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7/27/2011 Disclaimer Jonathan Moorman, M.D., Ph.D. Professor, Infectious Diseases Quillen College of Medicine July, 2011 NEITHER THE PUBLISHER NOR THE AUTHORS ASSUME ANY LIABILTY FOR ANY INJURY AND OR DAMAGE TO PERSONS OR PROPERTY ARISING FROM THIS WEBSITE AND ITS CONTENT Disclosures To discuss Grant funding from NIH/NIAID Overview of the problems Clinical trials with Gilead, GSK, and Wyeth/Pfizer What we think might be going on…. Novel pathways Novel treatments 1 7/27/2011 Co-infection: A Significant Problem HIV affects 40 million globally and about 1 million in the U.S. HCV affects 200 million globally and 4 million in the U.S. Prevalence of co-infection varies from 4% to greater than 90% depending on the population In IV drug users and hemophiliacs, the prevalence has been as high as 98% MSM sexually-acquired HCV appears to occur in the setting of high risk exposures (STDs, traumatic intercourse) Sulkowski MS. J Hepatol 2008; 48: 353‐367. HIV and HCV: more similar than you might think HIV Genome Transmission Viral kinetics Viral load Major target Latency Goal of therapy Drug resistance ss ssRNA N retrovirus et ov us Sexual/IVDU Massive production Correlates well with disease T cell Yes Viral suppression Occurs WHY PERSISTENCE? HCV ss ssRNA N flavivirus av v us IVDU>>sexual Massive production Correlates poorly with disease Liver but…..? No Viral eradication Occurs Kim AY and Chung RT. Gastroenterology 2009; 137: 795‐814. 2 7/27/2011 WHY PERSISTENCE? New Targets for chronic viral infection: the negative infection: the negative immunoreceptors Immune exhaustion Arlene H Sharpe, E John Wherry, Rafi Ahmed & Gordon J Freeman. Nature Immunology 8, 239 ‐ 245 (2007). 3 7/27/2011 Frazier AD, Zhang CL, Ni L, Ma CJ, Zhang Y, Wu XY, Atia AN, Yao ZQ, Moorman JP. Viral Immunol. 2010 Oct;23(5):487‐95. PD‐1 and HIV PD‐1 and HCV PD‐1 expression on HIV‐specific T cells is associated with T cell exhaustion and disease progression (Day et al. Nature 2006; 443: 350‐354) Immune dysfunction was reversible in HIV Immune dysfunction was reversible in HIV‐specific specific CD8+ T cells (Trautmann et al. Nat Med 2006; 12:1198‐1202.) Blocking PD‐1 in an SIV model enhanced SIV‐specific immunity (Velu et al. Nature 2009; 458: 206‐210.) Ma CJ, Ni L, Zhang Y, Zhang CL, Wu XY, Atia AN, Thayer P, Moorman JP, Yao ZQ. Immunology. 2011 Mar;132(3):421‐31. PD‐1 modulates regulatory T cells and suppresses T‐cell responses in HCV‐ associated lymphoma. Ni L, Ma CJ, Zhang Y, Nandakumar S, Zhang CL, Wu XY, Borthwick T, Hamati A, Chen XY, Kumaraguru U, Moorman JP, Yao ZQ. Immunol Cell Biol. 2010 Oct 26. [Epub ahead of print] 4 7/27/2011 Ma CJ, Ni L, Zhang Y, Zhang CL, Wu XY, Atia AN, Thayer P, Moorman JP, Yao ZQ. Immunology. 2011 Mar;132(3):421‐31. New Targets: the Tim‐3 story 5 7/27/2011 Differential expression of TIM-3 on the surface of T cells regulates susceptibility to viral infection or development of autoimmune injury. HCV and Tim‐3: T cells Up‐regulation on HCV‐specific T cells* Blockade is associated with improved CD4+ and CD8+ functions* Dual expression of Tim‐3/PD‐1 on T cells has been D l i f Ti /PD T ll h b described in co‐infected patients and correlates with progression of liver disease+ •Golden‐Mason et al. J Virol 2009; 83: 9122‐9130. •+Vali et al. Eur J Immunol 2010; 40: 2493‐2505. Hafler D A , Kuchroo V J Exp Med 2008;205:2699-2701 Tim‐3 in monocytes P=0.0012 P<0.001 P=0.1878 P=0.0017 P<0.001 % of Tim‐3+ CD1 14+ M/MØ P<0.001 P<0.001 P<0.001 % of IL12+ CD14+ M/M MØ PD-1 Naïve Activated Naïve Activated Naïve Activated Naïve Activated Healthy Subjects Chronic HCV Patients 6 7/27/2011 Defining an Initial Virologic Response EVR: HCV RNA ↓ ≥ 2 logs or Undetectable at Week 12 HCV RNA (log10 IU//mL) 8 PegIFN/RBV 7 6 5 2 log decline 4 3 2 EVR 1 66% SVR; 48 w Limit of detection RVR SVR 0 0 4 8 12 18 24 30 36 42 48 54 60 66 72 78 Weeks Initial Treatment of Chronic HCV - Predicting SVR Over Time Defining an Initial Virologic Response RVR: HCV RNA Undetectable at Week 4 100 5 2 log decline 4 SVR (% %) HCV RNA (log10 IU/mL) 90 GT 1[1] GT 2-3[2] 66 PegIFN/RBV 7 6 60 59 45 40 20 3 2 91 80 8 RVR 90% SVR; 24 w Limit of detection 1 SVR 0 0 4 8 12 18 24 30 36 42 48 54 60 66 72 78 Weeks 0 4 24 12 Week Undetectable HCV RNA Achieved No matter what genotype, achieving RVR is crucial for a SVR 1. Ferenci P, et al. J Hepatology. 2005;43:453-471. 2. Shiffman ML, et al. N Engl J Med. 2007;124-134. 7 7/27/2011 HCV monoinfection: Sustained Virologic Response With Peg-interferon and Ribavirin Combination Treatment Drug Peginterferon alfa-2a plus ribavirin Peginterferon alfa-2b plus ribavirin Weight-based dosing Overall Genotype 1 Genotype 2 or 3 56% 46% 76% 54% 42% 82% 48% 88% Fried et al. N Engl J Med 2002; 347: 975. Hadziyannis et al. Ann Intern Med 2004; 140; 346. New Targets STAT-C: Specifically Targeted Antiviral Therapy for Hepatitis C IFN + RBV + small molecule agents specifically inhibit HCV life cycle achieve RVRs and increase SVRs from 50 to 80%; Pretreatment quasispecies confer resistance to all classes of inhibitors All therapies will still be IFN‐based Sides effect: skin rash, renal toxicity 8 7/27/2011 Therapies arrived: NS3/4A inhibitors The NS3/4a complex acts as a serine protease to process the HCV polyprotein Peptidomimetic inhibitors developed p ((oral)) Boceprevir Telepravir •McCutshison et al. NEJM 2009; 360:1827. •Hezode et al. NEJM 2009; 360:1839-1850. 9 7/27/2011 10 7/27/2011 Summary: Treatment‐naïve, Genotype 1 Addition of protease inhibitor increases SVR by 1.7 fold Boceprevir: Telaprevir: 24 (28) weeks of treatment is effective for many patients Adverse events include Boceprevir: anemia, dysgusia Telaprevir: skin rash, anemia Effective in African‐Americans and patients with cirrhosis first line treatment for genotype 1 HCV now Summary Summary – Treatment‐Experienced Patients Boceprevir and telaprevir increase SVR for non‐responders 48 weeks of treatment Probability of SVR depends on prior response to y p p p PegIFN/RBV 75 – 85%% in relapsers 50‐65% in non‐responders (non‐null) 30% in null‐responders Null responders not optimally served by either drug Protease + (nN)Polymerase Inhibitors ± PegIFN +Ribavirin Genotype 1, treatment‐naïve; 4 weeks of PI+PI; PI+PI+RBV; PI+PI+Peg+RBV Protease inhibitor + pegIFN/RBV expected to be the next standard of care for most patients with HCV genotype 1 Treatment‐naive patients can anticipate SVR rates from 63%‐75% Shorter duration for many patients (response‐guided therapy) Treatment‐experienced patients can anticipate SVR rates ranging from 29%‐88% depending on response to pegIFN/RBV 9 p g p p g / Side effects: Boceprevir: anemia, dysgusia Telaprevir: rash, anemia Resistance in patients who don’t respond to pegIFN/RBV New agents are promising, probably with pegIFN + RBV Zeuzem AASLD 2010 abstract LB‐1 11 7/27/2011 Summary HCV and HIV present similar challenging issues and perhaps underlying immunopathology Novel treatments for HCV will likely lead to substantial improvements in sustained virologic responses in both mono‐ and co‐infected populations Novel pathways that mediate immune exhaustion are potential targets to improve host responses Thanks…. John Yao, MD, PhD Ying Zhang, MD, PhD Jerry Ma, MD, PhD Ni Lei, MD, PhD Ni Lei MD PhD Chunlan Zhang, MD, PhD Xiaojun Ji, MD, PhD Jiamin Wang, MD, PhD Rose Wu Ashley Frazier Antwan Atia, MD 12 7/27/2011 Consequences: not just persistence Vaccine responses in chronic HCV infection 80 * % CD69+ in CD4+ + T cells 70 60 IgG * a‐PDL‐1 50 40 * 30 20 10 0 HBsAg stimulation a‐CD3/28 stimulation * p=0.002 A Vaccine (Failure) Model PD-1 Does having HIV make HCV worse? Co-infected patients had higher HCV RNA viral loads* Co Co-infected infected patients had more rapid HCV viral replication and progressed more rapidly and frequently to hepatic fibrosis and cirrhosis than HIV (-) patients with HCV† In a large group of hemophiliacs, progression to liver failure was more likely and was inversely correlated with CD4 count‡ *Bonacini et al. J Viral Hepat 1999, 6:405. †Allory et al. J Infect Dis 2000, 181:442; Benhamou et al. Nat Struct Biol 1999, 6:937. ‡Telfer et al. Med Microbiol Immunol 1994, 183:159. 13 7/27/2011 HIV/HCV Co‐infection RR for ESLD 6.14 RR for Cirrhosis 2.07 Sulkowski MS. J Hepatol 2008; 48: 353‐367. Kim AY and Chung RT. Gastroenterology 2009; 137: 795‐814. 14