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  • 1. Viral Hepatitis Management in 2012 Paul Y Kwo, MD Professor of MedicineMedical Director, Liver TransplantationGastroenterology/Hepatology DivisionIndiana University School of Medicine 975 W. Walnut, IB 327 Indianapolis, IN 46202-5121 phone 317-274-3090 fax 317-274-3106 pkwo@iupui.edu
  • 2. Hepatitis B Virus • Nucleic Acid: 3.2 kb DNA • Classification: Hepadnaviridae • Multiple serotypes and genotypes 42 nm A-H • Enveloped 22 nm • In vitro model: primary HBsAg hepatocyte culture and transfection of cloned HBV DNA42 nm HBcAg • In vivo replication: in cytoplasm, cccDNA in nucleus; hepatocyte HBsAg and other tissues, human and HBV DNA other primates 22 nm
  • 3. Prevalence of HBV: Global Estimates HBsAg 350 million With Chronic HBV Positive (%) Taiwan 10-13.8 Viet Nam 5.7-10 China 5.3-12 Africa 5-19 Philippines 5-16 Thailand 4.6-8 Japan 4.4-13 Indonesia 4.0 South Korea 2.6-5.1HBsAg Prevalence High (>8%) India 2.4-4.7 Russia 1.4-8 Intermediate (2%-7%) Low (<2%) United States 0.2-0.5Weinbaum CM, et al. MMWR Recomm Rep. 2008;57(RR-8):1-20.Custer B, et al. J Clin Gastroenterol. 2004;38(10 suppl):S158-S168.
  • 4. HBV Infection in the United States• Revised HBV prevalence in the United States taking into account recent estimates of foreign-born persons • 847,145 to 2,243,757 persons with chronic HBV • Average chronic HBV prevalence rate among foreign-born persons living in the United States is 2.0% to 5.4% Welch S, et al. Hepatology. 2008;48(suppl):687A-688A. Abstract 853.
  • 5. HBV: How Do People Get Infected? • Hepatitis B is transmitted by contact with blood or body fluids of an infected person • The main ways of getting infected with HBV are: • Perinatal (from mother to baby at birth) • Child-to-child transmission • Unsafe injections and transfusions • Sexual contact • HBV is 50 to 100 times more infectious than HIV • Household contact is a documented risk factorFrom http://www.who.int/vaccines/en/hepatitisb.shtml. Accessed 09/20/06.American Journal of Epidemiology Vol. 132, No. 2: 220-232.
  • 6. HBV - Epidemiology Risk of Chronic Infection 100 80 60 % Risk 40 20 0 Neonates Infants Children Adults Age at Infection
  • 7. Tests Used to Screen for HBV InfectionTest SignificanceViral antigens HBsAg Acute or chronic infection; infectivity HBeAg Acute or chronic infection; infectivity, wild type viral infectionViral antibodies Anti-HBc Marker of exposure Anti-HBe Low infectivity Anti-HBs Marker of immunityMolecular test HBV DNA Acute or chronic infection; infectivity, risk of progression to cirrhosis or causeLok AS, et al. Hepatology. 2007;45:507-539.
  • 8. Typical Interpretation of Serologic Test Results for HBV Infection Serologic Marker ResultsHBsAg Total IgM Anti- Anti-HBc Anti-HBc HBs Interpretation Never infected and no evidence of immunization - - - - Acute infection + + + - Chronic infection + + - - Recovered from past infection and immune - + - +/- Immune (immunization or natural) - - - +Weinbaum CM, et al. MMWR Recomm Rep. 2008;57(RR-8):1-20.
  • 9. Natural Course of Chronic HBV Infection HBeAg Anti-HBeHBVDNAALT Immune Immune Inactive Reactivation Tolerance Clearance Carrier
  • 10. Incidence of HCC (Hepatocellular cancer) Increases with Increasing HBV DNA Baseline Viral Level 20% % cumulative incidence of HCC 14.9% 15% 12.2% 10% 5% 3.6% 1.3% 1.4% 0% <300 >300 - 103> 103 - 104>104 - 106 ≥106 Baseline HBV DNA (copies/mL)Chen JC, et al. JAMA. 2006;295:65-73.
  • 11. HBV Indications for HBV vaccination • HBIG and HB vaccine to infants of HBsAg+ mothers • Routine vaccination of infants and adolescents • Catch-up vaccination of children • Vaccination of adults at risk of infection
  • 12. HBV Treatments 2012 Interferon or 5 oral agentsAdefovir Interferon Lamivudine Pegylated IFN Telbivudine Entecavir TenofovirPros • Finite duration of • Oral • Oral therapy • Negligible side • Effective against • Durable response effects lamivudine-resistant post treatment mutants • Resistant mutants • Resistant mutants not not reported reported at 1 yearCons • Injection • Long / indefinite • Long / indefinite duration of duration of therapy • Frequent side therapy effects • Long-term renal • Resistant mutants toxicity unknown • Higher with lamivudine/telbivudine
  • 13. Surrogate Clinical Markers for Hepatitis B OutcomesLiver histology Improves Serum HBV DNA declines Prevention of Death, Cirrhosis, and HCC Seroconversion (loss of HBeAg, ALT normalization production of anti-HBe)
  • 14. Cirrhosis Reversal Following Lamivudine Rx in HBV Courtesy of Ian Wanless, MD.
  • 15. Suggested Management of HBV Infection During Pregnancy HBsAg Positive Yes HBV DNA HBV DNA >108 Copies/mL <108 Copies/mL ** Refer for consideration for treatment with Lamivudine, Tenofovir DF, or Telbivudine at Week 32 Infant Receives HBIG + HBV Vaccine at Birth**May consider treatment if previous child HBV positiveTran TT. Cleve Clin J Med. 2009;76(suppl 3):S25-9.
  • 16. HBV Reactivation with chemotherapy/immunosuppression• HBV reactivation is common after immune suppression, can be clinically severe, and result in death from acute liver failure or progressive liver disease and cirrhosis• Screen for HBsAg and anti-HBc in all patients undergoing cancer chemotherapy, marked immunosuppressive treatment, or solid organ or bone marrow transplantation• Prophylaxis against HBV reactivation • Chemotherapy • Continue HBV prophylaxis for >6 months after stopping chemotherapy • Prolonged immunosuppressive therapy • Consider long-term HBV prophylaxis with an antiviral with a high genetic barrier to resistance (tenofovir DF, entecavir)Hoofnagle JH. Hepatology. 2009;49(5 suppl):S156-S165.Hollinger FB, et al. J Viral Hepat. 2010;17:1-15.
  • 17. Proposed Algorithm for Patients Exposed to HBV Prior to ChemotherapyLubel JS, et al. J Gastroentrol Hepatol. 2010;25:865-871.
  • 18. Bottom Line: When to Start Therapy: 1) Elevated HBV DNA Level 2) ALT Level above ULNThe Threshold and Guidelines for treating HBV arefalling and dynamic
  • 19. Hepatitis C: A Global Health Problem 170-200 Million Carriers Worldwide Far East Asia Eastern 60 M Western Europe Europe US 5M 10 M 3-4 M South East Asia Africa 30-35 M Americas 12-15 M 30-40 M Australia 0.2 M World Health Organization, 1999.
  • 20. Cirrhosis Due to HCV Expected to Peak Over the Next Decade 25% 1,200,000 of patients with HCV currently have cirrhosis 1,000,000 Number of Patients 800,000 600,000 37% 400,000 of patients with HCV are projected to develop cirrhosis by 200,000 2020, peaking at 1 million 1990 2000 2010 2020 2030 YearAdapted from Davis GL, et al. Gastroenterology. 2010;138:513-521.
  • 21. HCV Is Nearly 4 Times as Prevalent as HIV and HBV 4,000,000 ~2.7-3.9 M 3,000,000 Diagnosed Undiagnosed Infected Number Undiagnosed Diagnosed 2,000,000 1.1 M ~0.8-1.4 M 1,000,000 0 HIV HBV HCVHBV=hepatitis B virus.HCV=hepatitis C virus.HIV=human immunodeficiency virus.Institute of Medicine. Hepatitis and Liver Cancer: A National Strategy for Prevention and Control of Hepatitis B and C. 2010.Available at: http://books.nap.edu/openbook.php?record_id=12793&page=23. Accessed April 7, 2011.
  • 22. Risk Factors for Acute Hepatitis C United States, 1991-1995 Injection Drug Use 43.0% Other High Risk* 30.0%*Other High Risk Unknown 1.0% Household 3.0% 16% drug related •11% previous drug use Occupational 4.0% not within last 6 months • 5% intranasal cocaine use Transfusion** 4.0% 4% history of STDs **None in 1995 1% prison Sexual (Multiple Partners) 15.0% 9% lower socio-economic status (fewer years of education) Alter MJ. Presented at the NIH Consensus Development Conference, March 24, 1997.
  • 23. HCV Genotypes and Subtypes Developed countries 2 Americas + Western Europe South Africa 5 1Middle EastNorth Africa 4 IVDU Asia 3 Simmonds P, Journal of Hepatology, 1999 6
  • 24. Chronic HCV Infection HCV RNA 1000 + + + + + + + + + + + + + 800 ALT (U/L) Anti-HCV 600 Chronic 400 Symptoms Hepatitis C 200 0 0 2 4 6 8 10 12 24 1 2 3 4 5 6 Weeks Months Time After ExposureHoofnagle JH. Hepatology.1997;26:15S-20S.
  • 25. Why Do We Treat Chronic HCV? 1000 HCC 800 4+ ALT 3+ 2+ ALT (U/L) 1+ 600 Fibrosis Cirrhosis Anti-HCV 400 HCV RNA 200 0 0 0.5 1 2 5 10 15 20 25 30 35 40 45 50 Years After ExposureHoofnagle JH. Hepatology 2002;36:S21-S29.
  • 26. HCV Is “Curable” Long-Term, Follow-Up Studies IFN IFN alfa-2a IFN alfa-2b Number of patients 997 492 Average follow-up 4.1 years 5.6 years Undetectable HCV RNA 989 (99.2%) 487 (99.0%) Relapse 9 5 Time of relapse 2 years (1.1-2.9) <2 yearsMcHutchison JG, et al. EASL. 2006. Abstract 744.Swain MG, et al. J Hepatol. 2007;46(Suppl 1):S3. Abstract 1.
  • 27. A Polymorphism on Chromosome 19 Predicts SVR 60 Mb IL28B gene IFN Lambda-3 gene 3 kb 19q13.13 Polymorphism rs12979860 Chromosome 19Ge D, et al. Nature. 2009;461:399-401.Chromosome 19 graphic courtesy of Oak Ridge National Laboratory. Available at:http://www.ornl.gov/sci/techresources/meetings/ecr2/olsen.gif. Accessed on: October 21, 2009.
  • 28. IL-28 CC allele is associated with SVR Ge et al, Nature, 2009
  • 29. 2 Protease Inhibitors Approved for Genotype 1 HCV Infection Protease Inhibitor Additional Regimen Considerations Components Boceprevir 800 mg TID PegIFN alfa  Naive to previous therapy (q7-9hrs)[1,2] +  Previous treatment failure weight-based RBV  Compensated cirrhosis  RGT Telaprevir 750 mg TID PegIFN alfa  Naive to previous therapy (q7-9hrs)[2,3] +  Previous treatment failure weight-based RBV  Compensated cirrhosis  RGT For patients with genotype 2/3 infection, HCV therapy with pegIFN/RBV remains the standard of care1. Boceprevir [package insert]. 2011. 2. Ghany MG, et al. Hepatology. 2011;54:1433-1444.3. Telaprevir [package insert]. 2011.
  • 30. Clinical Pharmacology and Drug Interactions• Boceprevir • Strong inhibitor of CYP3A4/5 • Partly metabolized by CYP3A4/5 • Potential inhibitor of and substrate for P-gp• Telaprevir • Substrate of CYP3A • Inhibitor of CYP3A • Substrate of P-gp• Must perform DDI survey or work with clinic pharmacology• http://www.hep-druginteractions.org/ P-gp = p-glycoprotein Boceprevir capsules [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.; 2011. Telaprevir tablets [package insert]. Cambridge, MA: Vertex Pharmaceuticals Incorporated; 2011.
  • 31. Telaprevir + PegIFN/RBV: Genotype 1 Treatment-Naive Patients Dosage and Administration • 750 mg (two 375-mg tablets) TID (every 7-9 hrs) with food (standard fat meal 20 g,)eg, ½ cup nuts or 2 oz cheddar cheese) • Must be administered with both pegIFN and RBV • Telaprevir dose must not be reduced or interrupted eRVR; stop at Wk 24/ f/u F/u TVR + PegIFN + RBV PegIFN + RBV 24 No eRVR; PegIFN + RBV wks 0 4 12 24 48 Wks Week 4 HCV RNA Week 12 HCV RNA Week 24 HCV RNAFutility > 1000 IU/ml > 1000 IU/ml detectable Treatment duration • Patients with extended RVR (eRVR, undetectable* HCV RNA at Week 4 and 12) receive 24 wks of therapy • Patients without eRVR continue on pegIFN + RBV for a total of 48 wks • Treatment-naive patients with compensated cirrhosis and eRVR may benefit from additionalTelaprevir package insert. pegIFN + RBV (ie, to Week 48) 36 wks of May 2011. *Assay should have a lower limit of HCV RNA quantification ≤ 25 IU/mL.
  • 32. What can we tell our patients? Significantly Higher SVR rates in Telaprevir-Treated Patients Compared to Peg IFN/Ribavirin Alone T12PR PR 100 P<0.0001 90 80 75 Percent of patients 70 60 50 44 40 with SVR 30 20 10 0 n/N = 271/363 158/361 SVRJacobson IM, et al. Hepatology 2010;52(Suppl 1):Abstract 211.
  • 33. REALIZE: SVR in Prior Relapsers, Prior Partial Responders and Prior Null Responders Prior Prior partial Prior null relapsers * responders responders * * SVR (%) * * * T12/ LI T12/ Pbo/ T12/ LI T12/ Pbo/ T12/ LI T12/ Pbo/ PR48 PR48 PR48 PR48 PR48 PR48 PR48 PR48 PR48 n/N= 121/145 124/141 16/68 29/49 26/48 4/27 21/72 25/75 2/37 *p<0.001 vs Pbo/PR48
  • 34. Telaprevir: Rash• Patients treated with telaprevir • Rash reported in 56% of subjects (vs 34% with PR48); 4% severe • Typically eczematous, maculopapular, and papular-lichenoid • In most subjects, the rash was mild-moderate • Rash events resulted in discontinuation of TVR in 6% of subjects • Occurred early, usually within first 4 weeks, but can occur at anytime • < 1% Stevens Johnson Syndrome or DRESS• Mechanism of rash remains unknown; however, pyrazinoic acid is a major metabolite of TVR & may contribute to rash/pruritus • Structural analog of niacin• Improvement occurs after dosing completion or D/C; may take weeks for complete resolutionAdvisory Committee Briefing Document for NDA 201-917 Telaprevir 375 mg tablets. Silver Spring, MD; April 1, 2011.http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AntiviralDrugsAdvisoryCommittee/UCM252561.pdf. Accessed April 26, 2011.Telaprevir tablets [package insert]. Cambridge, MA: Vertex Pharmaceuticals Incorporated; 2011.
  • 35. Stevens-Johnson Syndrome(SJS)/Drug rash with eosinophilia and systemic symptoms (DRESS)• SJS: Fever, target lesions, mucosal erosions/ulcerations• Drug rash with eosinophilia and systemic symptoms • Rash, fever, facial edema, internal organ involvement • ±eosinophilia• Stop all medicines• Urgent Dermatology referral
  • 36. Gastrointestinal Side effects• Nausea: Promethazine, ondansetron• Telaprevir should be taken with 20 grams of fat to help with absorption• Perianal symptoms • Anal Pruritus with telaprevir: antihistamines • Topical therapies: Witch hazel topical, hydrocortisone cream, mesalamine suppositories• Diarrhea: loperamide, Bulk/fiber supplement 36
  • 37. Telaprevir: Anemia • Mechanism of anemia thought to be result of bone marrow suppressive effect associated with telaprevir, not RBC hemolysis • Patients treated with telaprevir had • A higher frequency of anemia, hemoglobin level < 10 g/dL (36% vs 17%) • A higher frequency of hemoglobin reductions to Grade 3 or higher toxicity (7.0 to < 8.9 g/dL or any decrease > 4.5 m/dL) levels (55% vs 25%) • A higher frequency of hemoglobin level < 8.5 g/dL (14% vs 5%) • More anemia-related SAEs (2.5% vs < 1%) • A higher frequency of anemia-related discontinuations (4% vs < 1%)Telaprevir tablets [package insert]. Cambridge, MA: Vertex Pharmaceuticals Incorporated; 2011.Advisory Committee Briefing Document for NDA 201-917 Telaprevir 375 mg tablets. Silver Spring, MD; April 1, 2011.http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AntiviralDrugsAdvisoryCommittee/UCM252561.pdf. Accessed April 26, 2011.
  • 38. Boceprevir for genotype 1 naïve HCV Milestones: Weeks 8, 12, 24 Week 4 Week 28 Week 48 Week 72 TW 8-24 HCV-RNA Undetectable* Follow-up PR PR + BOC (24 weeks) lead-in Non-cirrhotic Week 36 PR+BOC (32 weeks) PR Follow-up Week 12 Week 24 TW 8 HCV-RNA Detectable/ TW 24 undetectable PR PR + BOC (44) weeks for cirrhotic patients/ Follow-up lead-in poorly responsive pts Week 12 Futility Week 24 Futility HCV > 100 IU/ml Detectable HCV RNA*assay should have a lower limit of HCV-RNA quantification < 25 IU/mL, and limit of HCV-RNAdetection of approximately 10-15 IU/mL
  • 39. SPRINT 2: SVR* and Relapse Rates SVR Relapse Rate p <0.0001 p =0.004 p < 0.0001 100 100 p = 0.044 80 67 68 80 60 60 53 Percent 211 213Percent 40 316 311 42 40 40 29 125 23 23 22 55 311 14 52 12 17 20 37 9 8 20 12 6 162 21 18 52 2 3 35 0 232 230 0 14 25 48 P/R BOC RGT BOC/PR48 48 P/R BOC RGT BOC/PR48 Non-Black Patients Black Patients*SVR was defined as undetectable HCV RNA at the end of the follow-up period. The 12-week post-treatment HCV RNA level was used if the 24-week post-treatmentlevel was missing (as specified in the protocol). A sensitivity analysis was performed counting only patients with undetectable HCV RNA documented at 24 weekspost-treatment and the SVR rates for Arms 1, 2 and 3 in Cohort 1 were 39%, 66% and 68%, respectively and in Cohort 2 were 21%, 42% and 51%, respectively.
  • 40. SVR by Historical Response Non-responders and Relapsers* Arm 1: Arm 2: Arm 3: 48 P/R BOC RGT BOC/PR48 N = 80 N = 162 N = 161Non-responder – 2/29 (6.9) 23/57 (40.4) 30/58 (51.7)n/n (%)Relapser 15/51 (29.4) 72/105 (68.6) 77/103 (74.8)– n/n (%)*Non-responders had a decrease in plasma HCV-RNA of at least 2-log10 by week12 of prior therapy but with detectable HCV-RNA throughout the course oftherapy. Relapsers had undetectable HCV-RNA at end of prior therapy withoutsubsequent attainment of a sustained virologic response.
  • 41. SVR and Relapse† Rates, 100 by Prior Treatment Response 90 80 68 % of Patients 70 60 56 50 40 40 30 20 14 15 17 10 19/47 53/78 5/9 3/22 9/62 1/6 0 SVR Relapse Nulls Partials Relapsers • SVR was also achieved in all 4 patients with ‘other’ prior non-response. • Overall, 81 of 138 patients (59%) achieved SVR.SVR rates if lead-in dropouts included: nulls 38% (19/50), partials 68% (53/78), relapsers 50% (5/10), overall 57% (81/142).† denominator for relapse rate = patients with undetectable HCV RNA at EOT and not missing end of follow-up data. 41
  • 42. Results – Primary and Key Efficacy End Points • End-of-treatment response, relapse, and SVR were comparable between RBV DR and EPO arms ∆ (95% CI) –0.7% (– 8.6 , 7.2)* Patients, % 203/249 205/251 178/249 178/251 19/196 19/197CI, confidence interval; DR, dose reduction; EOT, end of treatment; EPO, erythropoietin; RBV, ribavirin;SVR, sustained virologic response.*The stratum-adjusted difference (EPO vs RBV DR) in SVR rates, adjusted for stratification factors and protocol cohort.
  • 43. Anemia Management Recommendations With TVR or BOC-based Therapy• Monitoring: CBC pretreatment, every 2 weeks until treatment week 8, then monthly• Primary strategy: RBV dose reduction • BOC—Hgb < 10 g/dL: decrease in dosage or interruption of RBV is recommended • TVR—If anemia occurs, use RBV dose reductions; if inadequate, consider D/C TVR• Hgb < 8.5 g/dL: discontinue all therapy• If RBV is permanently D/C, BOC or TVR also must be D/C• Do not reduce PI dose to manage anemia• Once RBV dose reduction has been tried, erythropoietin can be consideredPeginterferon alfa-2a Solution for Subcutaneous Injection [package insert]. South San Francisco, CA: Genentech, Inc.; 2011. Peginterferonalfa-2b Injection, Powder for Solution for Subcutaneous Use [package insert]. Kenilworth, NJ: Schering Corporation; 2011. Boceprevir capsules [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.; 2011. Telaprevir tablets [package insert]. Cambridge, MA: Vertex Pharmaceuticals Incorporated; 2011.
  • 44. Boceprevir Plus Peginterferon/Ribavirin for the Treatment of HCV/HIV Co-Infected Patients: End of Treatment (Week 48) Interim ResultsJ Mallolas1, S Pol2, A Rivero3, H Fainboim4, C Cooper5, J Slim6, S Thompson7, J Wahl7, W Greaves7, M Sulkowski8 1 Hospital Clinic-University of Barcelona, Barcelona, Spain; 2Universite Paris Descartes, APHP, Hopital Cochin, Paris, France; 3University Hospital Reina Sofia, Córdoba, Spain,4 Muñiz Hospital, Buenos Aires, Argentina; 5University of Ottawa, Ottawa, ON, Canada; 6Saint Michaels Medical Center, Newark, NJ; 7Merck Sharp & Dohme, Whitehouse Station, NJ; 8 John Hopkins University School of Medicine, Baltimore, MD. Abstract #366 International Liver Congress 2012 47 Annual Meeting of the European Association for the Study of the Liver th Barcelona, Spain April 20, 2012
  • 45. Virologic Response Over Time† 100 PR B/PR 80 73.4Undetectable% HCV RNA 65.6 59.4 60.7 60 42.2 40 32.4 29.4 26.5 23.5 20 14.7 8.8 4.7 3/34 3/64 5/34 27/64 8/34 38/64 11/34 47/64 10/34 42/64 9/34 37/61 0 4 8 12 24 EOT SVR12 Treatment Week † Three patients undetectable at FW4 have not yet reached FW12 and were not included in SVR12 analysis. 45 45
  • 46. Telaprevir in Combination withPeginterferon Alfa-2a/Ribavirin in HCV/HIV Co-infected Patients: SVR12 Interim Analysis Douglas T. Dieterich1, Vincent Soriano2, Kenneth E. Sherman3, Pierre-Marie Girard4, Jurgen K. Rockstroh5, Joshua Henshaw6, RaymondRubin6, Mohammad Bsharat6, Nathalie Adda6, Mark S. Sulkowski7 On behalf of the Study 110 Team 1Mount Sinai School of Medicine, New York, NY, United States, 2Hospital Carlos III, Madrid, Spain, 3University of Cincinnati College of Medicine,Cincinnati, OH, United States, 4Hopital St Antoine, Paris, France, 5Universityof Bonn, Bonn, Germany, 6Vertex Pharmaceuticals Incorporated, Cambridge, MA, United States, and 7Johns Hopkins University School of Medicine, Baltimore, MD, United States. 46
  • 47. 47
  • 48. Evolving Treatment Landscape of Direct Acting Anti-viral agents (DAAs) …it is busy DAA combinations Preclinical Nuc- Gilead Polymerase Phase I BI inhibitors Roche Japan Tobacco R0622 (Roche) Vertex Phase II Medivir (Tibotec) Others R7128 BMS/Pharmasset (Roche/Pharmasset) GL59393 (GSK) Nitazoxanide (Romark) Phase III PSI938(Pharmasset) PSI-7977 Biocryst INF lambada (Zymogen / Taribavirin (Valeant) (Pharmasset) NovoNordisk Approved DEB025 cyclophilins INX189 (Inhibitex) IDX-184 (Idenix) Telaprevir Boceprevir (MSD) BMS-791325 (nuc/non-nuc BMS)) MSD BMS790052 NSSA (BMS) (J&J/Vertex) AZD07259 NSSA (AZN) GS9190 (Gilead) ABT33. ABT7072 Idenix TMC435 (ABT) (J&J/Tobizer) ANA598 (Anadys) GSK Presidio BI201335 (BI) IDX375 VX222 (Vertex) (Idenix/NVS) BMS824393 NS5A NSSA (BMS) BMS650032 (BMS) inhibitor Enanta BI201127 (BI) GS9256 (Gilead) Non Nuc- Vertex MK7009 (MSD) ITMN-191/R7227 Polymerase (Roche/Intermune) MK5172 (MSD) inhibitors ACH1625 ABT450 (ABT) (Achillion) Protease inhibitors
  • 49. DAAs - Key CharacteristicsNS3 /4A Inhibitors (Protease inhbitorP I) NS5B Nucleos(t)ide Inhibitors (NI)High potency Intermediate potencyLimited genotypic coverage Pan genotypic coverageLow barrier to resistance High barrier to resistanceNS5A Inhibitors NS5B Non Nucleoside Inhibitors (NNI)High potency Intermediate potencyMulti-genotypic coverage Limited genotypic coverageIntermediate barrier to resistance Low barrier to resistance 49
  • 50. BMS-790052 (NS5A inhibitor) + BMS-650032 (PI) ± PR in G1 null responders: phase IIa study BMS-790052 60 mg qd plus BMS-650032 600 mg bid no cirrhotics, N=21 responder to PR, CHC, G1, null BMS-790052 60 mg qd + BMS-650032 600 mg bid plus PR 0 Study weeks 24 RandomisationNull response defined as <2 log10 decline in HCV RNA following12 weeks of treatment with PR Lok A, et al. EASL 2011, oral
  • 51. Virologic Response before and after treatment 100 100* 100 90 46 46 36 36•Group A: 4(2/9 GT1a and 2/2 GT1b) patients achieved SVR12 and SVR24•Group B; 10/10 achieved SVR12 and 9 had SVR24 •1 patient had HCVRNA<LLQ at post treatment week 24, and undetectable 35 d later
  • 52. 52
  • 53. 53
  • 54. PROTONPSI-7977 is a Potent and Specific Nucleotide Analog Polymerase Inhibitor for HCV PSI-7977Antiviral activity (IC50 0.7-2.6 µM GT1b, GT3a,GT4a) with broad HCV genotype coverageOnce-daily dosingHigh barrier to resistance: To date, no virologicbreakthrough during 12+ weeks of PSI-7977 QDGenerally safe and well tolerated in clinical studies to dateLow potential for drug-drug interactions
  • 55. Background • GS-7977 (formerly PSI-7977) is a specific nucleotide analog inhibitor of HCV NS5B • Safe and well-tolerated in clinical studies • Once-daily, with or without food • Potent antiviral activity with broad HCV genotype coverage with or without IFN in treatment-naïve patients • ELECTRON genotype 2/3: 100% SVR1 • ELECTRON genotype 1: 100% RVR2 • PROTON genotype 1: 91% SVR3 • PROTON genotype 2/3: 94% SVR4• High barrier to resistance1 Gane E, et al. AASLD 2011; 2Gane E, et al. CROI; 3Lawitz E, et al. AASLD 2011; 4Lalezari J, et al. EASL 2011.
  • 56. Atomic Study Design Day 1 Wk Wk 24 12 Group A GS-7977 + PEG + GT 1 N = 52 RBV Group B GS-7977 + PEG + RBV GT 1, 4, 6 N = 125* Group C GS-7977 + PEG + GS-7977 (n = 75) GS-7977 + RBV (n = GT 1 N = 155† RBV 75)♦ Patients with HCV genotype 1 were randomized 1:2:3 into 1 of 3 open-label arms♦ Stratified by: • IL28B genotype (CC vs non-CC) • HCV RNA at screening (≤ vs >800,000 IU/mL)♦ HCV RNA analyzed by TaqMan® HCV Test 2.0 (LOD: 15 IU/mL) *Of the 125 patients enrolled in Arm B, 16 were genotype 4 or 6 † 5 of the 155 patients were not re-randomized at Week 12
  • 57. 90% of Patients Achieved SVR12: GS-7977 + PEG/RBV 12-Week Regimen% Patients 7977+P/R 7977+P/R 7977+P/R 0 12 Wks 24 Wks 12+12 Wks 0 14 42 70 8 126 14 • 94% of patients in Arm A who reached follow up Week 12 were <LOD
  • 58. Electron Study Design
  • 59. PSI-7977 ELECTRON Study Design for HCV GT2/3  Treatment-naïve, non-cirrhotic, age ≥18 years  HCV RNA >50,000 IU/mL  Allowed concurrent methadone use  Stratified by HCV genotype and IL28Β genotype  Randomized 1:1:1:1 into IFN-sparing or IFN-free Wk 0 4 8 12 24n=10 PSI-7977 + RBV + Peg-IFN SVRn=10 PSI-7977 +RBV + Peg-IFN PSI-7977 + RBV PSI-7977 + RBV 12 SVRn=10 PSI-7977+RBV+Peg-IFN PSI-7977 + RBV PSI-7977 + RBV 12 SVRn=10 PSI-7977 + RBV PSI-7977 + RBV 12 SVR 12
  • 60. PSI-7977 ELECTRON IFN-free PSI-7977/RBV  100% SVR12Time PSI-7977 PSI-7977 PSI-7977 PSI-7977 Wk RBV RBV RBV RBV 12 weeks PEG 8 weeks PEG 4 weeks PEG NO PEG n %<LOD n %<LOD n %<LOD n %<LOD 2 9/11 82 7/8 88 8/9 89 8/10 80 4 11/11 100 10/10 100 9/9 100 10/10 100 8 11/11 100 10/10 100 9/9 100 10/10 100 12 11/11 100 10/10 100 9/9 100 10/10 100SVR4 11/11 100 10/10 100 9/9 100 10/10 100SVR8 11/11 100 10/10 100 9/9 100 10/10 100SVR12 11/11 100 10/10 100 9/9 100 10/10 100
  • 61. On Treatment Viral Suppression
  • 62. M12-267 Study Design 12 Weeks (On Treatment) Follow Up Period†Treatment-naïve (N=11) ABT-450/r 150/100 mg QD + ABT-072 400 mg QD + RBV* † All subjects followed for 48 weeks after end of treatment *Weight-based ribavirin 1000-1200mg/day Registered with ClinicalTrials.gov as NCT01221298
  • 63. Virologic Results Based on Assay Lower Limit of Quantitation (LLOQ)
  • 64. Co-Pilot (M12-746) Study Design 12 Weeks (On Treatment) Follow Up Period†Arm 1 ABT-450/r 250/100 mg QD +Treatment-naïve (N=19) ABT-333 400 mg BID + RBV*Arm 2 ABT-450/r 150/100 mg QD +Treatment-naïve (N=14) ABT-333 400 mg BID + RBV*Arm 3 ABT-450/r 150/100 mg QD +Prior P/R non- ABT-333 400 mg BID + RBV*responders (N=17) † All subjects followed for 48 weeks after end of treatment *Weight-based ribavirin 1000-1200mg/day Registered with ClinicalTrials.gov as NCT01306617
  • 65. Virologic Results by Treatment Arm based on Assay Limit of Detection (LLOD)eRVR: pre-specified primary analysis based on HCV RNA < LLOD
  • 66. SVR12 in Subgroups of Arm 3 (Prior Non- Responders)
  • 67. Evolution of Therapy in HCV Genotype 1 1990 1999 2001 2011 2015 100 ? 80 60SVR (%) 100 40 75 60 20 40 25 10 15 0 2 IFN IFN PEG/R/PI IFN/RBV IFN/RBV PEG/RBV All Oral 6m 12m 12m 6-12m 6m 12m DAA 12-24 weeks
  • 68. A Randomized, Placebo-Controlled Trial of Oral Silymarin (Milk Thistle) For Chronic Hepatitis C: Final Results of the SYNCH Multicenter Study M.W. Fried, V.J. Navarro, N.H. Afdhal, S.H. Belle, A.S. Wahed, R.L. Hawke, E.C. Doo, C.M. Meyers, K.R. Reddy for the SYNCH Study Group University of North Carolina, Thomas Jefferson University, Beth Israel Deaconess Medical Center, University of Pittsburgh, NIDDK, NIH, NCCAM, NIH, University of Pennsylvania This study was funded by NIH NCCAM and NIDDK
  • 69. Silymarin for Hepatitis C ITT Analysis of Primary EndpointsEndpoint Placebo Silymarin Silymarin p-value 420 mg 700mg (n=52) (n=50) (n=52)ALT < 45 IU 1 (1.9%) 2 (4%) 2 (4%) 0.8Serum ALT decline of 2 (3.8%) 1 (2%) 2 (3.8%) 0.8at least 50% to < 65 IU Either of the above 2 (3.8%) 2 (4%) 2 (3.8%) 1.0
  • 70. Silymarin for Hepatitis C Analysis of Secondary EndpointsEndpoint* Placebo Silymarin Silymarin p-value 420 mg 700 mgChange in ALT (IU/L) -4.3 -14.4 -11.3 0.75Change in HCV RNA (log10 0.07 -0.03 0.04 0.54IU)Changes in Quality of Life CESD score -0.26 -0.73 -0.41 (12.5)M8 0.97 SF36 (Physical) -0.69 -2.86 -0.27 0.18 SF36 (Mental) 0.24 0.35 -0.90 0.68 Chronic Liver Disease 0.12 -0.10 -0.03 0.26Questionnaire (CLDQ)* Data provided as mean values
  • 71. Will Hepatitis C Therapy Parallel Helicobacter pylori Therapy?H pylori HCV All Oral Therapy Duration 12-24 weeks Polymerase Inhibitor All Oral Therapy, ± single tablet Protease Inhibitor ± NS5a ± Cyclophylin Inhibitor ± ribavirin
  • 72. What I Tell Patients Regarding Treatment of Hepatitis C• HCV can be cured in 3/4ths of all cases• Therapy is evolving: about ½ of all genotype 1 individuals will can be treated with 6 months of therapy• Genotype 2/3 still has SVR rates of >75% with peg interferon/ribaviirn• IL-28 CC genotype will identify those who can be treated for shorter duration• Silymarin …don’t bother• Have a patient interested in a study?• Email : pkwo@iupui.edu or you may call (317) 278- 4633 or email pasparks@iupui.edu