factors associated with sustained virological response to pegifn-rbv therapy in il28b rs12979860...
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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
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Antiviral Immune modulation
Unphosphorylated RBV
Switch in T-helper cells phenotype
Direct
• Chain terminator
• Hypermutagenesis
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
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Uninfectedhepatocyte
Infectedhepatocyte
Cell death
Cell death
Ribavirin(enhances defective particles)
Interferon(blocks virus production / release)
HCV
Early HCV Dynamics
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Monitoring+24w
Pegasys 180 g/s + RBV 1000-1200 mg/d
G-2,3: 24w ttG-1,4: 48w tt
Pegasys 180 g/s + RBV 1000-1200 mg/d
G-2,3: 48w ttG-1,4: 72w tt
Pegasys 180 g/s + RBV 1000-1200 mg/dduring 4w
Monitoring+24w
RVR -
RVR +
Monitoring+24w
Pegasys 180 g/s + RBV 2000 mg/d + Epo β 450
UI/kg/sduring 4w
Monitoring+24w
Randomization
Pegasys 180 g/s + RBV 1000-1200 mg/d
G-2,3: 24w ttG-1,4: 48w tt
Pegasys 180 g/s + RBV 1000-1200 mg/d
G-2,3: 48w ttG-1,4: 72w tt
RVR -
RVR +
Design of PERICO Study
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Covariates - rs12979860 (2-level), ethnicity (4-level), age (≤ 40), gender, BMI (< 30), VL (≤ 600,000), ALT (≤ ULN), fasting glucose (< 5.6), hepatic steatosis (N/Y[>0%]), fibrosis (METAVIR F012), RBV (>13 mg/kg/d)Thompson AJ, et al Gastroenterology 2010
P <0.0001
P <0.0001
P <0.0001
P <0.0001
P <0.0001
P= 0.004
Baseline Predictors of SVR after pegIFN-RBV
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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
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ALL CC CT/TT p-value
No. of patients 204 53 68
Male gender (%) 157 (77) 34 (65) 52 (76) 0.4
Mean age (years) 43±6 44±6 43±6 0.7
Under HAART (%) 191 (94) 52 (98) 64 (94) 0.3
HIV-RNA <50 copies/mL 177 (87) 51 (96) 60 (89) 0.2
Mean CD4 count (cells/µL) 585±261 559±240 661±298 0.3
HCV genotype 1 or 4 (%) 171 (84) 33 (62) 65 (96) <0.01
HCV-RNA >500K IU/mL 151 (74) 38 (72) 49 (72) 0.9
Metavir F3-F4 97 (47) 21 (40) 34 (50) 0.3
High RBV doses 97 (47) 27 (51) 30 (44) 0.5
Patients with completed follow-up
386 patients in 12 Spanish Centers included in PERICO study
Baseline Characteristics of Patients
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HCV genotype HCV-RNA
METAVIR
RBV dose IL28B
Baseline
<0.01
NSNS
% of patients
<0.01<0.01
RVR by OT Analysis
Overall in 50 patients (24%)
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HCV genotype HCV-RNA
METAVIR
RBV dose Hgb decay HCV-RNA decay
4W outcomeBaseline
0.02
NSNSNS
NSNS
% of patients
SVR by OT Analysis (IL28B CC)
Overall in 44 patients (84%)
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HCV genotype HCV-RNA
METAVIR
RBV dose Hgb decay HCV-RNA decay
4W outcomeBaseline
0.08
<0.01
0.2
0.1 0.010.1
% of patients
SVR by OT Analysis (IL28B non-CC)
Overall in 22 patients (33%)
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OR (95% CI), p
HCV genotype 1-4 vs 2-3 0.53 (0.03-10.31), 0.7
HCV-RNA >500K IU/mL 0.45 (0.08-2.43), 0.3
Metavir F3-F4 0.19 (0.05-0.80), 0.02
High RBV dose first 4 wks 0.48 (0.10-2.23), 0.3
Hgb decay ≥2 g/dL at w4 3.71 (0.79-17.51), 0.09
RVR 1.1 (0.9-1.0), 0.8
Multivariable Analysis for SVR in IL28B non-CC Patients
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Conclusions
• Patients carrying unfavorable IL28B genotypes are more vulnerable to other negative factors for SVR, advanced live fibrosis in particularo This genetic drawback is not overcome by increasing
RBV doses
• Hemoglobin reduction is associated with greater chances for SVRo It may be that preemptive EPO prevents greater RBV
dosing to result in greater RBV exposure
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RBV
RBV-MP
RBV-DP
ENT-1 eRBVRBV-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)
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oRBV pRBV
eRBVEPO
o, Oralp, Plasmae, Erythrocyte
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oRBV pRBV
eRBVEPO
o, Oralp, Plasmae, Erythrocyte
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oRBV pRBV
eRBVEPO
o, Oralp, Plasmae, Erythrocyte
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Clinic LaboratoryFrancisco Blanco Carmen de MendozaPablo Labarga Ana Treviño Luz Martin-Carbonero Norma RallónEugenia Vispo Eva Poveda José Vicente Fernández Sonia Rodríguez-NovoaJosé Miguel BenitoJudit MorelloTamara Bar-Magen
Vincent SorianoJuan González-Lahoz
Acknowledgements