The Scope of The Problem US Prevalence: 1.8% are chronically infected with Hepatitis C virus (HCV)

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1 The Scope of The Problem US Prevalence: 1.8% are chronically infected with Hepatitis C virus (HCV) World Health Organization. Hepatitis C: Fact Sheet. June 211. Numb ber infected Hepatitis C is Underdiagnosed in US 4,, Undiagnosed Diagnosed 3,, ~75% 2 2,, 1,, ~21% HIV ~65% HBV HCV HIV=human immunodeficiency virus; HBV=hepatitis B virus; HCV=hepatitis C virus Institute of Medicine. Hepatitis and Liver Cancer: A National Strategy for Prevention and Control of Hepatitis B and C; 21. 1

2 Chronic Hepatitis C Infection in US (many populations not accounted for in surveillance studies) >5.2 million living with chronic HCV in US Prevalence: 1.8% Chronic HCV cases not included in NHANES estimate Homeless (n=142, ,61) Incarcerated (n= , ,826) Veterans (n=1,237,461-2,452,6) Active military (n=685) Healthcare workers (n=64,89-259,234) Nursing home residents (n=63,69) Chronic hemodialysis (n=2,578) Hemophiliacs (n=12,971-17,) Chak E, et al. Liver Int. 211;31: Number of Cases (in millions) Estimated Hepatitis C Cases Total 7.1 Conservative estimate Upper limit of estimate Not Included in NHANES 3.2 NHANES Hepatitis C-Related Cirrhosis Is Projected to Peak Over Next 1 Years Number of pat tients 1,2, 1,, 8, 6, 4, 2, 25% of patients with HCV currently have cirrhosis 37% of patients with HCV are projected to develop cirrhosis by 22, peaking at 1 million Year Davis GL, et al. Gastroenterology. 21;138: Annual Age-adjusted Mortality Rates from HBV, HCV, and HIV Rate per 1 Persons Ly KN, et al. Ann Intern Med. 212;156(4): Year 2

3 CDC HCV Testing Recommendations 1998: Ever injected illegal drugs Received clotting factors made before 1987 Received blood/organs before July 1992 Ever on chronic hemodialysis Evidence of liver disease (elevated ALT) Infants born to HCV-infected mothers HIV infection 212: Adults born receive 1-time HCV testing All persons with HCV infection: brief alcohol screening/intervention as appropriate, referral to treatment services CDC. MMWR Recomm Rep. 1998;47(RR-19)1-39. Smith BD, et al. MMWR Morb Mortal Wkly Rep. 212;61:1-32. HCV Infection Testing Algorithm REACTIVE (+) ANTI-HCV Point-of-care immunoassay (Rapid Test) or Bench immunoassay (EIA, CIA, MEIA, CMIA) NEGATIVE (-)* NAT for HCV RNA NEGATIVE (-) STOP ~POSITIVE (+) Active / Current HCV infection Refer to Care and Treatment * If immunocompromised status or acute infection is suspected, test for HCV RNA. If ongoing risk factors eg, injecting drug use or other recent exposures) repeat anti-hcv testing >6 months after most recent exposure Adapted from: Hepatitis C Virus (HCV) Infection Testing for Diagnosis. Available at: Accessed November 6, 212. Genotype and Viral Load in US Patients Genotype 4,5,6 High Genotype 4,5,6 Viral Load Low Viral Load 2.7% 1.3% Genotype 2,3 Low Viral Load 7.3% Genotype 2,3 HVL 14.7% Genotype 1 HVL 49.5% Genotype 1 LVL 24.5% Alter MJ, et al. N Engl J Med. 1999;341; Blatt LM, et al. J Viral Hepatitis. 2;7:

4 Why Do We Treat Chronic HCV? Majority of those infected develop chronic disease (U/L) ALT Fibrosis 4+ HCC Cirrhosis ALT 4 2 Anti-HCV HCV RNA Years After Exposure Hoofnagle JH. Hepatology. 22;36:S21-S29. HCC: Hepatocellular carcinoma SVR = CURE Sustained virological response (SVR): undetectable HCV RNA measured by PCR 24 weeks after therapy. Durable: HCV negative 99.2% of 1343 patients after 4.1 years. 1 1% in 433 patients after 18 years. 2 Slows and even reverses hepatic fibrosis. Improved morbidity and mortality with SVR. SVR with cirrhosis: less ascites, encephalopathy, variceal bleeding, hepatocellular carcinoma, and transplantation. 1. Swain MG, et al. Gastroenterology. 21;139: Maylin S, et al. Gastroenterology. 28;135: Two (2) Protease Inhibitors Approved for Genotype 1 (G1) HCV Infection Protease Inhibitor Boceprevir 8 mg TID (q7-9hrs) [1,2] Telaprevir 75 mg TID (q7-9hrs) [2,3] Additional Regimen Components PegIFN alfa + weight-based RBV PegIFN alfa + weight-based RBV Considerations Naive to previous therapy Previous treatment failure Compensated cirrhosis RGT Naive to previous therapy Previous treatment failure Compensated cirrhosis RGT For patients with genotype 2/3 infection, HCV therapy with PegIFN/RBV (PR) remains the standard of care RGT: response-guided therapy 1. Boceprevir [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.; Ghany MG, et al. Hepatology. 211;54: Telaprevir [package insert]. Cambridge, MA: Vertex Pharmaceuticals Incorporated;

5 Data to Assemble Prior to Referring for Treatment HCV genotype 1a/1b Quantitative viral level IL-28B genotype Previous viral kinetics if non-responder IL-28B not as helpful with accurate viral kinetics Fibrosis assessment Liver imaging Concomitant medicines/drug-drug interaction query Management plan for side effects Rash, anemia, GI side effects Set expectations with patients Time for approval, compliance A Polymorphism on Chromosome 19 Predicts SVR: IL-28B 6 Mb 6 19q13.13 IL-28B gene IFN Lambda-3 gene 3 kb Polymorphism rs Chromosome 19 Ge D, et al. Nature. 29;461: IL-28B CC Genotype Associated With SVR Used with permission. Ge D, et al. Nature. 29;461:

6 Fibrosis Assessment: Very Important in This Transition Era To treat or not to treat Efficacy of new therapies largely determined by PR responsiveness Achieving SVR in cirrhotic HCV patients is highly beneficial Preliminary data with new oral therapies shows higher efficacy/shorter duration/less side effects Limited data in cirrhosis patients Prognosis Cirrhotic patients require regular screening for hepatocellular carcinoma, varices, other complications Fibrosis Tests Available in 213 Liver biopsy: Gold standard Imaging of the liver: Axial CT/MRI, US can demonstrate cirrhotic morphology, portal hypertension Serum Markers of Fibrosis: FIBROSpect, FibroSURE, APRI, FIB-4 Elastography: Available at limited US centers AASLD Guideline Liver biopsy should be considered if more information is desired for prognostic purposes or to make a decision regarding treatment Currently available noninvasive tests may be useful in defining presence or absence of advanced fibrosis, but should not replace liver biopsy in routine clinical practice Ghany MG, et al. Hepatology. 29;49: Factors Predictive of Response to PR-based Therapy Genotype 2/3 No advanced fibrosis Low viral load Younger age <4 years Female Weight Lack of steatosis/insulin resistance Adherence Rapid viral response (RVR) Ribavirin dosage Race/ethnicity IL-28B Anemia 211-present Race/ethnicity Low viral load Absence of cirrhosis Statin use IL-28B Genotype 1a/1b On treatment viral response Lead-in ervr McHutchison JG, et al. N Engl J Med. 29;361(6): Manns MP, et al. Lancet. 21;358(9286): Patton HM, et al. J Hepatol. 24;4(3): Poynard T, et al. Lancet. 1998;352(9138):

7 Clinical Pharmacology and Drug Interactions Boceprevir (BOC) Strong inhibitor of CYP3A4/5 Partly metabolized by CYP3A4/5 Potential inhibitor of and substrate for P-gp Telaprevir (TVR) Substrate of CYP3A Inhibitor of CYP3A Substrate of P-gp Must perform DDI survey or work with clinic pharmacology P-gp = p-glycoprotein Boceprevir [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.; 211. Telaprevir [package insert]. Cambridge, MA: Vertex Pharmaceuticals Incorporated; 211. AASLD Guidelines for HCV Therapy Age 18, and HCV RNA positive, and Liver biopsy showing chronic hepatitis with significant fibrosis (bridging fibrosis or higher), and Compensated liver disease (total serum bilirubin <15 g/dl; INR 1.5; serum albumin >3.4; platelet count 75 mm and no evidence of hepatic decompensation (hepatic encephalopathy and ascites), and Acceptable hematological and biochemical indices (HG 13 g/dl (men)/ 12 g/dl (women); neutrophil 15/mm3 and serum creatinine <1.5 mg/dl), and Willing to be treated and adhere to treatment requirements. It must be re-emphasized that the recommendations on the selection of patients for treatment are guidelines and not fixed rules; management and treatment considerations should be made on a case-by-case basis, taking into consideration the experience of the practitioner together with the acceptance of risk by the patient. Ghany MG, et al. Hepatology. 211;54: TVR + PR in G1 Tx-Naïve Patients Important Futility Milestones: Weeks 4, 12, 24 TVR 75 mg q8h + PR PR ervr; stop at week 24/ f/u No ervr; PR f/u 24 wk Treatment duration: Patients with extended RVR (ervr, undetectable* HCV-RNA at Week 4 and Week 12): receive 24 weeks of therapy Patients without ervr continue on PR for a total of 48 weeks Weeks 48 Futility Week 4 HCV RNA >1 IU/ml Week 12 HCV RNA >1 IU/ml Week 24 HCV RNA detectable *assay should have a lower limit of HCV RNA quantification <25 IU/mL for RGT Jacobson IM, et al. Hepatology. 21;52(Suppl 1):Abstract

8 Rate (%) SVR /Cure What Can We Tell Our Patients? Significantly Higher SVR rates in TVR-Treated Patients Compared to PR Alone n/n = 75 P < / /361 SVR T12PR T12PR = telaprevir and pegylated interferon alfa-2a + ribavirin for 12 weeks, followed by peginterferon-ribavirin alone for 12 weeks if HCV RNA was undetectable at Weeks 4 and 12 or for 36 weeks if HCV was detectable at either time point. PR = placebo + PR for 12 weeks, then PR for 36 weeks. Jacobson IW, et al. N Engl J Med. 211;364: PR ADVANCE Study: Influence of Race on SVR With PR ±TVR SVR /Cure Ra ate (%) 1% 75% 5% 25% PR+TVR (16/26) 6) 46 PR 25 (7/28) % Race White Black Race White Black Jacobson IW, et al. N Engl J Med. 211;364: Influence of Patient and Virus Factors on SVR With PR + TVR SVR /Cure Ra ate (%) 1% 75% 5% 25% % Genotype HCV RNA Fibrosis 1a 1b <8, 8, F-2 F3-F4 Marcellin P, et al. # 451; Dusheiko GM, et al. # 415. Posters at: EASL: The International Liver Congress

9 ADVANCE Study: Role of IL28B on SVR With PR±TVR 42% (454 /188) of patients available for IL28B analysis; all were White TVR associated with increased SVR rates across IL28B genotypes 1% 9 PR+TVR PR SVR /Cure Rate (%) 75% 5% 25% % IL-28B IL-28B Genotypes: CC CT TT CC CT TT Marcellin P, et al. # 451; Dusheiko GM, et al. # 415. Posters: EASL: The International Liver Congress 211. TVR for All Non-responders 4-week PR lead-in neither improves nor reduces SVR rates TVR + PR PR Follow-up RGT therapy with relapsers receiving 24 weeks of therapy who undergo ervr All others (nulls, partial responders, cirrhotics) 48 weeks Futility (no LI) Wk 4 HCV RNA >1 IU/ml Wk 12 HCV RNA >1 IU/ml Weeks Wk 24 HCV RNA detectable Zeuzum S, et al. N Engl J Med. 211;364(25): REALIZE: SVR in Prior Relapsers, Prior Partial Responders, and Prior Null Responders Prior relapsers * * Prior partial responders Prior null responders SVR (% %) * * * * T12/ PR48 LI T12/ PR48 Pbo/ PR48 T12/ PR48 LI T12/ PR48 Pbo/ PR48 T12/ PR48 LI T12/ PR48 Pbo/ PR48 n/n= 121/ /141 16/68 29/49 26/48 4/27 21/72 25/75 2/37 Zeuzum S, et al. N Engl J Med. 211;364(25): *P <.1 vs Pbo/PR48 9

10 REALIZE: SVR by Baseline Fibrosis Stage and Prior Response Prior relapsers Prior partial responders Prior null responders Pooled T12/PR48 Pbo/PR48 SVR (% %) n/n= 53/62 2/15 2/15 1/18 144/16712/38 /5 11/32 1/5 15/38 34/47 3/17 /9 48/57 24/59 1/18 7/5 1/1 Stage No, minimal or portal fibrosis Bridging fibrosis Cirrhosis No, minimal or portal fibrosis Zeuzum S, et al. N Engl J Med. 211;364(25): Bridging Cirrhosis fibrosis No, minimal or portal fibrosis Bridging fibrosis Cirrhosis Lead-in Strategy: A Strategy to Determine Who to Treat 4 weeks of PR lead-in prior to BOC (or TVR): Lowers HCV RNA burden May identify rapid responders who may not need DAA Allows assessment of interferon responsiveness Provides useful information regarding likelihood of SVR with addition of DAA Clinicians can determine who can tolerate PR backbone Assess hematologic response to PR therapy, especially in marginal patients; make needed dose adjustments before addition of DAA SVR by Response at Week 4 in Lead-In Arm of REALIZE: Is There a Role for Lead-in With PR Before TVR? 94 SVR (% %) Decline in HCV RNA at week 4 Zeuzum S, et al. N Engl J Med. 211;364(25):

11 BOC for G1 naïve HCV Milestones: Weeks 8, 12, 24 Week 4 Week 28 Week 48 Week 72 TW 8-24 HCV RNA Undetectable* Follow-up PR lead-in PR + BOC (24 weeks) Non-cirrhotic Week 36 PR+BOC (32 weeks) PR Follow-up PR lead-in Week 12 Week 24 TW 8 HCV RNA Detectable/ TW 24 undetectable PR + BOC (44) weeks for cirrhotic patients/ poorly responsive pts Follow-up Week 12 Futility Week 24 Futility HCV >1 IU/ml Detectable HCV RNA *assay should have a lower limit of HCV-RNA quantification <25 IU/mL, and limit of HCV RNA detection of approximately 1-15 IU/mL Poordad F, et al. N Engl J Med. 211;364(13): SPRINT 2: SVR and Relapse Rates P <.1 SVR Relapse Rate P =.4 1 P <.1 1 P =.44 Percent P/R BOC RGT BOC/PR48 Non-Black Patients Percent P/R BOC RGT BOC/PR48 Black Patients Poordad F, et al. N Engl J Med. 211;364(13): SVR (% %) SVR by Week 4 PR Lead-In Response A >1 log1 decrease in HCV RNA at week 4 of therapy is the strongest predictor of a SVR log1 HCV RNA decline from baseline <1 log1 HCV RNA decline from baseline P/R BOC RGT BOC/PR48 Non-Black Patients SVR (% %) Black Patients P/R BOC RGT BOC/PR Poordad F, et al. Gastroenterology. 212;143(3):

12 SPRINT-2 SVR: Influence of Patient and Virus Factors on SVR With PR + BOC 1% 8 75% SVR (%) 5% 25% 52 % Genotype HCV RNA Fibrosis 1a 1b <8, 8, F-2 F3-F4 Marcellin P, et al. # 451; Dusheiko GM, et al. # 415. Posters: EASL: The International Liver Congress 211. SPRINT-2: SVR by IL28B Polymorphism 62% of individuals (653/148) had consented to IL-28B pharmacogenomic studies *~9% eligible for short duration therapy SVR (% %) * Marcellin P, et al. # 451; Dusheiko GM, et al. # 415. Posters: EASL: The International Liver Congress 211. BOC for G1 Non-responders HCV Key Time Points: Weeks 8, 12, 24 Week 4 Week 36 Week 48 Week 72 TW 8 and 24 HCV RNA Undetectable Follow-up BOC RGT for Noncirrhotics PR lead-in PR + BOC (32 weeks) PR Follow-up Week 12 Week 24 TW 8 HCV RNA Detectable/ TW 24 undetectable PR lead-in PR + BOC (44) weeks for cirrhotic patients/ poorly responsive pts Follow-up Week 12 Futility Week 24 Futility HCV > 1 IU/ml Detectable HCV RNA *assay should have a lower limit of HCV-RNA quantification <25 IU/mL, and limit of HCV RNA detection of approximately 1-15 IU/mL Bronowicki JP, et al. EASL

13 SVR by Historical Response Partial-responders and Relapsers 1% 75% PR PR+ BOC RGT PR+ BOC 69 (72/15) 75 (77/13) SVR (%) 5% 25% 7 (2/29) 29 (15/51) 4 (23/57) 52 (3/58) % Partial Responder Relapser Partial Responder Relapser Partial Responder Relapser Bronowicki JP, et al. EASL 212. SVR in Advanced Fibrosis/Cirrhosis Recommendation: All cirrhotic patients receiving BOC + PR should receive 48 weeks of therapy [1,2] Subgroup Analysis of SPRINT-2 and RESPOND BOC/PR48 BOC RGT 48 P/R SVR (%) n= F/1/2 F3/4 1. Boceprevir [package insert]. May Ghany MG, et al. Hepatology. 211;54: Bruno S, et al. EASL 211. Abstract Bacon BR, et al. N Engl J Med. 211;364: SVR by Week 4 PR Lead-In Response VR (%) S Poorly Responsive to IFN <1 log1 viral load decline at treatment week PR 48 BOC RGT BOC/PR48 PR 48 BOC RGT BOC/PR48 Responsive to IFN 1 log1 viral load decline at treatment week 4 Bronowicki JP, et al. EASL

14 PROVIDE Study: SVR Rates by Prior Treatment Response % of Patients /52 57/85 27/29 16/168 SVR (ITT) Nulls Partials Relapsers All All includes: Nulls, Partials, Relapsers and Others Bronowicki JP, et al. EASL 213. Resistance-Associated Variants Develop When SVR Not Achieved Recommendation: Patients with virologic failure on one PI should not be retreated with the other. Similar mutations selected in resistance-associated variants detectable in patients failing BOC or TVR. Clinical significance of resistance-associated variants unknown. Predominant strain returns to wild type in majority within 2 yrs. Slower process in subtype 1a Recommendation: Follow stopping rules strictly to minimize selection of resistance-associated variants. Boceprevir [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.; 211. Telaprevir [package insert]. Cambridge, MA: Vertex Pharmaceuticals Incorporated; 211. Ghany MG, et al. Hepatology. 211;54: TVR: Severe Rash Generalized rash, or rash with vesicles, bullae, or ulcerations No Stevens Johnson Syndrome/DRESS Stop telaprevir, if no improvement in 7 days, stop PR Do not reintroduce telaprevir If no improvement, refer to Dermatologist 14

15 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 Gastrointestinal Side effects Nausea: promethazine, ondansetron TVR should be taken with 2 g of fat to help with absorption Perianal symptoms Anal pruritus with TVR: antihistamines Topical therapies: witch hazel topical, hydrocortisone cream, mesalamine suppositories, Topical lidocaine for perineal pain Diarrhea: loperamide, bulk/fiber supplement ADVANCE/ILLUMINATE: Anemia and RBV Dose Reduction Did Not Affect SVR in TVR Arms Anemia: Hgb <1 g/dl 145/ 116/ 247/ 44/ 26/ 173/ 164/ 135/ n/n = n/n = Anemia No Anemia 135/ / / 3 37/ 48 RBV Dose Reduction 226/ / / / 245 No RBV Dose Reduction 15

16 Anemia Mechanism of anemia thought to be result of bone marrow suppressive effect associated with agents, not due to RBC hemolysis. Compared to PR: Patients treated with TVR had: Higher frequency of anemia, Hgb level <1 g/dl (36% vs 17%) Higher frequency of Hgb reductions to Grade 3+ toxicity (7. to <8.9 g/dl or any decrease >4.5 m/dl) levels (55% vs 25%) Higher frequency of Hgb level <8.5 g/dl (14% vs 5%) More anemia-related SAEs (2.5% vs <1%) Higher frequency of anemia-related discontinuations (4% vs <1%) Patients treated with BOC had: Average additional decrease of Hgb of approximately 1 g/dl Anemia reported as a SAE (1% vs none with PR) A higher frequency of Hgb reductions to Grade 3+ toxicity US FDA; April 27, 211. Boceprevir [package insert]. Whitehouse Station, NJ: Merck & Co, Inc; 211. Telaprevir [package insert]. Cambridge, MA: Vertex Pharmaceuticals Incorporated; 211. Advisory Committee Briefing Document for NDA Telaprevir 375 mg tablets. Silver Spring, MD; April 1, 211. A Randomized Trial Comparing RBV Dose Reduction vs EPO for Anemia Management in Previously Untreated Patients With Chronic Hep C Receiving PR + BOC End-of-treatment response, relapse, and SVR were comparable between RBV DR and EPO arms Δ (95% CI).7% ( 8.6, 7.2)* SVR (%) 23/249 25/ / /251 19/196 19/197 CI, confidence interval; DR, dose reduction; EOT, end of treatment; EPO, erythropoietin; *The stratum-adjusted difference (EPO vs RBV DR) in SVR rates, adjusted for stratification factors and protocol cohort. Poordad F, et al. EASL 212. Results SVR by Secondary Anemia Intervention (cont) SVR ( %) Secondary Anemia Intervention Poordad F, et al. EASL

17 Anemia: Management Recommendations With TVR- or BOC-based Therapy Monitoring: CBC pretreatment, every 2 weeks until treatment week 8, then monthly Week 1 CBC in those with advanced fibrosis Primary strategy: RBV dose reduction BOC Hgb <1 g/dl: decrease in dosage by 2 mg TVR When anemia occurs, first RBV reduction to 6 mg Hgb <8.5 g/dl: PI says to stop all therapy Consider secondary anemia strategies: EPO, further RBV dose reduction, transfusion Transfusions occurred in phase 3 trials and occur in clinical practice If RBV is permanently D/C, BOC or TVR also must be D/C Do not reduce PI dose to manage anemia Peginterferon alfa-2a Solution for Subcutaneous Injection [package insert]. South San Francisco, CA: Genentech, Inc.; 211. Peginterferon alfa-2b Injection, Powder for Solution for Subcutaneous Use [package insert]. Kenilworth, NJ: Schering Corporation; 211. Boceprevir [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.; 211. Telaprevir [package insert]. Cambridge, MA: Vertex Pharmaceuticals Incorporated; 211. Futility Rules for BOC or TVR + PR Recommendation: All therapy should be discontinued in patients with the following BOCEPREVIR [1,2] Time Point Criteria Action Wk 12 HCV RNA 1 IU/mL Discontinue all therapy Wk 24 HCV RNA detectable Discontinue all therapy Recommendation: < 1 log reduction with lead in, DC if less than 3 log reduction at week 8 with boceprevir TELAPREVIR [2,3] Time Point Criteria Action Wk 4 or 12 HCV RNA >1 IU/mL Discontinue all therapy Wk 24 HCV RNA detectable Discontinue PR Assay should have a lower limit of HCV RNA quantification of 25 IU/mL and a limit of HCV RNA detection of approximately 1-15 IU/mL. 1. Boceprevir [package insert]. May Ghany MG, et al. Hepatology. 211;54: Telaprevir [package insert]. May 211. Summary Both TVR and BOC added to PR improve SVR rates. Now at least half of individuals can be treated for 6 mos. IL-28B CC predicts 6 month duration of treatment On treatment response, lead-in ervr also predict response TVR : Rash, GI side effects, anemia BOC: Anemia, dysgeusia y g Careful monitoring, especially in those with advanced fibrosis. Identify consultants prior to initiating therapy. Dermatologist Drug-drug interactions must be assessed. virtually all interactions can be addressed 17

18 Direct-Acting Antiviral Agents (DAAs) - Key Characteristics NS3 /4A Inhibitors (Protease inhibitor PI) High potency Limited genotypic coverage Low barrier to resistance NS5B Nucleos(t)ide Inhibitors (NI) Intermediate potency Pan genotypic coverage High barrier to resistance NS5A Inhibitors High potency Multi-genotypic coverage Low barrier to resistance NS5B Non Nucleoside Inhibitors (NNI) Intermediate potency Limited genotypic coverage Low barrier to resistance What Is in Our Near Future? More Triple Therapy DAA plus IFN backbone plus ribavirin (RBV) Second-generation PIs Nucleoside polymerase inhibitors Nonstructural protein (NS)5A inhibitors EXPECTATIONS RVR >9% Sustained virologic response (SVR): >8% Tolerability and side effects RGT Two New Protease Inhibitors Are Coming in Combination With PEG IFN/RBV Simeprevir NS3 protease Inhibitor Q daily dosing Improved side effect profile No anemia Fewer DDIs Faldaprevir NS Protease inhibitor Q daily dosing Improved side effect profile No anemia 18

19 QUEST-1 and QUEST-2: Simeprevir (PI) + PegIFN + RBV in Treatment-Naive GT1 85%-91% qualified for shortened therapy Baseline Q8K mutation in genotype 1a may affect SVR 12 (%) Patients Achieving SVR Simeprevir + PR (RGT 12+12) 8 81 Placebo + PR n/n = 211/ 65/ 28/ 67/ QUEST-1 QUEST-2 Manns M, et al. 48 th EASL; Amsterdam, Netherlands; April 24-28, 213. Abst Jacobson I, et al. 48 th EASL; Amsterdam, Netherlands; April 24-28, 213. Abst STARTVerso: Primary Endpoint SVR12 (ITT) 87%-89% Qualified for Short Duration Therapy 1 8 ( = 26.7; 95% CI, ; P <.1) ( = 28.6; 95% CI, ; P <.1) SVR12 (%) /132 SVR12 rates adjusted for race and genotype ITT, intention-to treat Ferenci P, et al. EASL 213. Abst /259 21/261 Placebo FDV 12 mg FDV 24 mg Sofosbuvir (SOF, GS-7977) HCV-specific nucleotide polymerase inhibitor (chain terminator) Potent antiviral activity against HCV genotypes 1 6 High barrier to resistance Once-daily, oral, 4-mg tablet Favorable clinical pharmacology profile No food effect No significant drug interactions Generally safe and well tolerated in clinical studies to date (>2 patients) No safety signal in preclinical/clinical studies H 3 C H 3 C O O CH 3 O HN P O O NH O O N O CH 3 HO F 19

20 NEUTRINO Study: 12 Weeks of Sofosbuvir+ PEG IFN/RBV SVR12 by HCV Genotype Patients with HCV RNA <LLOQ (%) 295/ /292 27/28 7/7 Overall GT 1 GT 4 GT 5,6 Error bars represent 95% confidence intervals. Lawitz E, et al. EASL 213. Abst Multiple All Oral Regimens in Clinical Trials Nucleotide analogue polymerase inhibitor alone or plus NS5A inhibitor Sofosbuvir + RBV Sofosbuvir + daclatasvir ± RBV Sofosbuvir + GS RBV Protease inhibititor + NS5A inhibitor ± nonnucleoside polymerase inhibitor ± RBV ABT45/r + ABT267 + ABT333 ± RBV Asunaprevir + daclatasvir ± BMS-325 Faldaprevir + BI RBV ELECTRON: Sofosbuvir + Ledipasvir 12 Week Regimens in GT1 Patients with HCV RNA <LOD* over time, n/n (%) SOF + RBV SOF + LDV + RBV Naïve (n=25) Null (n=1) Naïve (n=25) Null (n=9) Week 1 8/25 (32) 1/1 (1) 11/25 (44) /9 () Week 2 17/25 (68) 7/1 (7) 22/25 (88) 4/9 (44) Week 4 25/25 (1) 1/1 (1) 25/25 (1) 8/9 (89) EOT 25/25 (1) 1/1 (1) 25/25 (1) 9/9 (1) SVR4 22/25 (88) 1/1 (1) 25/25 (1) 9/9 (1) SVR12 21/25 (84) 1/1 (1) 25/25 (1) 9/9 (1) * Analyzed by TaqMan HCV Test 2. with limit of detection (LOD) of 15 IU/mL. Includes 1 patient who stopped all treatment due to a serious adverse event (AE) at Week 8; this patient subsequently achieved SVR12. EOT, end of treatment; SVR4, sustained virologic response 4 weeks after EOT. Gane E, et al. EASL 213. Abst

21 AVIATOR Study: ABT-45/r, ABT-267, ABT-333 ± RBV in Non-Cirrhotic, Naïve and Null Responders atment-naïve Trea Null Responder N ABT-45 ABT-267 ABT-333 RBV Regimen/Duration ABT-45 ABT-45 ABT-267 ABT-333 RBV ABT-45 ABT-267 ABT-333 RBV ABT-45 ABT-267 ABT-333 RBV ABT-45 ABT-267 ABT-333 RBV Wk Wk 8 Wk 12 Wk ABT-45 ABT-267 RBV ABT-45 ABT-267 ABT-333 RBV ABT-45 ABT-267 ABT-333 RBV 43 N = 571 SVR 12 % * 8 patients with SVR12 have not returned for >24 weeks and are counted as virologic failures for SVR24; 3 patients relapsed between SVR12 and SVR24. Kowdley K, et al. EASL 213. Abst. 3. SVR 24 * % Breakthrough / Relapse / / / / / / / / / Faldaprevir (PI) + BI With or Without RBV ITT n/n BI dosing Duration (weeks) RBV 48/81 47/8 4/77 54/78 18/46 TID 16 + TID 28 + ITT, intention-to-treat All groups received faldaprevir 12 mg QD for the same duration as BI (16, 28, or 4 weeks) Soriano V, et al. 63rd AASLD; Boston, MA; November 9-13, 212. Abst. 84. TID 4 + BID 28 + TID 28 - SOUND-C2 Study Sub-analysis: Efficacy/Safety of the IFN-free Combination of BI BI ± RBV in Treatment-naive G1 Patients With Compensated Liver Cirrhosis SOUND-C2 (N=362); 33 patients (9%) had liver cirrhosis (liver biopsy or Fibroscan) Pooled data from pts who received BI TID + RBV (TID16W, TID28W and TID4W) Cirrhosis G1a No Cirrhosis G1b BI 7127 dosing Duration (weeks) RBV +/- 3/7 8/14 2/4 4/5 / 1/3 4/93 84/124 11/26 37/43 2/18 15/25 Safety and tolerability profile good did not differ significantly in cirrhotics vs noncirrhotics Plasma exposure of faldaprevir and BI higher in cirrhotics (less apparent in BID arm) Soriano V, et al. 63rd AASLD; Boston, MA; November 9-13, 212. Abst

22 Evolution of Therapy in HCV G ? 8 SVR (%) IFN 6m IFN 12m IFN/RBV 6m 25 IFN/RBV 12m 4 PEG/RBV 12m 6 75 PEG/R/PI 6-12m 1 All Oral DAA weeks Genotypes 2/3 will have an oral regimen first FISSION Study: Treatment-Naïve, Genotype 2 or 3 Patients Week SOF + RBV*, n=256 SVR12 PegIFN + RBV* (SOC), n=243 SOF + RBV n=256 Peg-IFN + RBV n=243 Mean age, y (range) 48 (2 72) 48 (19 77) Male, n (%) 171 (67) 156 (64) White, n (%) 223 (87) 212 (87) IL28B CC, n (%) 18 (43) 16 (44) GT 3, n (%) 183 (72) 176 (72) Mean HCV RNA, log 1 IU/mL (range) 6. ( ) 6. ( ) Cirrhosis, n (%) 5 (2) 5 (21) *RBV dose 1,-1,2 mg/day for SOF + RBV and 8 mg/day for PegIFN + RBV Gane E, et al. EASL 213. Abst. 5. SV12 22

23 Results: Virologic Response V RNA <LLOQ Patients with HCV (%) 231/251 76/ /25 158/ /244 27/224 NA Week 2 Week 4 Week 12 Week 24 On treatment *Study met primary endpoint of non-inferiority of SOF + RBV to Peg-IFN + RBV. Error bars represent 95% confidence intervals. Gane E, et al. EASL 213. Abst /19 P <.1* 17/ /243 Week 12 Post-treatment Hepatitis C Therapy Will Parallel Helicobacter pylori Therapy H pylori HCV All Oral Therapy Duration weeks Polymerase Inhibitor ± Protease Inhibitor ± All Oral Therapy, single tablet NS5a ± Cyclophylin Inhibitor ± ribavirin Conclusion Testing and Assessment Diagnosing and classifying HCV Assessment of likelihood of SVR Treatment Guideline recommendations Individualizing therapy Utilizing newly approved agents Managing comorbidities Managing side effects Emerging therapies 23

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