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Influence of IL28B Gene Polymorphisms and Interferon λ3 Plasma Levels on HCV Outcomes in HIV Patients

This study explores the impact of IL28B gene polymorphisms and interferon λ3 plasma levels on hepatitis C virus (HCV) outcomes in HIV patients. The results show that the CC genotype of IL28B gene increases the likelihood of sustained virological response to pegIFN+RBV therapy, particularly in patients with HCV genotypes 1 and 4. Additionally, patients with the CC genotype have a higher rate of rapid and early virological response. This study provides valuable insights into the predictors of treatment response in HCV/HIV co-infected patients.

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Influence of IL28B Gene Polymorphisms and Interferon λ3 Plasma Levels on HCV Outcomes in HIV Patients

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  1. 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

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

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

  4. 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 Rallón 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

  5. LESSONS LEARNED

  6. 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% Spontaneous HCV clearance Chronic HCV infected CC patients CT/TT patients n=24 n=164 Rallón et al. AIDS 2010; 24:F23-9

  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 Rate of SVR in distinct HCV genotypes according to rs12979860 SNP CT/TT patients Rallón et al. AIDS 2010; 24:F23-9 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 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 Rallón et al. AIDS 2010; 24:F23-9 CC patients

  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. ClinInfect Dis 2010; 51:1209-16.

  10. Baseline prediction of the likelihood of SVR to pegIFN-RBV Diagnostic performance in the derivation and validation groups PROMETHEUS INDEX • HCV genotype (1/4) • Serum log10 HCV-RNA • Stiffness (KPa) • IL28B rs12979860 (CT/TT) Medrano et al. ClinInfect Dis 2010; 51:1209-16.

  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 (n=135) % % % % % % % % % % CT/TT patients CC patients Rallón et al. AIDS 2011; in press

  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 (n=135) % % % % % % % % % % CT/TT patients CC patients Rallón et al. AIDS 2011; in press

  14. 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

  15. 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

  16. The rs12979860 CC genotype increases the probability of SVR in prior true non-responders infected with G1/4 p=0.36 p=0.006 % of patients with SVR p=0.02 No. 29 33 18 29 11 4 Labarga et al. AIDS 2011; in press

  17. 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 press

  18. 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 press

  19. 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 p =0.01 28% p=0.04 25 24% p=0.23 22% 20 18% % of patients with liver cirrhosis 15% 15% 15 13% 10 6% 5 0 All HCV - 1 HCV - 3 HCV - 4 patients genotype n=304 n=170 n=96 n=38 CT/TT patients CC patients Barreiro et al. J Infect Dis 2011; in press

  20. 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 p =0.01 HR= 3.02 (95% CI, 1.24 - 7.39), p= 0.015 100 28% p=0.04 25 24% p=0.23 80 22% 20 18% Cumulative proportion of cirrhotic patients (%) 60 % of patients with liver cirrhosis 15% 15% 15 13% 10 40 6% 5 20 0 0 All HCV - 1 HCV - 3 HCV - 4 patients 0 10 20 30 40 genotype length of infection (years) n=304 n=170 n=96 n=38 CT/TT patients CT/TT patients CC patients CC patients Barreiro et al. J Infect Dis 2011; in press

  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 All patients SVR patients Non-responder patients Rallón et al. CROI 2011

  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 All patients SVR patients Non-responder patients Rallón et al. CROI 2011

  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 All patients SVR patients Non-responder patients Rallón et al. CROI 2011

  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 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 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 Duke Clinical Research Institute, Durham, NC Susanna Naggie Alex Thompson Kevin Shianna John McHutchison 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 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 NEAT European Project (LSHP-CT-2006- 037570)

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