1. 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

2. IL28B Gene Genetic Variation HCV-Monoinfected Patients % SVR to pegIFN+RBV by rs12979860 genotypes Ge et al. Nature 2009; 461:399-401

3. IL28B Gene Genetic Variation HCV-Monoinfected Patients % SVR to pegIFN+RBV by rs12979860 genotypes Ge et al. Nature 2009; 461:399-401 % spontaneous HCV clearance by rs12979860 genotypes Thomas et al. Nature 2009; 461:798-801

4. DESCRIPTION Hospital Carlos III Cohort 650 HIV/HCV Co-infected individuals VariablenIL28BEffectReference Spontaneous HCV clearance24CCEnhanced in genotypes 1 and 4 Rallón et al. AIDS 2010 Response to pegIFNα-RBV therapy 164CCIncreased SVR mainly in genotypes 1 and 4 Response to pegIFNα-RBV therapy 159/86CCPredictive of SVR (Prometheus index)Medrano et al., Clin Inf Dis 2010 Early viral kinetics on therapy196CCIncreased 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 62CCIncreased SVR only in genotypes 1 and 4 prior true non-responders Labarga et al. AIDS 2011 (in press) Serum HCV-RNA levels289CC/CTGreater viral loadLabarga et al. AIDS 2011 (in press) Liver fibrosis progression304CCGreater rate of cirrhosisBarreiro et al. J Infect Dis 2011 (in press) Liver enzymes elevation304CCIncreased ALT levels Serum IFN λ3 levels112CCNo impact at baseline but greater increase during IFNα therapy Rallon et al. CROI 2011

5. LESSONS LEARNED

6. 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 HCV infected p=0.007 n=164n=24 % of patients CT/TT patients CC patients

7. 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 patients CC patients

8. 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 patients CC patients

9. 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 log 10 HCV-RNA Stiffness (KPa) IL28B rs12979860 (CT/TT)

10. Baseline prediction of the likelihood of SVR to pegIFN-RBV Medrano et al. Clin Infect Dis 2010; 51:1209-16. Diagnostic performance in the derivation and validation groups PROMETHEUS INDEX HCV genotype (1/4) Serum log 10 HCV-RNA Stiffness (KPa) IL28B rs12979860 (CT/TT)

11. http://ideasydesarrollo.com/fundacion/prometheusindex.php

12. 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)

13. 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)

14. 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)

15. 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)

16. 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=0.00 6 p=0.0 2 p=0.3 6 % of patients with SVR No.29331829114

17. 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

18. 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

19. 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 AllHCV-1 -3 -4 genotype patients p=0.01 p=0.04 p=0.23 n=170n=96n=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

20. 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 AllHCV-1 -3 -4 genotype patients p=0.01 p=0.04 p=0.23 n=170n=96n=38n=304 0 20 40 60 80 100 010203040 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

21. 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 patientsSVR patientsNon-responder patients

22. 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 patientsSVR patientsNon-responder patients

23. 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 patientsSVR patientsNon-responder patients

24. 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

25. ACKNOWLEDGMENTS Duke Clinical Research Institute, Durham, NC Susanna Naggie Alex Thompson Kevin Shianna John McHutchison Institute for Genome Sciences and Policy, Durham, NC David Goldstein NEAT European Project (LSHP- CT-2006- 037570) 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 Infectious Diseases Unit, Hospital de Valme, Sevilla, Spain Juan A. Pineda Karin Neukam Juan Macias José A. Mirá Federico Di Lello 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 Molecular Epidemiology, Infectious Diseases Lab National Centre of Microbiology, ISCIII, Madrid, Spain Salvador Resino Aida Calvino