EOT Riba Concentration predicts relapse

[timothy141]

The end-of-treatment ribavirin concentration predicts HCV relapse
0

    Friday, August 16, 2013
    Posted by New HCV Drugs
    File Under hcv abstracts, HCV News, ribavirin

Ther Drug Monit. 2013 Aug 12. [Epub ahead of print]

The end-of-treatment ribavirin concentration predicts HCV relapse

Bodeau S, Durand-Maugard C, Lemaire-Hurtel AS, François C, Castelain S, Helle F, Andréjak M, Nguyen-Khac E, Duverlie G, Brochot E.

Source
*Departments of Pharmacology and †Virology, Amiens University Medical Center; ‡Virology Research Unit, EA 4294, Jules Verne University of Picardie; and §Department of Hepatogastroenterology, Amiens University Medical Center, Amiens, France.

Backgrounds and aims: The optimization of combination therapy with ribavirin (RBV) and pegylated interferon alpha has substantially improved sustained virologic response (SVR) rates and lowered virologic relapse rates in patients infected with hepatitis C virus (HCV). In order to improve therapeutic of patients infected with HCV in our hospital, we developed a LC/ESI-MS-MS ribavirin assay. We then conducted a retrospective study of the relationship between the end-of-treatment plasma RBV concentration and virologic relapse.

Methods: Thirty-four HCV patients treated with PEG-IFN/RBV and with an end-of-treatment response were assayed for plasma ribavirin concentration on the last day of treatment by LC/ESI-MS-MS with a triple quadrupole mass spectrometer (3200 QTRAP, ABsciex, Les Ulis, France) in positive-ion selected reaction monitoring mode. [13C5]-Ribavirin has been used as internal standard. CV of intra-day repeatability of the technique varies from 2.53 to 8.49 % and inter-day repeatability from 2.98 to 10.74 %. The technique is linear from 7.5 to 10 000 ng/mL and the lower limit of detection is 4.5 ng/mL.

Results: Eleven patients (32.4%) relapsed and 23 patients (67.6%) achieved an SVR.

The mean plasma ribavirin concentration on the last day of treatment was 1380 ng/mL for relapse patients and 2278 ng/mL for SVR patients (p=1.44x10-6).

A receiver operating characteristic analysis showed that a threshold of 1960 ng/mL was associated with the greatest sensitivity and specificity (100% and 83% respectively, with an area under the curve of 0.94; p<0.0001) for discriminating between relapse patients and non-relapse patients. A bivariate analysis indicated that a plasma ribavirin concentration

Discussion and conclusion: Our study results highlight the relevance of measuring plasma ribavirin concentrations during and at the end of treatment, with a view to avoiding virologic relapse. These findings should be analyzed in the context of three-drug combination therapy (with a revaluation of the relevance of the therapeutic drug monitoring of ribavirin) in order to optimize the sustained virologic response (SVR) rate.

Keywords : Therapeutic drug monitoring, ribavirin, Hepatitis C virus, LC-MS/MS

PMID:23942546 [PubMed - as supplied by publisher]

[timothy141]

These all such great answers, and I appreciate each one. As of now nothing has changed with my tx meds. Dr. Prince nor his nurse got back with me about the above test. Went in yesterday for my standard CBC etc blood draw and have not been contacted about any thing being amiss. I have again, started being vigilant about my fat intake, peanut butter shakes, real butter, bacon and cashews. I some how forgot to beware of that.
Thank you again,
Tim  

[bbj2856]

I was geo. 3 .   I am a  female and I did peg injection 180 and rib. 2 ribs daily 400 mg each total of 800 . My starting weight was 159 I was 128 when I finished. I did not have big problem with the blood it was low at end of  20 weeks but I made it to end of my 24th week.   I was UND at first blood work 4 weeks and stayed UND all 24 weeks finished in June 2012 and so very thankful I was ok at end of Dec, in 2012. I  still had little bit enlarged liver  and spleen, but praying it be normal in Dec when I go back. blood enzymes were high all during treatment but was normal at end of 6 months. My Dr, said he was real pleased with my progress,  It got hard the  last 8 weeks and sure glad it is over GL to you and hope you get SVR



bbj2856

[timothy141]

Thank you, fat fat fat.

[hrsepwrguy]

http://www.spfiles.com/pipeg-intron.pdf

Effect of food on absorption of ribavirin:

Both AUC and C-MAX increased by seventy percent when Rebetol Capsules were administered with a high fat meal: (841 kcal, 53.8 g fat, 31.6 g protein, and 57.4 g carbohydrate) in a single-dose pharmacokinetic study

If you do the math you will have to eat 26.9 grams of fat for a 35% increase in absorbtion

[hrsepwrguy]

"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."

How many grams of fat per meal are needed to get 46% increase ?

[Idyllic]

As a recovering addict myself I know just what you mean. I did not lose all that much weight during treatment but I lost lots of volume in my face which made me look gaunt. Throw in the hair loss and loss of muscle from not working out and I looked sicker than I really was. These meds are harsh and you sound like you are really hanging in there. I treated 48 weeks as well however the bulk of it was Winter through Spring. It is triple digit heat where I live and I cannot imagine being on Peg and Riba right now.
Hang in there you are almost finished!

[BoceprevirGal]

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1804105/

The component of the final population pharmacokinetic model that describes the absorption phase is complex. 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. The type of meal also influenced the first-order input part of the absorption model (Table 1).

  I noticed that you said you were losing weight, so I thought I'd include this info about high fat diet and Riba absorption~   katy

[BoceprevirGal]

  Tim, are you thinking of increasing your Riba dosage a bit, here at the end,  to increase yr levels? Why dont you ask Dr P about this?  

[timothy141]

Yes I am a GT3, Pegasus ( 2a ) And have lost the weight during my tx, my weight fluctuates between 168 and 172, my baseline weight was 208. My Dr.'s haven't been concerned because of my BMI which is normal now...LOL. I just don't like it because I feel as if I look so gaunt. And strung. Being a recovering addict this has hidden implications to me.  
After reading those links I have been directed to, I understand my dosing is not weight based, and in truth for me to continue to second guess is crazy. truly part of my insanity.
As you noted I am in fact I at the mid way point of week 38, and I have finally really begun to find some peace.  

[Idyllic]

I saw elsewhere you are a GT3 and using peginterferon-alf2a. You mean you lost 40 pounds since the beginning of treatment and now you weigh 168? Still, if you weighed 208 then I am thinking along the same line as Mikesimon.   Not sure what other factors could influence why you are on 800mg/day rather than a standard weight-based dose (1,000 or 1,200mg/day).
http://www.gene.com/media/product-information/pegasys


The thing is aren't you on week 37 or so?

[mikesimon]

I don't believe that you're ribavirin dose is weight based.

At 208 a weight based ribavirin dose would have probably been 1200 mg per day (15mg per kilogram) and an aggressive does would have been 1400 mg per day. That is how type 1s were weight base dosed.

800 mg ribavirin is a fixed dose and was commonly used in treating types 2 and 3.

Extended Treatment for Patients who do not Achieve RVR

Patients with genotype 2 or 3 who do not achieve a rapid virological response have low SVR rates, ranging from 26 to 41% (Figure 6)[16,22].  Although current guidelines recommend treating all patients with genotype 2 or 3 infection for 24 weeks, the benefit of longer therapy for these non-RVR patients continues to be debated. Weight-based ribavirin may also benefit this subset of patients with genotypes 2 or 3 infection who do not achieve a RVR. One retrospective analysis of genotype 2 or 3 patients who did not achieve an RVR found a trend toward higher SVR rates among those who received 48 weeks of weight-based ribavirin compared with those in other treatment categories (24 weeks of weight-based ribavirin, 24 weeks of fixed-dose ribavirin, or 48 weeks of fixed-dose ribavirin)[23].  Another study found that treatment up to 36 weeks resulted in a small but statistically insignificant increase in SVR compared with the standard 24 weeks among genotype 3 patients who did not achieve an RVR (62% versus 52%, P=0.25)[24]. There are currently insufficient data to make clear recommendations supporting the strategy of intensifying treatment for this patient group.  

http://depts.washington.edu/hepstudy/hepC/mgmt/gt23/discussion.html

[timothy141]

As far as I know my riba is weight based, I have been trying to find how that is determined, but have had no luck. I am still on the same dosages as I have been from the beginning. 800 mg a day, my has changed from 208 lbs to a 168, I guess I am getting more saturation now than at the unset of tx.
Tim

[Dee1956]

Tim, good post, thanks for sharing :)
D

[pooh55811]

"Conclusion: Long durations of P/R therapy improve SVR, regardless of genotype. This effect is nonetheless negligible in rapid responders, with the most favorable conditions for SVR (G2, G1 with low viral load, and G3 with weight-adjusted ribavirin regimen). "
----------------------------------

Tim, you were not a rapid responder. You are not G2.

However, hopefully you are on weight based Ribavirin.

[timothy141]

I am still confused!!!  :(
Hepatology. 2011 Sep 2;54(3):789-800. doi: 10.1002/hep.24480. Epub 2011 Jul 19.
Response-guided peg-interferon plus ribavirin treatment duration in chronic hepatitis C: meta-analyses of randomized, controlled trials and implications for the future.
Di Martino V, Richou C, Cervoni JP, Sanchez-Tapias JM, Jensen DM, Mangia A, Buti M, Sheppard F, Ferenci P, Thévenot T.
Source

Service d'Hépatologie, CHU Jean Minjoz, Besançon, France. [email protected]
Abstract

Response-guided pegylated interferon (peg-IFN) plus ribavirin (P/R) therapy trials on genotype (G)1 and G2/G3 hepatitis C virus-infected patients provide contradictory results. We conducted meta-analyses of randomized, controlled trials to address (1) the benefit of a 72-week extended-duration therapy in G1-slow responders and (2) adequate shortened duration therapy in G1 and G2/G3-rapid responders. Seventeen trials were selected, including 624 G1 rapid responders, 570 G1 slow responders, and 2,062 G2/G3 rapid responders. Virologic outcomes and treatment discontinuation data were collected from published articles and by asking investigators. Pooled estimates of sustained virologic response (SVR), relapse, and dropouts were calculated using the random effects model, considering the variability of shortened duration, ribavirin dose, genotype, and baseline viral load. In G1 slow responders, a 72-week extended duration increased SVR (+10.7%; 95% CI [confidence interval]: +4.4% to + 17.1%), decreased relapse (-12.3%; 95% CI: -25.4% to 0%), and did not significantly increase drop-out rates (+4.5%; 95% CI: -0.6% to + 9.6%). The benefit of extended duration was lower when using a weight-based ribavirin regimen (+8.7%; 95% CI: +1.7% to + 15.8%). In G1 rapid responders, a 24-week shortened duration decreased SVR (-12.5%; 95% CI: -19.2% to -5.8%) and increased relapse rates (+8.8%; 95% CI: +2.9% to + 14.8%). Such differences were not significant in patients with baseline viral load <400,000 UL/mL (-4.4%; 95% CI: -9.8% to + 1%). In G2/G3 rapid responders, SVR was more common for standard 24-week duration than for shortened durations (+4.1%; 95% CI: +0.1% to + 8.5), but this benefit was not significant when ribavirin was weight-adjusted and the short duration was 16 weeks (-1.7%; 95% CI: -6.1% to + 2.7%) and for G2 patients (+1.6%; 95% CI: -0.2% to + 5.5%). Conclusion: Long durations of P/R therapy improve SVR, regardless of genotype. This effect is nonetheless negligible in rapid responders, with the most favorable conditions for SVR (G2, G1 with low viral load, and G3 with weight-adjusted ribavirin regimen).

Copyright © 2011 American Association for the Study of Liver Diseases.

PMID:
    21674553
    [PubMed - indexed for MEDLINE]

[timothy141]

True, it is based on interferon dual therapy, the basic SOC for GT3a's, which I am, I had a very low baseline VL of 514,000. Which at week 4 drop to 130 and because of that the decision was made to treat a full 48 weeks. There was no VL done on week 8. So I have no idea when I truly went UND, I believe before week 8 but will never know.
From what I understand, we G3 have a higher rate of relapse, I will now research that for real. But if there is any chance to offset a possible relapse I want to know, and if possible will take.
Tim

[Idyllic]

The study in the post says it was based on Interferon based duel therapy (and makes no mention of triple). My comment was related to duel therapy as well (even though like you I find a negligible drop of Hgb as very telling indeed).

[timothy141]

After reading this I had to post it, if there is any chance to increase my shot at SVR I'll take it. I have been very lucky so far all my blood work has held steady. I will talk to Dr. Prince next week before my next blood draw and see what he says about it.
Started doing my own research, thank you for bearing with me for so long, it nice to be able to think again.
Tim  

[can-do-man]

While not everyone becomes anemic on treatment it has always gave me concern when people don't have much of a drop in their HGB. But I am not sure if this study is just for SOC treatment since they claim dose reduction with one of the two PI's don't have much of a effect... Under just SOC dose reducing has never been a good ideal........ Thanks Tim

[Idyllic]

I guess this makes sense since some studies suggest Ribavirin dose reduction is risky for patients on interferon dual therapy since it helps lessen the likelihood of post-treatment relapse.

[ActingBrandNew]

Interesting stuff! Thanks for posting it.