Factors Associated with Sustained Virological Response to pegIFN-RBV Therapy in IL28B rs12979860 Non-CC HCV/HIV Coinfected Patients Pablo Labarga*, Pablo.

Presentación del tema: "Factors Associated with Sustained Virological Response to pegIFN-RBV Therapy in IL28B rs12979860 Non-CC HCV/HIV Coinfected Patients Pablo Labarga*, Pablo."— Transcripción de la presentación:

1 Factors Associated with Sustained Virological Response to pegIFN-RBV Therapy in IL28B rs12979860 Non-CC HCV/HIV Coinfected Patients Pablo Labarga*, Pablo Barreiro*, Eugenia Vispo*, Violeta Rodriguez (H. 12 Oct), Angeles Castro, Luis Morano, J.Antonio Pineda, Victor Asensi, José Hernandez Quero, Celia Miralles, Pilar Miralles, Mª Jesús Tellez, Norma Rallón*, Rafael Torres (H.Leganes), Koldo Aguirrebengoa, Santiago Echeverría (H.Valdecilla), Jose Guardiola, Alberto Terrón (Hospital General de Jerez), I. Santos, Rafael Rubio, Sonia Rodríguez-Nóvoa*, Llucia Bonet, Juan Luis Gomez Sirvent, Ana Mariño (H.Arquitecto Marcide Ferrol), Matilde Sanchez, Maria José Rios (H. Virgen de la Macarena, Sevilla), J. Portu, Jesús Santos (H.Virgen de la Victoria, Málaga) Judit Morello* and Vincent Soriano* *Department of Infectious Diseases. Hospital Carlos III, Madrid, Spain A Substudy of PERICO Trial

2 AntiviralImmune modulation Unphosphorylated RBV Switch in T-helper cells phenotype Direct Chain terminator Hypermutagen esis RBV-TP activity at HCV polymerase Indirect RBV-MP inhibition of cellular IMPDH Dysbalance in GTP pools Abacavir Competition in the phosphorylation pathway Mechanisms of Action for Ribavirin

3 Uninfected hepatocyte Infected hepatocyte Cell death Ribavirin (enhances defective particles) Interferon (blocks virus production / release) HCV Early HCV Dynamics

4 Monitoring +24w Pegasys 180 g/s + RBV 1000-1200 mg/d G-2,3: 24w tt G-1,4: 48w tt Pegasys 180 g/s + RBV 1000-1200 mg/d G-2,3: 48w tt G-1,4: 72w tt Pegasys 180 g/s + RBV 1000- 1200 mg/d during 4w Monitoring +24w RVR - RVR + Monitoring +24w Pegasys 180 g/s + RBV 2000 mg/d + Epo β 450 UI/kg/s during 4w Monitoring +24w Randomization Pegasys 180 g/s + RBV 1000-1200 mg/d G-2,3: 24w tt G-1,4: 48w tt Pegasys 180 g/s + RBV 1000-1200 mg/d G-2,3: 48w tt G-1,4: 72w tt RVR - RVR + Design of PERICO Study

5 Covariates - rs12979860 (2-level), ethnicity (4-level), age ( 40), gender, BMI ( 0%]), fibrosis (METAVIR F012), RBV (>13 mg/kg/d) Thompson AJ, et al Gastroenterology 2010 P <0.0001 P= 0.004 Baseline Predictors of SVR after pegIFN-RBV

6 Objectives Analyze factors associated with RVR rates: -IL28B genotype -Dose of RBV during the first 4 weeks of therapy Analyze factors associated with SVR rates in IL28B non-CC patients

7 Patients with completed follow-up 386 patients in 12 Spanish Centers included in PERICO study Baseline Characteristics of Patients

8 HCV genotypeHCV- RNA METAVIR RBV dose IL28B Baseline <0.01 NS % of patients <0.01 RVR by OT Analysis Overall in 50 patients (24%)

9 HCV genotypeHCV- RNA METAVIRRBV doseHgb decayHCV-RNA decay 4W outcome Baseline 0.02 NS % of patients SVR by OT Analysis (IL28B CC) Overall in 44 patients (84%)

10 HCV genotypeHCV- RNA METAVIRRBV doseHgb decayHCV-RNA decay 4W outcome Baseline 0.08 <0.01 0.2 0.10.01 0.1 % of patients SVR by OT Analysis (IL28B non-CC) Overall in 22 patients (33%)

11 OR (95% CI), p HCV genotype 1-4 vs 2-30.53 (0.03-10.31), 0.7 HCV-RNA >500K IU/mL0.45 (0.08-2.43), 0.3 Metavir F3-F40.19 (0.05-0.80), 0.02 High RBV dose first 4 wks0.48 (0.10-2.23), 0.3 Hgb decay 2 g/dL at w43.71 (0.79-17.51), 0.09 RVR1.1 (0.9-1.0), 0.8 Multivariable Analysis for SVR in IL28B non-CC Patients

12 Conclusions Patients carrying unfavorable IL28B genotypes are more vulnerable to other negative factors for SVR, advanced live fibrosis in particular o This genetic drawback is not overcome by increasing RBV doses Hemoglobin reduction is associated with greater chances for SVR o It may be that preemptive EPO prevents greater RBV dosing to result in greater RBV exposure

13 RBV RBV-MP RBV-DP ENT-1 eRBV RBV-TP Adenosin Kinase Half-life of 40 days Half-life of 1 day pRBV [eRBV] / [pRBV] = 60 / 1* Courtesy of Sonia Rodríguez-Novoa Ribavirin is Sequestered in the Erythrocyte *in steady-state (2-4 weeks)

14 oRBV pRBV eRBV EPO o, Oral p, Plasma e, Erythrocyte

15 oRBV pRBV eRBV EPO o, Oral p, Plasma e, Erythrocyte

16 oRBV pRBV eRBV EPO o, Oral p, Plasma e, Erythrocyte

17 Clinic Laboratory Francisco Blanco Carmen de Mendoza Pablo Labarga Ana Treviño Luz Martin-Carbonero Norma Rallón Eugenia Vispo Eva Poveda José Vicente Fernández Sonia Rodríguez-Novoa José Miguel Benito Judit Morello Tamara Bar-Magen Vincent Soriano Juan González-Lahoz Acknowledgements