNA test 24 weeks after the end of treatment, 86.3% of the 14-week treatment group and 93.2% of the 24-week treatment group had a sustained viral response.
"In conclusion, we cannot formally claim that 14 weeks treatment is non-inferior to 24 weeks treatment," Dr. Dalgard and colleagues write. "However, the sustained virologic response rate after 14 weeks treatment is high, and although longer treatment may give a slightly better sustained viral response rate, we believe considerable economical savings, good response to re-treatment, and less side effects make it rational to treat patients with genotype 2 or 3 and rapid viral response for only 14 weeks."
Hepatology 2008.

[Trish77]

Thanks for the heads up on this other article, I will also add that to the mix of my reading.

As for my tests.  I wish it were that simple.  I'm dealing with labs who don't do private testing for people.  You'd think I could find one.  I'm working on it.  I'll be widening my search to the U.S. soon, simply so that I know what options are available.

The labs here are used to doing testing under government guidelines and protocols.  What I'm asking for falls outside of that.  So I walk in and say I want this done and I want to pay for it and they say "oh no...you don't have to pay for that, the government does." Then I launch into my spiel and I say that what I want is different than what the government pays for and how can I get this test done and pay for it myself?  So far I've been met with blank stares and frustration on their part at such a seemingly simple question.  They have a standard form to fill out for HCV PCR's and they have no procedure outside of that. The last place I went, she said " I don't KNOW how to give you what you want!" and I told her that's fine...but someone up above her must.  And she gave me a couple of phone numbers to call.  And I'm chipping my way through a system that operates on standard protocols when what I want is non-standard.   The next phone call is to the lab that actually does the testing on the blood itself.  And that happens to be the Public Health lab....as apparently I'm told not just any lab can do HCV RNA testing.  And that's where it's done here.  Argh.  By the time I'm done...I'll have yet another educational experience under my belt.. but it's worth it because, well, of what I hope to accomplish in the bigger picture as a result and I'll leave it at that.

I'll keep in mind what you've said and pull it out as a stratagem if it fits within what they're willing to do.  I just need to know how to pay for what I want and then get a process in place to be able to have me and others follow it.  

[willing]

that is a good review, but please note the date - 1999. Some of the infomation in Lindhal's dissertation (2005) and in the references she cites is more timely. Also, with respect to the rbv fat/bioavailability question that recent,  2006, article seems quite clear :

" Although a standard meal did not affect ribavirin bioavailability (F1), administration of ribavirin with a high-fat meal increased bioavailability by 46% relative to the fasting state. A high-fat meal prolonged the duration of the zero-order input part of the absorption model, with D1 increasing from 0.498 h (fasting and standard meal) to 0.740 h"

It's worth researching this further, but some of the doubts about the merits of combining rbv with fat may have been settled over the past few years.

Also Trish, if you're really wiling to pay for your tests out of pocket you may be better off by simply having the local lab do the draw, keep the blood at -80 then ship it to the lab of your choice. One advantage of this is building up a library of blood samples should you want to go back and have one retested.

[Trish77]

Thank you very much for this.  I had meant to get out to the gym much earlier and I made the mistake of starting to read this article.  I have been reading and cross-referencing since...lol  :)   It doesn't actually tell me all I WANT to know about ribavirin...however, it is an excellent starting point and a good foundational article.  Also gives me more questions which might mean more posts but I'll see.

Good article.  Thanks again.

Trish

[Mr Liver]

This article contains just about all there is to know about ribavirin.

http://www.medscape.com/viewarticle/416602_3

[Trish77]

It's an interesting experience at the moment.  My family doctor was awesome.  I saw him yesterday, told him why I wanted a script for quant PCR's and for how often.  He didn't give me ANY grief.. pulled out his pad and started filling in the details.  Asked me.. "So..once a month okay?" and he filled out a request for quantitative PCR's at a rate of one per month repeating.  First step easily accomplished!!

Next I go to the lab.  Now it gets weirder and harder.  All they understand is that HCV tests are covered by the government and that they go to the health unit.  I keep trying to tell them that it's not covered and I want to PAY for it.  They don't know how to deal with out of the box requests.  I get given the number for their main lab and the Health Unit.  

I called the Health Unit today and talked to their HCV "point person".  She tells me that the labs only DRAW the blood, not test it.  That the blood actually gets tested at Public Health LABS.  So THAT is what they meant by "it" goes to to Public Health.. the BLOOD does.  

So the Public Health nurse gives me the number for the Lab next...I called around 4pm and the young woman told me to call again on Tuesday (Monday is a stat holiday in Ontario) when everybody would be back and they'd help me wade through my request and see what can be done.  

Step by step.  I'll see how it goes.

[Lady Lauri]

Found it! (linked to me on my post to read)
  haven't gotten thru all this as have to get off line awhile but....

Flguy.......Another aspect could be a person who wants to evaluate tx response and make an early decision to continue or not..........

I have had VL results from starting day to 2 weeks, 4 weeks and on. I have needed these in my changes, decisions thru out.Without reading all......I believe starting VL and 2, 4, and so on is important in tx. And the sensitive testing.

Re-read all later, but as some said......you should be able to ask for it, NOT unreasonable  request.

LL

[merryBe]

I almost hate to add to all the advice, but been on both sides of this, so,
pros: keeping up on your blood lets you know you are making progress, if you are
cons: now reverse that if your results aren't primo.

in the end, it can make you crazy, thing is, they say insurance wants to cut you off at 12 weeks if you don't get a 2 log drop

but that is NOT ALWAYS TRUE.  Mine didn't, and was fine with me going out 6 months to get that 2 log drop....
(which means all that fear of being cut off is being put on people unnessessarily, and God knows how good that is NOT to our mental states)...
While ins may not be basing it on 12 week results. Since the VL moves around a LOT, especially if you have other illnesses as I did...then you can be discouraged when you really may not be down for the count.
PS, my doc is a statistical nut.....I had to pitch a fit and quote 50 studies to NOT become another....tombstone. Being treated as an individual, regardless of whether you have a 90 percent chance or a 10 percent chance, is still our right in this country...for how much longer is seriously in doubt...but for now it is....but you must assert your rights.

For myself, I decided to go along with the doc on waiting from month 4 to month 6 on the PCR (not the CBC's) mainly because I had made up my mind to go the distance and not give up prematurely because there are exceptions to every rule.At first I did not see his point, as he did not give me ANY rational...but later I reasoned.... If 2 out of 10 people clear late, then that's 2 out of ten that would be sick and die, because they let a doc, insurance company, or blood test make them quit.
Likewise if I tie myself up in knots at 4 1/2 5 5 1/2 months...what good will that do??

the question becomes one of statistics vs. sanity. Even if your VL goes back up for a while, do you automatically want to quit? Once you resolve whether to follow statistics or your own resolve it will get easier.
In either case, I think some monitor too much, and other's not enough.

think of it like a war, which it is.  One day on the battlefield, the bad guys may win 2 to 1...but the next day you may win 3-1.  In the end, it's your life that's at stake so how do you not just keep up the battle until there's no one left standing to fight?
If you were a soldier on a blody battlefield, you'd want to go home every day, as you are experiencing the carnage right?  Unless you can look past all the blood, and keep the goal, and what is at stake clearly in mind.  So that's what I'm doing, not looking at the blood or set backs, so to speak, looking at the hill upon which I intend to stand and plant a victory flag.
hope you find peace with this.
maryB

[merryBe]

if fat is not the vehicle for greater absorption than perhaps the increased bile it creates is the vehicle, which might explain why some folks not on high fat get good absorption?
Maybe they just naturally produce more bile or some other digestive enzyme helping the Riba absorb for which the fat is merely the stimulant???
One would also think intestinal flora, it's health and the general permiability of the intestines would have some effect.
In any case, I'd want some actual data as to WHY Lindahl thinks it makes no difference.
We do know that fat aides digestion, and that fiber tends to bind other things up right??
Well, based on my side effects and blood work both my Riba absorption took a leap when I included fat AND excluded fiber from my dosing times.
While I would be more likely to conclude the elimination f fiber had more to do with my absorption rate, it doesn't rule in or out the role of fat/bile and there are more than a few studies on pubmed noting as much as a 1.5 increase in absoption with fat.
(I think that mean one and a half times greater absorption not 1.5 percent, someone correct me if this is wrong please).

I admire the work K Lindahl has done on Riba absorption, it's a key to SVR and should be monitored through blood work to obtain optimal results for all, but I'd still wonder, if she hasn't done any double blinds herself, then upon what does she base her cynism here. I assume she has some rational.  ????

[willing]

zazza: thank you for posting her dissertation! it's a good wrap-up of her research in this area.

all: That 3-day vs 6-month gap also suggests that the hplc-based plasma concentration tests may not be all that informative, even if they were more readily available. What one would really like to measure is the amount of rbv in cells and, for now,  hgb drop may be the best scale, crude as it is. The take-home message seems to be that if one's hgb drop is closer to 1.5 than to 4 there *may* be grounds to increase the dose...

[zazza]

Fascinating! Thanks for helping me understand this.

[willing]

Lindhal's dissertation which you posted (maybe we can just call her Karin since we're talking about her so much) sheds some light on the numbers  given by your pharmacist. She cites Preston'99

http://www.ncbi.nlm.nih.gov/pubmed/10508023

(free-access) with respect to rbv kinetics, and they largely agree with  your pharmacist. The effect of taking a new dose seems to peak in about 90 minutes "a time to Cmax of 1.33 ± 0.034 h after oral dose administration". Decrease of  plasma concentration varies across individuals, but as shown in Figure 2 of that paper is 0 or near 0 for most after 75 hours.

An important detail however, is that plasma levels don't tell the whole story. The rbv in red blood cells is *not* cleared and the rbv molecules stored there will go back into circulation when the rbc dies off. The wikipedia rbv article

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

puts total turnover of  one's rbcs at 6-months. I didn't follow this up, but this  detail seems to account for the 3 day vs. several month discrepancy.

Interestingly, Lindahl also casts  doubt on the "take it with fat" recommendation:

"The extent to which food affect ribavirin bioavailability differs between studies. It is also unknown whether any food effect might be altered by the type of meal consumed (e.g. high versus low fat content), if a food effect still would be evident upon multiple dosing and what clinical implications this might have (79)."

though more recent data supports the peanut-butter chaser:

http://www.ncbi.nlm.nih.gov/pubmed/17118126

[willing]

bobby: 17->11.7 is about a 31%drop, which would indeed suggest you are strongly responding, even  at 1000. You can get an idea of where that 31% drop puts you relative to others by looking at Fig. 8 from Lindhal's dissertation  which zazza posted above (not many blue dots above 31%..) and  also from the following summary from Dahari'07

(http://www.ncbi.nlm.nih.gov/pubmed/17412448)

"We also evaluated hemoglobin declines stratified by treatment outcome. Although median baseline hemoglobin levels were roughly equivalent in SVRs and NRs (p = 0.20), hemoglobin decline during the first month of therapy was significantly greater in SVRs than NRs (3.9 vs. 1.4 gm/dl, p = 0.002) "

all: the rbv mystery deepens...writing last July in a review comparing two recent assessments of rbv's effect as an hcv mutagen, Perelson, maybe the world's leading hcv kinetics expert,  closed with:

"In summary, both papers[1] and [2] demonstrated that RBV has an early effect in elevating mutation rates, consistent with the mutagenesis hypothesis. Although further tests, using infectious HCV clones or additional sequencing may be performed, the proof may be in the pudding. If RBV is acting mainly as a mutagen, then according to the Dixit et al14 model, it should have little effect in combination with therapies that efficiently block viral production. If a lack of effect of RBV could be shown for combinations of IFN with effective small molecule HCV inhibitors, we can stop arguing about RBV’s mode of action and simply remove it from future therapies."
(from http://www.ncbi.nlm.nih.gov/pubmed/17484896)

however... it looks like the arguing will go on for quite awhile to come since,  as summarized in that quote by Jacobson that mike posted in the r-1626 thread above:
"this study also showed that ribavirin contributes significantly, just as it did with telaprevir, to the antiviral activity seen with combination therapy containing R1626."

not only is rbv not going away, neither the mechanism of its effect nor  the proper way to gauge "optimal" dosage seems to be coming into view.

One interesting point, and perhaps others can tell me if I'm hallucinating or not,
but from both Fig. 10 of Lindahl's dissertation (thanks zazza)  and Fig 1a of Dahari'07 (free access) it seems that the striking difference in rbv plasma levels between svrs and nrs is not so much the mean as the variance. The svrs all cluster around one level whereas the nr values are all over the map...

[jmjm530]

A number of doctors are using weight-based riba for geno 2's and 3's.

At 190 lbs, you just entered the 1200 mg./day dosing range but maybe your doc played it conservative since you weren't a geno 1 -- as he just as easily could have given you 1200 mg. (I started at 1200 mg/day and weighed 176 but was a geno 1).

In any event, you had a significant drop in hgb so one might assume that the current dose is getting into your system efficiently and frankly I'm surprised such a drop didn't land you flat on your back. BTW there's a "helper drug" called Procrit (epo) that helps many of us function better with low hemoglobin. If your symptons are persisting something to talk to your doctor about.

The low range for hgb on my lab report is 13.2, but keep in mind that most of us are anemic to one degree or another on tx.

-- Jim