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

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

Uninfectedhepatocyte

Infectedhepatocyte

Cell death

Cell death

Ribavirin(enhances defective particles)

Interferon(blocks virus production / release)

HCV

Early HCV Dynamics

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

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

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

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

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%)

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%)

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%)

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

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

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)

oRBV pRBV

eRBVEPO

o, Oralp, Plasmae, Erythrocyte

oRBV pRBV

eRBVEPO

o, Oralp, Plasmae, Erythrocyte

oRBV pRBV

eRBVEPO

o, Oralp, Plasmae, Erythrocyte

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