1. Hepatitis C & HIV in 2011 Vincent Soriano Infectious Diseases Department Hospital Carlos III, Madrid, Spain

2. HCV epidemiology 2-3% of the world population. >40% undiagnosed Routes of infection: sporadic >50% Risk factors: transfusions <1990; IVDU 30% of chronic carriers will develop cirrhosis HCV is the primary reason for liver transplantation HCV is the major cause of liver cancer No vaccine Only curable (eradication) chronic viral infection

3. 400 200 35 HBV HCV HIV The most prevalent chronic viral infections in humans 7 million

4. Deaths in a cohort of 23,441 HIV patients on HAART Weber et al. Liver-related deaths in persons infected with HIV: the D:A:D study. Arch Intern Med 2006; 166: 1632-41. Hep B, C, D Drug-related toxicity HCV

5. Progression of HCV-related liver fibrosis in HIV patients No HAART HIV-neg Uncontrolled HIV replication Low CD4 counts HAART Metabolic abnormalities Hepatotoxicity of meds years

6. RCT with PegIFN + RBV in HCV/HIV pts APRICOT RIBAVIC No. with Peg+RBV 288194 IDUs 62%81% Cirrhotics 15%40% (F3-F4) Genotypes 1-4 67%69% Normal ALT levels 016% Mean CD4 count 520525 On HAART 84%82% EOT (ITT) 49%36% SVR (ITT) 40%27%

7. Unique AEs in HCV/HIV-coinfected patients under pegIFN+RBV APRICOTRIBAVIC No.860383 Mitochondrial toxicity 2011** Hepatic decompensation 14*7*** * All seen in cirrhotics. Overall, it affected 10% of cirrhotics; associated to ddI (+ RBV) ** 1 out of 5 patients treated with ddI *** Associated with ddI and cirrhosis (OR = 9)

8. Current algorithm for HCV therapy in HIV (peginterferon + ribavirin) W4 W12 W24 W48W72 HCV-RNA neg HCV-RNA pos > 2 log drop in HCV-RNA < 2 log drop in HCV-RNA HCV-RNA neg HCV-RNA pos G2/3 G1/4 Stop G2/3 G1/4 24 weeks therapy 48 weeks therapy 72 weeks therapy Soriano et al. AIDS 2007; 21: 1073-89.

9. Predictors of response to HCV therapy  HCV genotype  Baseline serum HCV-RNA  Liver fibrosis stage  RVR  EVR  IL28B polymorphisms

10. IL28B polymorphisms & hepatitis C outcome Chromosome 19 IL28B gene Interferon 3 Ge et al. Nature 2009; 461: 399-401. Thomas et al. Nature 2009; 461: 798-802. Suppiah et al. Nature Gen 2009; 41: 1100-4. Tanaka et al. Nature Gen 2009; 41: 1105-9. SNP: rs12979860 (CC, CT, TT) Spontaneous HCV clearance Response to pegIFN+RBV

11. SVR CCCT/TTCCCT/TTCCCT/TTCCCT/TT 34 61 35 166 12 75 89 75% AllHCV-3HCV-1HCV-4 164519518 38% 65% 30% 86% 81% 67% 25% p=0.684 p=0.087 p=0.001 p<0.0001 AIDS 2010

12. Odds ratio (95% confidence interval) HCV-RNA <600,000 IU/ml HCV genotype 3 rs12979860 CC genotype Liver fibrosis stage F0-F2 0510152025303540 11.9 8.0 3.7 3.5 p<0.001 p=0.002 p=0.009 Rallon et al. AIDS 2010 IL28B polymorphisms in HIV-HCV coinfection

13. Prometheus index HCV genotype Fibrosis stage (KPa) Serum HCV-RNA IL28B SNPs http://ideasydesarrollo.com/fundacion/prometheusindex.php

15. A new era for hepatitis C – new diagnostic tools & new weapons DiagnosisTherapy IL28B alleles Non-invasive liver fibrosis methods Viral load HCV geno/subtyping Drug resistance Protease inhibitors Polymerase inhibitors NS5A inhibitors Interferon lambda Alisporivir

17. Challenges using DAA in HIV-HCV coinfection  More elevated HCV load. More virological failures?  Faster selection of drug resistance?  Drug-drug interactions  Overlapping toxicities – rash & anemia  Drug compliance with polymedication  Additional cost

18. Study 110 Telaprevir in HIV-HCV coinfected pts Week 4 372276148168 70 5 71 0 64 0 75 12 totalNo ARVATV/rEFV % HCV-RNA <10 IU/ml PRT PR Week 12 372276148168 68 14 71 17 57 12 75 12 totalNo ARVATV/rEFV % HCV-RNA <10 IU/ml Sulkowski et al. CROI 2011, LB146

19. Implications of widespread use of DAA  Shift in HCV genotypes in the infected population, being other genos replacing geno 1.  Changes in HCV-infected populations, with accumulation in poor regions and/or communities within rich countries.  Growing number of patients with drug-resistant mutant viruses and potential for transmission.

20. A shift in care providers for hep C liver hepatologist virus infectologist The HCV doctor

21. 8th International Coinfection Workshop Madrid, May 30 - June 1, 2012 Chairmen: Vicente Soriano & Mark Sulkowski HIV HBV HCV www.virology-education.com

22. Acknowledgments ClinicLaboratory Pablo Barreiro Norma Rallon Pablo Labarga Ana Treviño Luz Martin-Carbonero Carmen de Mendoza Eugenia VispoEva Poveda Jose MedranoSonia Rodriguez-Novoa Jose V FernandezJose Miguel Benito Juan Gonzalez-Lahoz