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Ribavirin Levels & Viral Response to PegIFN/RBV HCV Therapy
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Reported by Jules Levin
Two studies at the 40th European liver meeting EASL April 2005 address the question of ribavirin levels & if they are associated with the sustained viral response (SVR) to Peginterferon+RBV therapy. A number of recently reported studies have found that taking the full ribavirin dosing particularly in the first few months after starting PegIFN/RBV therapy is important to achieving an SVR. In fact, these studies show that full adherence to RBV is more important than to PegIfn in the early period after starting therapy. In fact, the most recent study reporting this was presented in a poster at EASL, where researchers reported this finding in studying Pegasys/RBV studies & study authors said:
"...Reductions in the dose of ribavirin were more likely to compromise the liklihood of achieving an SVR than reductions in the dose of Pegasys. Avoiding RBV dose reductions & discontinuations within the first 12 weeks particularly, but as well between weeks 12 and 48, will likely improve overall SVR rates in patients infected with genotype 1. These findings have been observed in studies previouslyÉ.." my added comments: It is important to consider taking EPO if anemia (reduced hemoglobin occurs). Studies show that taking EPO improves hemoglobin, and improves fatigue & quality of life.
To read the full report here is the link:
Age & Ribavirin Dose Reductions Reduce SVR to Peginterferon+Ribavirin
http://www.natap.org/2005/EASL/easl_5.htm
So, having said how important ribavirin is to achieving SVR, two studies were reported at EASL addressing whether RBV concentration levels are associated with treatment response. The first study found an association & the 2nd study did not. The ribavirin dosing did however vary between the two studies, 800 to 1200mg daily vs 1000-1200mg daily, as well, there might have been other differences between the two studies. I think the only clinical relevance in trying to associate RBV concentration levels to viral outcomes is if care providers will start measuring RBV levels to check on compliance.
RELEVANCE OF RIBAVIRIN PLASMA CONCENTRATION FOR THE PREDICTION OF TREATMENT RESPONSE
M. Maynard1, M.C. Gagnieu2, P. Pradat1, F. Bailly1, C. Trepo1
1 Department of Hepatology, Hotel-Dieu, Lyon, France
2 Department of Biochemistry, Hopital Edouard-Herriot, Lyon, France
Background and Aim: Combination therapy with ribavirin and pegylated interferon is the standard treatment for chronic hepatitis C virus (HCV) infection. Approved ribavirin dosages vary from 800 to 1200 mg/d on the basis of body weight. Pharmacokinetics studies indicate that there is no relation between ribavirin ingested dose and plasma concentration. However, a relationship between sustained virological response and ribavirin concentration has been previously reported, a high plasma concentration being associated with a decrease of HCV RNA levels. The aim of this study was to define the target ribavirin concentration associated with optimal HCV clearance at W12 of treatment.
Methods: 22 patients with HCV infection treated with pegylated interferon 1.5 µg/kg/week and ribavirin at a dose of 800-1200 mg/day were assessed for trough ribavirin plasma concentration at W4 under therapy using a high-performance liquid chromatography method. Virological response was defined as undetectable HCV-RNA (or HCV-RNA drop ³2 log from baseline) at W12.
Results: Among 22 patients, 14 achieved a virological response at W12 whereas 8 were non-responders. The median ribavirin plasma concentration at W4 was 1.90 mg/l but varied from 1.55 mg/l in non-responders to 2.13 mg/l in responders (p = 0.02).
A ROC curve analysis indicated that the threshold of 2 mg/l gave the best sensitivity/specificity ratio with a sensitivity of 57% and a specificity of 100% (AUC = 0.804; p = 0.02).
Using this threshold, the ribavirin plasma concentration had a positive predictive value of 100% meaning that all patients with a concentration above 2 mg/l achieved a virological response at W12.
Conversely, only 43% of patients with a concentration below 2 mg/l at W4 achieved a virological response (negative predictive value 57%).
Conclusions: Although conducted on a small number of cases, this study provided the following significant results: 1. A clear-cut difference in ribavirin plasma concentration appeared between responders and non-responders with significantly higher levels in virological responders. 2. The observed median ribavirin plasma concentration at W4 of treatment was similar to those previously reported. 3. All patients reaching a concentration higher than 2 mg/l at W4 were virological responders at W12 which confirms the relevance of plasma ribavirin levels for monitoring therapy. 4. The threshold of 2 mg/l could therefore be used as the target concentration for ribavirin dose adjustment.
EVIDENCE THAT SERUM RIBAVIRIN STEADY-STATE CONCENTRATIONS DO NOT CORRELATE WITH EARLY VIROLOGICAL RESPONSE DURING PEGINTERFERON a-2a + RIBAVIRIN COMBINATION THERAPY FOR CHRONIC HEPATITIS C
C. Souvignet1, F. Stanke-Labesque2, J.-P. Bronowicki3, S. Larrat1, J.-L. Quesada4, J.-P. Zarski1
1 HGE Dpt., C.H.U. Grenoble/Hopital A. Michallon, Grenoble, France
2 Pharmacology Laboratory, C.H.U. Grenoble/Hopital A. Michallon, Grenoble, France
3 HGE Dpt., C.H.U. Nancy/Hopital Nancy-Brabois, Nancy, France
4 Clinical Investigation Center, C.H.U. Grenoble/Hopital A. Michallon, Grenoble, France
Background and Aims: Ribavirin in combination with pegylated interferon is the standard treatment for chronic hepatitis C. Despite recommendations for ribavirin dosage based on body weight of the patient, serum ribavirin concentrations display high inter-individual variability that could explain severe side effects or lack of efficacy in some patients. The present study aimed to define the relation between serum ribavirin concentration and viral load drop on combination treatment.
Methods: Thirty-six patients chronically infected with the hepatitis C virus (genotypes 1 or 4) were treated with standard treatment (180 µg Peginterferon a-2a once weekly and 1000-1200 mg ribavirin twice daily). During the first three months of treatment, the serum ribavirin concentration was sequentially monitored using a HPLC specific assay, in parallel with measures of viral load (Roche Amplicorª HCV test, v2.0) and haemoglobin level at the same time points (Days 0, 7 and 14, and Weeks 4 and 12).
Results: The steady-state concentration of ribavirin was reached at Week 4: 1.99±0.73 mg/ml (Variation coefficient = 41%). Mean drop of viral load was _2.26±0.97 log UI/ml at Week 4 and _2.93±0.77 log UI/ml at Week 12.
Undetectable HCV-RNA was noted in 36% of the patients at Week 4 and 83% at Week 12.
No significant correlation was found between serum ribavirin concentration (Week 4) and viral load drop (Week 12): r = 0.071 (p = 0.679).
The ribavirin concentration that gave an early virological response in 50% of the patients (ED50) was 2.17 mg/ml.
The ribavirin concentration that gave 2 g/dl drop of haemoglobin in 50% of the patients (TD50) was 2.44 mg/ml at the same timepoint (Week 12).
Conclusions: During the first three months of combination treatment for chronic hepatitis C (Peginterferon a-2a + ribavirin), the drop of viral load does not correlate with serum ribavirin concentration. These data suggest that interindividual variations of serum ribavirin levels do not significantly impact early virological response rate. Actually, the interest of therapeutic drug monitoring of ribavirin will depend on further analysis of sustained virologic response data after long-term follow-up of this patient cohort.
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