Broader Influence of IL28B Gene
Polymorphisms and Interferon λ3
Plasma Levels on HCV Outcomes in
HIV Patients
Norma I Rallón, Jose M. Benito, Pablo Barreiro, Eugenia Vispo, Pablo
Labarga, Sonia Rodriguez-Novoa & Vincent Soriano
Infectious Diseases Department, Hospital Carlos III, Madrid, Spain.
•
•
Financial Disclosure
No financial relationships to disclose within the past 12 months relevant to my
presentation.
No discussion of off-label or investigational drugs
IL28B Gene Genetic Variation
HCV-Monoinfected
Patients
Ge et al. Nature 2009; 461:399-401
% SVR to pegIFN+RBV
by rs12979860 genotypes
IL28B Gene Genetic Variation
HCV-Monoinfected
Patients
Ge et al. Nature 2009; 461:399-401
% SVR to pegIFN+RBV
by rs12979860 genotypes
Thomas et al. Nature 2009; 461:798-801
% spontaneous HCV clearance
by rs12979860 genotypes
DESCRIPTION
Hospital Carlos III Cohort
650 HIV/HCV Co-infected
individuals
Variable
n
IL28B
Effect
Reference
Spontaneous HCV clearance
24
CC
Enhanced in genotypes 1 and 4
Response to pegIFNα-RBV
therapy
164
CC
Increased SVR mainly in genotypes 1
and 4
Response to pegIFNα-RBV
therapy
159/86
CC
Predictive of SVR (“Prometheus” index)
Medrano et al., Clin Inf Dis
2010
Early viral kinetics on therapy
196
CC
Increased RVR and EVR mainly in
genotypes 1 and 4
Rallón et al. AIDS 2011 (in
press)
Response to pegIFNα-RBV
therapy in prior non-response or
relapse patients
62
CC
Increased SVR only in genotypes 1 and
4 prior true non-responders
Labarga et al. AIDS 2011 (in
press)
Serum HCV-RNA levels
289
CC/CT
Greater viral load
Labarga et al. AIDS 2011 (in
press)
Liver fibrosis progression
304
CC
Greater rate of cirrhosis
Barreiro et al. J Infect Dis
2011 (in press)
Liver enzymes elevation
304
CC
Increased ALT levels
Serum IFN λ3 levels
112
CC
No impact at baseline but greater
increase during IFNα therapy
Rallón et al. AIDS 2010
Rallon et al. CROI 2011
LESSONS LEARNED
• Higher prevalence of CC genotype in patients who
spontaneously clear HCV compared with chronically infected
HCV patients
HCV/HIV-Coinfected
Patients
rs12979860 genotypes
p=0.007
75%
54%
46%
% of patients
25%
CC patients
CT/TT patients
Spontaneous HCV
clearance
n=24
Chronic HCV
infected
n=164
Rallón et al. AIDS 2010; 24:F23-9
• The rs12979860 CC genotype exerts a beneficial effect on
the probability of SVR to pegIFN+RBV, mainly in HIV/HCVcoinfected patients with HCV G1/4
Rate of SVR in distinct HCV genotypes according
to rs12979860 SNP
CT/TT patients
CC patients
Rallón et al. AIDS 2010; 24:F23-9
• The rs12979860 CC genotype exerts a beneficial effect on
the probability of SVR to pegIFN+RBV, mainly in HIV/HCVcoinfected patients with HCV G1/4
Rate of SVR in distinct HCV genotypes according
to rs12979860 SNP
CT/TT patients
CC patients
Predictors of SVR to pegIFNα/RBV
therapy in HIV/HCV coinfected patients
Rallón et al. AIDS 2010; 24:F23-9
• Baseline prediction of the likelihood of SVR to pegIFN-RBV
PROMETHEUS
INDEX
•
•
•
•
HCV genotype (1/4)
Serum log10 HCV-RNA
Stiffness (KPa)
IL28B rs12979860 (CT/TT)
Medrano et al. Clin Infect Dis 2010;
• Baseline prediction of the likelihood of SVR to pegIFN-RBV
PROMETHEUS
INDEX
•
•
•
•
Diagnostic performance in the derivation
and validation groups
HCV genotype (1/4)
Serum log10 HCV-RNA
Stiffness (KPa)
IL28B rs12979860 (CT/TT)
Medrano et al. Clin Infect Dis 2010;
http://ideasydesarrollo.com/fundacion/prometheusindex.php
• The CC genotype increases the rate of RVR and EVR in G1/4
patients, potentially driven by faster viral kinetics during the
first weeks of therapy
(n=135)
%
%
%
%
%
%
%
%
%
%
CT/TT patients
CC patients
Rallón et al. AIDS 2011; in press
• The CC genotype increases the rate of RVR and EVR in G1/4
patients, potentially driven by faster viral kinetics during the
first weeks of therapy
(n=135)
%
%
%
%
%
%
%
%
%
%
CT/TT patients
CC patients
Rallón et al. AIDS 2011; in press
• Marginal effect of IL28B variants on G2/3, potentially due to
similar viral kinetics during the first weeks of therapy
(n=61)
%
%
%
%
%
%
%
%
%
%
CT/TT patients
CC patients
Rallón et al. AIDS 2011; in press
• Marginal effect of IL28B variants on G2/3, potentially due to
similar viral kinetics during the first weeks of therapy
(n=61)
%
%
%
%
%
%
%
%
%
%
CT/TT patients
CC patients
Rallón et al. AIDS 2011; in press
• The rs12979860 CC genotype increases the probability of
SVR in prior true non-responders infected with G1/4
p=0.3
6
% of patients with
SVR
No.
p=0.00
6
29 33
p=0.0
2
18 29
Labarga et al. AIDS 2011; in
11
4
• Patients with the C allele harbor higher serum HCV-RNA
Median serum HCV-RNA in HIV-HCV
coinfected patients with distinct IL28B
genotypes
Labarga et al. AIDS 2011; in
• Patients with the C allele harbor higher serum HCV-RNA
Median serum HCV-RNA in HIV-HCV
coinfected patients with distinct IL28B
genotypes
Proportion of HIV-HCV coinfected patients with
HCV-RNA >600,000 IU/ml according to IL28B
genotypes
Labarga et al. AIDS 2011; in
• The CC genotype is associated to a higher rate of liver
cirrhosis in HIV/HCV coinfected patients
Proportion of patients with liver cirrhosis
by IL28B variants and HCV genotype
p=0.04
30
25
p=0.01
28%
24%
p=0.23
22%
20
tients 15
with liver
13%
cirrhosis
p=0.04
18%
15%
15%
10
6%
5
0
All
patients
HCV -1
HCV -3
HCV -4
genotype
n=304
n=170
n=96
n=38
CT/TT patients
CC patients
Barreiro et al. J Infect Dis 2011; in
• The CC genotype is associated to a higher rate of liver
cirrhosis in HIV/HCV coinfected patients
Proportion of patients with liver cirrhosis
by IL28B variants and HCV genotype
Risk for liver cirrhosis over time of HCV
infection according to IL28B rs12979860
genotype
p=0.04
30
25
p=0.01
28%
24%
tients 15
with liver
13%
cirrhosis
p=0.04
p=0.23
22%
20
100 HR= 3.02 (95% CI, 1.24 - 7.39), p= 0.015
18%
15%
15%
10
80
60
Cumulative
proportion of cirrhotic
patients (%)
40
6%
5
20
0
All
patients
HCV -1
HCV -3
HCV -4
0
genotype
n=304
n=170
n=96
0
n=38
10
20
length of infection (years)
CT/TT patients
CT/TT patients
CC patients
CC patients
Barreiro et al. J Infect Dis 2011; in
30
40
• IFN-λ3 is significantly up-regulated after 4 weeks of
pegIFNα+RBV therapy only in CC carriers
Median IFN-λ3 plasma levels during pegIFN-α/RBV therapy according to rs12979860
IL28B genotypes
All patients
SVR patients
Rallón et al. CROI 2011
Non-responder
patients
• IFN-λ3 is significantly up-regulated after 4 weeks of
pegIFNα+RBV therapy only in CC carriers
Median IFN-λ3 plasma levels during pegIFN-α/RBV therapy according to rs12979860
IL28B genotypes
All patients
SVR patients
Rallón et al. CROI 2011
Non-responder
patients
• IFN-λ3 is significantly up-regulated after 4 weeks of
pegIFNα+RBV therapy only in CC carriers
Median IFN-λ3 plasma levels during pegIFN-α/RBV therapy according to rs12979860
IL28B genotypes
All patients
SVR patients
Rallón et al. CROI 2011
Non-responder
patients
TAKE HOME MESSAGES
• Important role of IL28B genotypes on the rate of spontaneous
clearance and on likelihood of response to pegIFNα-RBV therapy in
HIV/HCV-coinfected individuals, including prior IFNα-experienced
patients.
• Broader influence of IL28B genotypes on HCV disease, including
viral replication and liver injury.
IMPLICATIONS
• Universal IL28B testing in all individuals with chronic hepatitis C.
Cheap and once in life.
• The Prometheus index might be a helpful baseline tool to guide
therapeutic decisions.
• Given the faster progression to cirrhosis and increased response to
therapy, IL28B CC carriers should be prioritized
ACKNOWLEDGMENTS
Infectious Diseases Department, Hospital Carlos III,
Madrid, Spain
José M. Benito Tamara Bar-Magen
Eugenia Vispo Clara Restrepo
Pablo Labarga Sonia Rodriguez-Novoa
José Medrano Pablo Barreiro
Luz Martin-Carbonero Eva Poveda
Norma I. Rallón Vincent Soriano
Duke Clinical Research Institute,
Durham, NC
Susanna Naggie Alex Thompson
Kevin Shianna John McHutchison
Institute for Genome Sciences and Policy,
Durham, NC
David Goldstein
Infectious Diseases Unit, Hospital de Valme,
Sevilla, Spain
Juan A. Pineda Karin Neukam
Juan Macias José A. Mirá
Federico Di Lello
Molecular Epidemiology, Infectious Diseases
Lab
National Centre of Microbiology, ISCIII,
Madrid, Spain
Salvador Resino
Aida Calvino
Hospital Universitario Reina Sofía, Cordoba,
Spain
Antonio Rivero
Angela Camacho
Molecular Biology Dept, Jaen University, Jaen,
Spain
Antonio Caruz
On behalf of CoRIS (Spain)
Enrique Bernal, Hosp Reina Sofía, Murcia
Javier Pinilla, Hosp San Pedro, Logroño
José Hernández-Quero, Hosp San Cecilio, Granada
Santiago Moreno, Hosp Ramón y Cajal, Madrid
José M Miró, Hosp Clínic, Barcelona
Manuel Leal, Hosp Virgen del Rocío, Sevilla
Felix Gutierrez, Hosp de Elche, Elche
Joaquin Portilla, Hosp de Alicante, Alicante
NEAT European Project (LSHPCT-2006- 037570)