Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
New Frontiers in HIV/HCV Therapy Todd S Wills, MD USF ETAC, Infectious Disease Specialist USF ETAC, Infectious Disease Specialist Potential Areas of Advancement in HIV/HCV Therapy / h • • • • Response guided therapy Response‐guided therapy Predictive Biomarkers S ifi C Specific HCV antiviral therapy i i l h Other new drugs HCV Response Guided Therapy HCV Response Guided Therapy • Using Using the rate of virologic response to predict the rate of virologic response to predict success of therapy • Using rate of response to determine duration Using rate of response to determine duration of therapy Response Guided Therapy in HCV Monoinfection Levin AASLD, Nov 2‐6, 2007, Boston, MA Response Guided Therapy in HCV Monoinfection Levin AASLD, Nov 2‐6, 2007 Response‐Guided Therapy in HIV/HCV C i f i Coinfection • Van den Eynde et al. Clin Infect Dis. (2009) 48 (8): y f ( ) ( ) 1152‐1159 • 60 HIV/HCV coinfected patients • 24 weeks of therapy for patients with Rapid Virologic Response (RVR) • 48 weeks of therapy for Early Virologic Response (EVR) • 60 weeks of therapy for partial EVR • Termination of treatment for null response p Response Guided Therapy – All Patients Response Guided Therapy All Patients ETR – End of Treatment Treatment Response SVR – Sustained Virologic Response RR – Relapse Rate Van den Eynde et al. Clin Infect Dis. (2009) 48 (8): 1152‐1159 Response Guided Therapy ‐ RVR Response Guided Therapy Van den Eynde et al. Clin Infect Dis. (2009) 48 (8): 1152‐1159 Response Guided Therapy ‐ EVR Response Guided Therapy Van den Eynde et al. Clin Infect Dis. (2009) 48 (8): 1152‐1159 IL‐28B Polymorphism and Treatment Response • Polymorphisms Polymorphisms near the IL near the IL‐28B 28B gene are gene are strong predictors of both spontaneous clearance of HCV and response to treatment clearance of HCV and response to treatment Percentage of SVR by genotypes for IL‐28B region DL Ge et al. Nature 461, 399‐401 (2009) Rate of SVR and IL‐28 region C‐allele frequency in diverse ethnic groups DL Ge et al. Nature 461, 399‐401 (2009) Interleukin 28B (IL‐28B) Polymorphism and Treatment Response in Coinfection i i f i • Nattermann J, et al. 2010 CROI Abstract #164 J et al 2010 CROI Abstract #164 • 183 Co infected patients versus healthy and monoinfected controls – C/C genotype SVR rates 58.1% – C/T 58.1% C/T 58 1% – T/T 40.6%; P =0.041 ITPA deficiency protects against clinically significant decline in Hb concentration induced by HCV anti‐viral treatment concentration induced by HCV anti viral treatment J Fellay et al. Nature, 1‐4 (2010) Potential HCV antiviral targets 5’ Internal ribosomal entry site C RNA binding site E1 E2/NS1 Envelope glyco‐ proteins NS2 Signal peptide NS3 NS4A NS4B Serine protease/ helicase telaprevir, boceprevir l i b i NS5A NS5B RNA dependent RNA polymerase 3’ Telaprevir and Boceprevir and Boceprevir • Both target HCV serine proteases Both target HCV serine proteases – Common resistance mutations and cross resistance described resistance described • • • • • Telaprevir NS3/NS4 protease inhibitor B Boceprevir i NS3 protease inhibitor NS3 t i hibit Studies in HCV monoinfection are complete Studies in HIV/HCV co‐infection ongoing Potential FDA review within 6‐12 Potential FDA review within 6 12 months months Telaprevir with PEGIFN and Ribavirin in treatment naïve patients ‐ ï i HCV Genotype 1 HCV ‐ G 1 80 PROVE 1 (USA) n = 250 PROVE 2 (Europe) n = 334 334 SUSTA TAINED VIRA AL RESPONSEE (%) 70 60 50 40 30 20 10 0 PR48 T12PR12 T12PR24 1. McHutchison et al, NEJM 2009; 2. Hezode et al, NEJM 2009 T12PR48 Telaprevir for previously treated (PEGIFN / ribavirin) HCV Genotype 1 ib i i ) HCV G 1 SUSTA TAINED VIRA AL RESPONSEE (%) 80 All patients n = 453 Non‐responders n = 260 Relapsers n = 162 70 60 50 40 30 20 10 0 PR48 McHutchison et al, NEJM 2010 T12PR24 T12PR48 Telaprevir Response in Previously Treated Patients McHutchison, J. et al. New England Journal of Medicine. 362(14):1292‐1303, April 8, 2010. Adverse Events Leading to Telaprevir Discontinuation McHutchison, J, et al. New England Journal of Medicine. 360(18):1827‐1838, April 30, 2009. Boceprevir in Treatment Naïve HCV Genotype 1 in Treatment Naïve HCV Genotype 1 Kwo PY et al. The Lancet ‐ PY et al The Lancet 28 August 2010 ( Vol. 376, Issue 9742, Pages 705‐716 ) 28 August 2010 ( Vol 376 Issue 9742 Pages 705 716 ) Kwo PY et al. The PY et al The Lancet ‐ 28 August 2010 ( Vol. 376, Issue 9742, Pages 705‐716 ) SVR Based on 4‐week Viral Load reduction in reduction in Boceprevir treatment Naïve Trial Naïve Trial Primary mutations conferring resistance to NS3/4A protease inhibitors hb . Soriano V et al. Clin Infect Dis. 2009;48:313‐320 Binding sites for HCV polymerase inhibitors Soriano V et al. Clin Infect Dis. 2009;48:313-320 Main features of new specifically targeted hepatitis C virus drugs. Soriano V et al. Clin Infect Dis. 2009;48:313‐320 The Direct Acting HCV Antiviral Pipeline The Direct Acting HCV Antiviral Pipeline • 22 22 agents in Phase 1 trials agents in Phase 1 trials • 18 agents in Phase 2 trials • Multiple trials involving combination therapy li l i l i l i bi i h with investigational agents • Trials are exploring virologic efficacy AND duration of treatment • All agents are protease or polymerase inhibitors http://www.hcvadvocate.org/hepatitis/hepC/HCVDrugs_2011.pdf accessed: January 23, 2011 Indirect Acting HCV Drug Pipeliine Indirect Acting HCV Drug Pipeliine • 14 agents in Phase 1 trials 14 agents in Phase 1 trials • 23 agents in Phase 2 trials • Mechanisms of action include Mechanisms of action include – Immunomodulators – Oral or alternative interferons Oral or alternative interferons – TLR antagonists – Therapeutic Vaccines Therapeutic Vaccines – Interfering RNAs – Existing Antimicrobials (nitazoxanide) Existing Antimicrobials (nitazoxanide) http://www.hcvadvocate.org/hepatitis/hepC/HCVDrugs_ 2011.pdf acessed: January 23, 2011