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RIBAVIRIN CONCENTRATION AT WEEK FOUR IS AN INDEPENDEND PREDICTOR FOR SUSTAINED VIROLOGICAL RESPONSE AFTER TREATMENT OF HEPATITIS C GENOTYPE 2/3 (NORDYNAMIC TRIAL)
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Reported by Jules Levin
43rd EASL Conference, April 23-27, 2008, Milan Italy
P.B. Christensen1, A.A. Alsio2, M.R. Buhl3, M. Farkkila4, K. Morch5, P. Sangfelt6, M. Lagging2, G. Norkrans2, C. Pedersen1
1 Department Of Infectious Diseases, Odense University Hospital, Odense, Denmark;
2 Department Of Infectious Diseases, Gothenborg University, Gšteborg, Sweden;
3 Department Of Infectious Diseases, Aarhus University, Aarhus, Denmark;
4 Department Of Gastroenterology, Helsinki University, Helsinki, Finland;
5 Department Of Infectious Diseases, Bergen University, Bergen, Norway;
6 Department Of Infectious Diseases, Uppsala University, Uppsala, Sweden
Author concluded: "plasma ribavirin oncentration is an independent predictor of SVR in patients infected with HCV genotype 2/3. RBV concentrations can not be predicted for individual patient from baseline parameters with sufficient precision. We suggest a prospective randomized trial to test the effect of concentration guided RBV dosing." During Q&A after talk someone rom audience suggested plasma level may not be best way to measure, I think they suggested intracellulr level
Background and Aims:
It is debated whether the plasma concentration of ribavirin during treatment predicts sustained virological response (SVR) in combination treatment of chronic hepatitis C.
We have previously reported the overall result of the NORDynamic trial: a randomised controlled trial for hepatitis C genotype 2 and 3 comparing 12 and 24 weeks of treatment. The aim of this analysis was to correlate ribavirin concentration at week four with SVR. To investigate whether plasma RBV concentration was associated with SVR. To investigate whether a concentration of 2mg/l or more was associated with a high SVR rate and an acceptable risk of anemia. To construct a model for predicting RB concentration at week 4 from baseline variables.
Methods
382 patients from 31 centres in Scandinavia were randomised to 12 or 24 weeks of treatment with pegylated interferon-a-2a 180 µg weekly and a fixed dose of 800mg ribavirin daily. Primary outcome was SVR (HCV-RNA negative (<15 IU) 24 weeks after treatment). Through plasma concentration of ribavirin was measured at day 29 and week 12 with HPLC (linear range 0.5-6 mg/l).
Trough plasma RBV concentration was measured by HPLC at day 29 and week 12 (linear range 0.6-6mg/l).
Results
Among 382 participants in the original study 355 had a ribavirin measurement at week 4 (day 29). Overall the SVR was 78% in the 24 week arm and 60% in the 12 week arm (p<0.001). The median concentration of ribavirin at week 4 was 1.5mg/l (IQR 1.3-2.0) among SVR and 1.3 (1.0-1.7) among non-SVR (p <0.001) For the 24 weeks arm the positive predictive value for SVR at 4 weeks was 91% (41/45) for a ribavirin concentration >=2mg/l (p =0.02). Correspondingly for the 12 weeks arm the PPV was 74% (25/34) (p=0.12).
In a multivariate analysis with SVR as outcome and ribavirin concentration at week 4 as independent variable, we included as covariates age, gender, fibrosis, baseline viral load, ribavirin dose in mg/kg, treatment duration and whether 80% of planed treatment was received. Ribavirin concentration at week 4 was an independent predictor of SVR (OR 2.3 95% CI 1.3 - 4.1, p =0.002). Variables independently associated with SVR: baseline HCV RNA; duration of treatment; HCV RNA negative at day 29 (RVR); RBV concentration at day 29; received 80% of both drugs 80% of time. Variables in full model not associated with SVR: agr, gender, weight, fibrosis score.
Here is the model they came up with:
Plasma RBV concentration day 29 (mg/) =
0.869 + [800 = dose(mg) / weight (kg)] x 0.0842 - 0.322 x gender (1 for men 0 for women).
Conclusion
Although 12 weeks of treatment was inferior to 24 weeks of treatment, a higher ribavirin concentration was associated with a significantly increased SVR. This indicates that a treatment regiment with ribavirin dose based on plasma concentration at week four could significantly improve treatment outcome. We propose this to be examined in a prospective randomized trial.
Acknowledgements
This study was supported by Roche a/s
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