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can anyone explain this?

Adequate Ribavirin exposure after the first dose predicts SVR in genotype 1 patients
Last updated:08July2008

7th July 2008 By Liz Highleyman hivandhepatitis.com

Studies continue to show that adequate doses of ribavirin, which helps to prevent relapse after completion of therapy, are important for optimal treatment of chronic hepatitis C virus (HCV) infection.

Hepatitis C is a virus-caused liver inflammation which may cause jaundice, fever and cirrhosis. Persons who are most at risk for contracting and spreading hepatitis C are those who share needles for injecting drugs and health care workers or emergency workers who may be exposed to contaminated blood.

But actual ribavirin concentrations achieved in the body after dosing may be more relevant than the amount administered, according to a French study published in the May 2008 issue of Hepatology.

As background, the authors noted that previous studies showed "marked inter-individual variability" of ribavirin concentrations despite dose adjustment based on body weight. Furthermore, data suggested that there was a correlation between single time point ribavirin concentrations and achievement of sustained virological response (SVR), or continued undetectable HCV viral load 24 weeks after completion of treatment. None of these studies, however, evaluated global exposure to ribavirin.

In the present study, the investigators conducted an exploratory pharmacokinetic-pharmacodynamic analysis of 28 genotype 1 chronic hepatitis C patients treated with pegylated interferon alfa-2a (Pegasys) plus weight-based ribavirin for 12 weeks, with amantadine (an influenza drug once studied as an experimental anti-HCV therapy) added for an additional 36 weeks; 24 participants completed the study.

Full and abbreviated ribavirin area under the concentration time curve from 0 to 4 and 0 to 12 hours (AUC(0-4h), AUC(0-12h)) were derived from plasma concentration profiles at day 0, week 12, week 12 + 1 day, and week 24. Virological response was assessed at day 0 (0, 12, and 24 hours), at weeks 2, 4, and 6, and then monthly through week 72, using a TaqMan polymerase chain reaction assay with an HCV viral load threshold of 15 IU/mL.

Results

• Patients who achieved SVR had a significantly higher ribavirin concentrations at day 0:
- AUC(0-4h): 2010 vs 1340 microg/hour/L (P = 0.03).
- AUC(0-12h): 3695 vs 2937 microg/hour/L (P = 0.03);



• Patients with day 0 AUCs above the cut-off values defined by receiver operating characteristic curves (1755 microg/hour/L for AUC(0-4h) and 3014 microg/hour/L for AUC(0-12h)) had a significantly better chance of achieving SVR than participants with AUCs under these thresholds (odds ratio 16.0 and 8.9, respectively; both P = 0.02).

"Ribavirin exposure at [day 0] is significantly related to SVR," the study authors concluded. "We propose a minimum AUC(0-4h) threshold of 1755 microg/hour/L at [day 0] as a target for ribavirin dose adjustment."

"To our knowledge, this is the first study to give an early pharmacokinetic predictor of SVR," they added.

If these findings are confirmed, early ribavirin concentration may be added to the several other factors (including HCV genotype, pre-treatment viral load, and rapid virological response) that can be used to predict - and ideally improve -- the chances of sustained response to hepatitis C treatment.

Reference
V Loustaud-Ratti, S Alain, A Rousseau, and others. Ribavirin exposure after the first dose is predictive of sustained virological response in chronic hepatitis C. Hepatology 47(5):1453-1461. May 2008. Abstract


16 Responses
Avatar universal
As I understand it the article is prosing that patients with higher blood plasma ribavirin levels on day 0 is a predictor of success at attaining SVR.  

This does NOT mean to anyone taking an s-load of ribavirin their first day will necessarily have a higher chance of SVR  It MAY mean that some people's metabolism create, for some unknown reason, higher blood levels of Riba during treatment.  For THOSE people their chances of SVR may be higher - although the authors do seem to be implying that higher Riba dosing on day 0 may be a good thing.

***** for me as my treating P.A. had me start the Riba 12 hours AFTER my first shot.  Veterans Administration .  Yeah.
Avatar universal
What it's saying in essence is that it's not only important to get the right dosage amount, the amount of ribavirin concentration / absorption achieved is also an important factor in the effectiveness of ribavirin, particularly in the first 12 weeks of treatment.  

It's also suggesting that the higher the ribavirin concentration in the first stage of treatment, the better chance at SVR ... one can potentially make a case for pre-dosing with ribavirin to achieve maximum concentration of ribavirin at start of treatment.

One of the best ways to increase concentration of ribavirin is to take it with a high-fat meal.  To take your riba with no meal or a regular meal has the equivalent absorption factor, while taking riba with a high-fat meal of some kind increases the absorption factor by a whopping 46%

http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1804105

I can tell you that I've increased my intake of ice cream eaten with my riba after reading that with alot less guilt. ;->

There are ways of measuring how well your body is "concentrating" the ribavirin, though I'm not well-versed in that.  I'm thinking it's what Willy50 referred to as "trough" levels of ribavirin.  I'm thinking that if it's able to be measured, then dosage can be adjusted according to how well the body is absorbing / concentrating it and titer the dosage upwards if necessary.   I did read and thought I had bookmarked an article on that and I guess it will depend which part of the article I found significant at the time as to where I filed it.  There was some mention in the article on measuring effective absorption of ribavirin by measuring the CL, or Creatinin clearance levels.  I'll look for it.

That's my take on it.

Perhaps others have some insight on this as well.

Trish







Avatar universal
Correction...the article you quoted doesn't mention the importance of adequate ribavirin in the first 12 weeks, other articles I've read mention that first 12 weeks as being important but not to the exclusion of the next 12 weeks or the ones after that,...just that the first 12 weeks is most important.

As well...I'm not suggesting that everyone should have their concentration levels tested and dosage adjusted accordingly...it's simply interesting food for thought in my mind at the moment when reading such things and definitely warrants more consideration IMHO.  I wonder where such studies will lead to down the road in determining appropriate ribavirin levels.

Trish
Avatar universal
While certainly not conclusive that pre-dosing ribavirin can help with SVR, the study certainly makes pre-dosing a more reasonable option. As to serum riba levels, the Lindahl Swedish research group has been on this train for some time now highlighted by their pilot high dose riba (HDR) study. For a number of years, Lindahl's thesis has been that body weight is a poor gauge of riba dosing, do to individual variances in how riba is metabolized. Lindahl mesured riba absorption through HPLC (high performance liquid chromatography) testing which is not available in this country, unless perhaps in some research labs. Unfortuantely, very little work here in this area which could potentially have salvaged many, many SVRs, but resources (money and white coats) are elsewhere, mostly with the PI's. I expect we will see some pre-dosing studies soon and maybe some enlightened clinicians will start demanding HPLC testing for their patients.

As a word of caution before people start getting overly enthusiastic about upping their ribavitin, its not a drug to play around with. Two or Three of Lindahl's small pilot study (10 participants) required two blood tranfusions each, not to mention increased side effects (and epo) for the rest. On a personal note, I tried to emulate the Lindahl study when I started tx and ended up in the ER, resulting in having to go off riba for close to a week which could have cost me my eventual SVR. It also terminated any HDR plans, including a planned trip to Sweden for HPLC testing. That said, for the right highly motivated patient, with the right medical team, focusing more on the riba is  something worth exploring, especially if prior treatments failed, PI's are not available, and if riba absorption from prior treatments is suspect. As to pre-dosing, I think it's a reasonable concept that anyone starting tx should discuss with their doctor. FWIW Dr. Dieterich in the professional forum, made a favorable mention of the concept recently.

-- Jim

-- Jim
148588 tn?1465782409
Ja gotta love a study that throws amantadine into the mix at this late date. I wonder if any of the patients got colloidial silver or leeches on top of everything else.
179856 tn?1333550962
Well pretty much we all already knew this - but I want to point out that Andromadaes statement of

"This does NOT mean to anyone taking an s-load of ribavirin their first day will necessarily have a higher chance of SVR"


Should be well heeded.  As I've freely admitted I went bonkers with riba way over my weight based dosage - almost had to stop treatment because of the drastic anemia in the 2/3 week mark and STILL had to extend treatment.

But we all know how  crucial getting and keeping the dose of riba up is - I just don't want anyone to think taking 2,000 a day of the junk will help...mostly all it did for me was get my hemo to drop 6 points in one week.  That was NOT good.

This article does make me think that pre-loading riba IS a good idea though to get that serum level up however we don't know for sure if because you've already gotten it inside of you whether or not that might be a negative in the long run.

Still a big crapshoot.
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