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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.
Broader Influence of IL28B Gene Polymorphisms and Interferon λ3
Plasma Levels on HCV Outcomes in HIV Patients
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
% SVR to pegIFN+RBVby rs12979860 genotypes
Ge et al. Nature 2009; 461:399-401
IL28B Gene Genetic Variation
HCV-Monoinfected Patients
% SVR to pegIFN+RBVby rs12979860 genotypes
Ge et al. Nature 2009; 461:399-401
% spontaneous HCV clearanceby rs12979860 genotypes
Thomas et al. Nature 2009; 461:798-801
DESCRIPTION
Hospital Carlos III Cohort650 HIV/HCV Co-infected
individualsVariable n IL28B Effect Reference
Spontaneous HCV clearance 24 CC Enhanced in genotypes 1 and 4Rallón et al. AIDS 2010
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
Rallon et al. CROI 2011
LESSONS LEARNED
• Higher prevalence of CC genotype in patients who spontaneously clear HCV compared with chronically infected HCV patients
Rallón et al. AIDS 2010; 24:F23-9
HCV/HIV-Coinfected Patients
rs12979860 genotypes
75%
46%
25%
54%
Spontaneous HCV clearance
Chronic HCVinfected
p=0.007
n=164n=24
% of patients
CT/TT patientsCC patients
• The rs12979860 CC genotype exerts a beneficial effect on the probability of SVR to pegIFN+RBV, mainly in HIV/HCV-coinfected patients with HCV G1/4
Rallón et al. AIDS 2010; 24:F23-9
Rate of SVR in distinct HCV genotypes according to rs12979860 SNP
CT/TT patientsCC patients
• The rs12979860 CC genotype exerts a beneficial effect on the probability of SVR to pegIFN+RBV, mainly in HIV/HCV-coinfected patients with HCV G1/4
Rallón et al. AIDS 2010; 24:F23-9
Rate of SVR in distinct HCV genotypes according to rs12979860 SNP
Predictors of SVR to pegIFNα/RBV therapy in HIV/HCV coinfected patients
CT/TT patientsCC patients
• Baseline prediction of the likelihood of SVR to pegIFN-RBV
Medrano et al. Clin Infect Dis 2010; 51:1209-16.
PROMETHEUS INDEX
• HCV genotype (1/4)• Serum log10 HCV-RNA• Stiffness (KPa)• IL28B rs12979860 (CT/TT)
• Baseline prediction of the likelihood of SVR to pegIFN-RBV
Medrano et al. Clin Infect Dis 2010; 51:1209-16.
Diagnostic performance in the derivationand validation groups
PROMETHEUS INDEX
• HCV genotype (1/4)• Serum log10 HCV-RNA• Stiffness (KPa)• IL28B rs12979860 (CT/TT)
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
CT/TT patients
CC patients
Rallón et al. AIDS 2011; in press
%
%
%
%
%
%
%
%
%
%
(n=135)
• 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
CT/TT patients
CC patients
Rallón et al. AIDS 2011; in press
%
%
%
%
%
%
%
%
%
%
(n=135)
• Marginal effect of IL28B variants on G2/3, potentially due to similar viral kinetics during the first weeks of therapy
CT/TT patients
CC patients
Rallón et al. AIDS 2011; in press
%
%
%% %
%%
% %
%
(n=61)
• Marginal effect of IL28B variants on G2/3, potentially due to similar viral kinetics during the first weeks of therapy
CT/TT patients
CC patients
Rallón et al. AIDS 2011; in press
%
%
%% %
%%
% %
%
(n=61)
• The rs12979860 CC genotype increases the probability of SVR in prior true non-responders infected with G1/4
Labarga et al. AIDS 2011; in press
p=0.006 p=0.0
2
p=0.36
% of patients with SVR
No. 29 33 18 29 11 4
• Patients with the C allele harbor higher serum HCV-RNA
Labarga et al. AIDS 2011; in press
Median serum HCV-RNA in HIV-HCV coinfected patients with distinct IL28B
genotypes
• Patients with the C allele harbor higher serum HCV-RNA
Labarga et al. AIDS 2011; in press
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
• The CC genotype is associated to a higher rate of liver cirrhosis in HIV/HCV coinfected patients
CT/TT patients
CC patients
24%
28%
22%
18%
13%15%
6%
15%
0
5
10
15
20
25
30
All HCV-1 HCV-3 HCV -4
genotypepatients
p=0.01
p=0.04
p=0.04
p=0.23
n=170 n=96 n=38n=304
Barreiro et al. J Infect Dis 2011; in press
Proportion of patients with liver cirrhosis by IL28B variants and HCV genotype
% of patients with liver cirrhosis
• The CC genotype is associated to a higher rate of liver cirrhosis in HIV/HCV coinfected patients
CT/TT patients
CC patients
24%
28%
22%
18%
13%15%
6%
15%
0
5
10
15
20
25
30
All HCV-1 HCV-3 HCV -4
genotypepatients
p=0.01
p=0.04
p=0.04
p=0.23
n=170 n=96 n=38n=304
0
20
40
60
80
100
0 10 20 30 40
length of infection (years)
HR= 3.02 (95% CI, 1.24 - 7.39), p= 0.015
Cumulative proportion of cirrhotic
patients (%)
CT/TT patients
CC patients
Barreiro et al. J Infect Dis 2011; in press
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
% of patients with liver cirrhosis
• 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
Rallón et al. CROI 2011
All patients SVR patients 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
Rallón et al. CROI 2011
All patients SVR patients 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
Rallón et al. CROI 2011
All patients SVR patients 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
Duke Clinical Research Institute, Durham, NCSusanna Naggie Alex ThompsonKevin Shianna John McHutchison
Institute for Genome Sciences and Policy, Durham, NCDavid Goldstein
NEAT European Project (LSHP-CT-2006- 037570)
Infectious Diseases Department, Hospital Carlos III, Madrid, SpainJosé M. Benito Tamara Bar-MagenEugenia Vispo Clara RestrepoPablo Labarga Sonia Rodriguez-NovoaJosé Medrano Pablo BarreiroLuz Martin-Carbonero Eva PovedaNorma I. Rallón Vincent Soriano
Infectious Diseases Unit, Hospital de Valme, Sevilla, SpainJuan A. Pineda Karin Neukam Juan Macias José A. MiráFederico Di Lello
Hospital Universitario Reina Sofía, Cordoba, SpainAntonio Rivero Angela Camacho
Molecular Biology Dept, Jaen University, Jaen, SpainAntonio Caruz
On behalf of CoRIS (Spain) Enrique Bernal, Hosp Reina Sofía, MurciaJavier Pinilla, Hosp San Pedro, LogroñoJosé Hernández-Quero, Hosp San Cecilio, GranadaSantiago Moreno, Hosp Ramón y Cajal, MadridJosé M Miró, Hosp Clínic, BarcelonaManuel Leal, Hosp Virgen del Rocío, SevillaFelix Gutierrez, Hosp de Elche, ElcheJoaquin Portilla, Hosp de Alicante, Alicante
Molecular Epidemiology, Infectious Diseases LabNational Centre of Microbiology, ISCIII, Madrid, SpainSalvador Resino Aida Calvino