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