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

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Factors Associated with Sustained Virological
Response to pegIFN-RBV Therapy in IL28B
rs12979860 Non-CC HCV/HIV Coinfected Patients
A Substudy of PERICO Trial

• 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

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Mechanisms of Action for Ribavirin
Antiviral
Immune modulation
Unphosphorylated RBV
Direct
Indirect
Switch in T-helper cells phenotype
RBV-MP inhibition of cellular IMPDH
RBV-TP activity at HCV polymerase
Competition in the phosphorylation pathway
Dysbalance in GTP pools

• Chain terminator
• Hypermutagenesis

Abacavir
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Early HCV Dynamics
Uninfected hepatocyte
Cell death
HCV
Ribavirin (enhances defective particles)
Infected hepatocyte
Cell death
Interferon (blocks virus production / release)
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Design of PERICO Study
Pegasys 180 ?g/s RBV 1000-1200 mg/d G-2,3
24w tt G-1,4 48w tt
Monitoring 24w
Pegasys 180 ?g/s RBV 1000-1200 mg/d during 4w
RVR
Pegasys 180 ?g/s RBV 1000-1200 mg/d G-2,3 48w
tt G-1,4 72w tt
RVR -
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 2000 mg/d Epo ß 450
UI/kg/s during 4w
Monitoring 24w
RVR
Pegasys 180 ?g/s RBV 1000-1200 mg/d G-2,3
48w tt G-1,4 72w tt
RVR -
Monitoring 24w
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Baseline Predictors of SVR after pegIFN-RBV
P lt0.0001
P 0.004
P lt0.0001
P lt0.0001
P lt0.0001
P lt0.0001
Covariates - rs12979860 (2-level), ethnicity
(4-level), age ( 40), gender, BMI (lt 30), VL (
600,000), ALT ( ULN), fasting glucose (lt 5.6),
hepatic steatosis (N/Ygt0), fibrosis (METAVIR
F012), RBV (gt13 mg/kg/d) Thompson AJ, et al
Gastroenterology 2010
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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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RVR by OT Analysis
Overall in 50 patients (24)
lt0.01
lt0.01
lt0.01
of patients
NS
NS
HCV genotype
HCV-RNA
IL28B
METAVIR
RBV dose
Baseline
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SVR by OT Analysis (IL28B CC)
Overall in 44 patients (84)
0.02
NS
NS
NS
NS
NS
of patients
HCV genotype
HCV-RNA
METAVIR
RBV dose
Hgb decay
HCV-RNA decay
4W outcome
Baseline
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SVR by OT Analysis (IL28B non-CC)
Overall in 22 patients (33)
lt0.01
0.2
0.1
0.01
0.08
0.1
of patients
HCV genotype
HCV-RNA
METAVIR
RBV dose
Hgb decay
HCV-RNA decay
4W outcome
Baseline
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Conclusions

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

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Ribavirin is Sequestered in the Erythrocyte
RBV-MP
Adenosin Kinase
RBV
eRBV
ENT-1
RBV-DP
RBV-TP
Half-life of 40 days
pRBV
Half-life of 1 day
eRBV / pRBV 60 / 1
in steady-state (2-4 weeks)
Courtesy of Sonia Rodríguez-Novoa
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EPO
eRBV
oRBV
pRBV
o, Oral p, Plasma e, Erythrocyte
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EPO
eRBV
oRBV
pRBV
o, Oral p, Plasma e, Erythrocyte
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?eRBV
EPO
oRBV
?pRBV
o, Oral p, Plasma e, Erythrocyte
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Acknowledgements

• 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