TREATMENT FOR HEPATITIS C: NEW TESTS, NEW DRUGS AND NEW RECOMMENDATIONS

TREATMENT FOR HEPATITIS C: NEW TESTS, NEW DRUGS AND NEW RECOMMENDATIONS Anthony Martinez, MD Associate Professor of Medicine University at Buffalo Division of GI and Hepatology

DISCLOSURE Speaking: Abbvie, Gilead, Bayer, Salix, BMS Consulting: Gilead, Intercept Research: Abbvie, Gilead, Merck, Tobira

LEARNING OBJECTIVES: 1.Explain the epidemiology of the hepatitis C virus (HCV). 2. Discuss laboratory testing and diagnosis of HCV infection. 3. Design a therapeutic regimen and monitoring plan for the treatment of HCV.

Total No. Infected (millions) HCV vs. HIV vs. HBV Prevalence 4 Prevalence of Chronic Viral Infections 2.7 to 3.9 Million 1 75% Unaware of Infection 3 2 1 1.1 Million 1 21% Unaware of Infection ~800,000 to 1.4 Million 1 65% Unaware of Infection Undiagnosed Diagnosed 0 HIV HBV HCV Estimated 5.2 million persons in US are HCV infected 2 HBV=hepatitis B virus; HCV=hepatitis C virus; HIV=human immunodeficiency virus. 1. Institute of Medicine. Washington, DC: The National Academies Press; 2010. 2. Chak E, et al. Liver Int. 2011;31(8):1090-1101.

HCV Can Now Be Cured in Most Patients Unlike HIV and HBV infection, HCV infection is a curable disease What does cure mean? Sustained Viral Response Undetectable HCV RNA 12 weeks after completion of antiviral therapy for chronic HCV infection 1 Long term morbidity and mortality benefits 1. Ghany MG, et al. Hepatology. 2009;49(4):1335-1374.

Rate per 100,000 People Deaths From HCV vs. HIV 7 6 HIV Change in Mortality Rates From 1999 to 2007 5 4 3 Hepatitis C 15,106 12,734 2 1 0 Hepatitis B 1,815 1999 2000 2001 2002 2003 2004 2005 2006 2007 Year Ly KN, et al. Ann Intern Med. 2012;156(4):271-278.

Individuals, N Majority of HCV-Infected Individuals Are Baby Boomers (Born Between 1945 1965) 1,600,000 Estimated Prevalence by Age Group 1,400,000 1,200,000 1,000,000 800,000 600,000 400,000 200,000 0 <1920 1920 1929 1930 1939 1940 1949 1950 1959 1960 1969 Birth Year Group 1970 1979 1980 1989 1990+ Centers for Disease Control and Prevention. MMWR. 2012;61(RR-4):1-32.

Most Patients with Chronic Hepatitis C in the US Are Not Aware That They Are Infected ~5,300,000 individuals are infected with the hepatitis C virus in the United States Lack of knowledge & awareness among health care providers Lack of knowledge & awareness among at-risk populations Insufficient understanding about the extent and seriousness of this public health problem 1,325,000 (~25%) AWARE 3,975,000 (~75%) UNAWARE

Number of Cases HCV-Related Decompensated Cirrhosis and HCC Projected to Rise in the US 160,000 140,000 120,000 100,000 80,000 Decompensated Cirrhosis 60,000 40,000 20,000 Hepatocellular Carcinoma 0 1950 1960 1970 1980 1990 2000 2010 2020 2030 HCV-related decompensated cirrhosis and HCC are rising as manifestations of liver disease in aging population 1 73.4% of HCV-related deaths occurred among persons 45-64 years of age Median age was 57 years; ~20 years less than the average lifespan of persons living in the US 2,* Projection based on a dynamic, multicohort, natural history model of data from the CDC, NHANES, and a review of the medical literature, with conservative estimates of disease progression and complications. Model assumes first-year mortality of 80%-85% for HCC. *During the period from 1999 to 2007. 1. Davis GL, et al. Gastroenterology. 2010;138:513-521; 2. Smith BD, et al. MMWR Recomm Rep. 2012;61(RR-4):1-32.

Increasing Health Care Costs Associated With Progressive Liver Disease in the Aging HCV- Infected Population Prevalence (95% CI) Health Care Cost (95% CI) While the prevalence of HCV infection is declining from its peak, the incidence of advanced liver disease and associated health care costs continue to rise Modeling does not take into account any impact of birth cohort screening A system dynamic modeling framework was used to quantify the HCV-infected population, the disease progression, and the associated cost from 1950-2030. CI=confidence interval. Razavi H, et al. Hepatology. 2013. Epub ahead of print.

Costs (per-patient-per-month) (US$) All-Cause Health Care Costs by Liver Disease Severity (US$, 2010) Numbers in parentheses are ± standard deviation. *P<.001 and P=.004 vs noncirrhotic liver disease. Total health care costs include pharmacy and medical costs. Pharmacy costs are based on 2-drug therapy with PegIFN and RBV. Adapted from Gordon SC, et al. Hepatology. 2012;56:1651-1660.

Estimated Mean Annual Costs Impact of Disease Severity on Health Care Costs in Chronic HCV Infection *Assumes follow-up time not associated with disease severity. ESLD=end-stage liver disease; OLT=orthotopic liver transplantation. Gordon SC, et al. Hepatology. 2012;56:1651-1660.

SVR Reduces HCC and Liver-Related Complications in Advanced Fibrosis/Cirrhosis Cumulative Incidence (%) Cumulative Incidence (%) HCC (n=307) Liver-Related Complications* (n=307) Follow-Up (years) Follow-Up (years) *Ascites, variceal bleeding. 307 HCV patients with bridging fibrosis (n=127) or cirrhosis (n=180) were evaluated by Cox regression analysis. Non-SVR in 67% of patients treated with pegylated interferon plus ribavirin. Median follow-up: 3.5 years. Cardoso A-C, et al. J Hepatol. 2010;52:652-657.

Cumulative Mortality (%) SVR Reduced Risk of All-Cause Mortality in a Retrospective VA Study Genotype 1 (n=12,166) SVR rate: 35% Genotype 2 (n=2904) SVR rate: 72% Genotype 3 (n=1794) SVR rate: 62% Years Years Years Retrospective analysis of veterans who received pegylated interferon plus ribavirin at any VA medical facility (2001-2008). SVR=sustained virological response. Backus LI, et al. Clin Gastroenterol Hepatol. 2011;9:509-516.

Acute HCV Cases By Age in the United States 1992-2009 Klevens, CID, 2012 16

Past Month and Past Year Heroin Use among Persons Aged 12 or Older: 2002-2012 Samhsa.gov 17

Increased Injection Drug Use In Adolescents and Young Adults is Shifting the US HCV Demographic 18

Number of HCV Cases HCV Prevalence In NYS HCV Cases 2001-2009 80000 70000 60000 50000 40000 30000 20000 10000 0 NYS (prevalence 0.6%)* Erie County (prevalence 1.2%) Erie County (prevalence 2.9%)** * Excludes NYC ** Based on CDC estimates 19

HCV Linking to Care

Treatment Cascade for People with Chronic HCV Infection in US Yehia BR et al. PLoS ONE July 2014

Updates in HCV Screening

Current Status of HCV in the US: Screening and Linkage to Care Rates Remain Low US population with chronic HCV infection 3.2 million HCV detected 1.6 million (50%) Referred to care 1.0 1.2 million (32%-38%) HCV RNA test 630,000 750,000 (20-23%) Liver biopsy 380,000 560,000 (12%-18%) Treated 220,000 360,000 (7-11%) Successfully treated 170,000 200,000 (5-6%) Holmberg SD et al, New Engl J Med. 2013; 1859-1861.

CDC Has Revised Screening Recommendations for HCV

Candidates for Screening for HCV 2012 Additional Recommendations 1 1998 Recommendations 2 Birth Cohort Screening Adults born during 1945 1965 should receive one-time testing for HCV without prior ascertainment of HCV risk Persons who have injected illicit drugs in the recent and remote past Persons with conditions associated with a high prevalence of HCV infection Prior recipients of transfusions or organ transplants prior to July 1992 Children born to HCV-infected mothers Health care, emergency medical and public safety workers after a needle stick injury or mucosal exposure to HCV-positive blood Current sexual partners of HCV-infected persons 1. Centers for Disease Control and Prevention. Recommendations for the identification of chronic hepatitis C virus infection among persons born during 1945-1965. MMWR Recomm Rep 2012;61 (RR-4):1-32. 2. Centers for Disease Control and Prevention. Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCVrelated chronic disease. MMWR Recomm Rep 1998;47:1-39.

Governor Signs Health Care Bill October 2013 Hepatitis C Virus Testing (Chapter 425 of the Laws of 2013) This new law requires a hepatitis C virus screening test to be offered to all patients born between 1945 and 1965 who are receiving health services as a hospital inpatient or receiving primary care services and applies to physicians, physician assistants, and nurse practitioners. The law further requires that the health care provider refer a patient who receives a positive screening test to another provider to receive confirmatory testing and follow-up care. In effect as of January 1, 2014 and expires on January 1, 2020

Hepatitis C Screening and Prevalence Among Veterans in 2012 Assess the extent to which Veterans in recent care, particularly those born between 1945-1965, have been screened for HCV Assess HCV infection prevalence by birth cohort to determine if the emphasis on birth cohort screening applied to the VA population Estimate the potential clinical impact of complete birth cohort screening Backus L, et al. AASLD 2013 Oral Presentation #21

Veterans with Outpatient Visits in 2012 Backus L, et al. AASLD 2013 Oral Presentation #21

HCV Screening Rates 2012 3,009,918 of the 5,500,309 (54.7%) Veterans in care in 2012 had been screened for HCV Backus L, et al. AASLD 2013 Oral Presentation #21

HCV Ab Prevalence 2012 95.1% had viral load or genotype testing Backus L, et al. AASLD 2013 Oral Presentation #21

HCV Infection Prevalence Among Veterans in Care in 2012 Born 1945-1965 Based on Year of First HCV Screening Backus L, et al. AASLD 2013 Oral Presentation #21

Screening In Emergency Department Identifies a Large Cohort of HCV-infected Baby Boomers University of Alabama at Birmingham implemented an opt-out HCV screening model for clinically stable baby boomers ER triage nurses identified all patient born between 1945-1965 and administered a brief prescreening questionnaire Exclusion criteria: Prior testing, opt-out or too sick All eligible patients offered HCV screening with confirmatory testing with PCR in Anti-HCV Ab positive persons Galbraith J, et al. AASLD 2013 Abstract

Screening In Emergency Department Identifies a Large Cohort of HCV-infected Baby Boomers Over a 6 week period, 1,721 patients born 1945 1965 were surveyed Unaware of status, 78.8% Accepted testing, 90.8% HCV seropositive, 12.0% HCV RNA detected, 72.5% Urban EDs are high-prevalence settings; challenges for linkage to care HCV prevalence by health insurance status Uninsured Public / Medicaid Other Medicare Private 22 175 168 5 (18.5%) 216 282 35 (17.2%) 35 (16.7%) 10 (4.4%) 33 (10.5%) 0 100 200 300 400 Non-Reactive Reactive Galbraith JW et al. The Liver Meeting 2013; LB-6 Overall HCV + 12%

ICD-9 and CPT HCV Screening Codes

HCV Antibody Test Patient exposed to HCV Need HCV RNA test to confirm chronic infection Patient Not Exposed Continue to screen based on active risk factors If HIV positive and CD4 <200, need HCV RNA test

HCV Antibody HCV RNA Confirmatory Testing Patient is NOT chronically infected Tell the patient he/she can still become infected if high risk activity continues Educate regarding transmission and exposure Counsel on harm reduction

HCV Antibody HCV RNA Confirmatory Testing Patient IS chronically infected Emphasize that HCV is progressive and highlight complications Explain that HCV is curable with oral interferon free regimens Explain how to limit risk of transmission (clean works; don t share razors, toothbrush; bleach for tattooing equipment Advise patient how to prevent further liver damage ETOH cessation

Linkage To Care Refer for specialist care REGARDLESS of viral load and liver enzyme levels Viral load level does not correlate with disease severity Liver enzymes may be normal in chronic infection, even with advanced disease Most chronically infected patients have no symptoms Explain what to expect when seen by specialist Emphasize importance of keeping the appointment

HCV Screening Algorithm HCV RNA Negative Stop. Patient is a spontaneous resolver (antibody positive, negative viral load) HCV Antibody Screen HCV Antibody Positive Check HCV RNA Quant and Genotype HCV RNA Positive CBC with diff, Comp. Metabolic Panel AFP, RhF PT/INR Platelets <120 Albumin <3.5 INR > 1.3 Bilirubin >2 Do US with PV diameter and Spleen size Consider CT or MRI with and without contrast to confirm cirrhosis and screen for HCC Refer to Liver Clinic

HEPATITIS C TREATMENT

HCV Therapy: Past, Present and Future Ribavirin Suppression of HCV with DAA combination (PI + NI) Interferon Proof of concept for DAA (PI) Approval of Telaprevir and Boceprevir Approval of Sofsobuvir/L edipasvir and Viekira 1990 2000 2005 2010 2011 2012 2013 2014 2015- Pegylated interferons Approval of simeprevir and sofosbuvir w/ifn (G1) -First approved IFNfree therapy: SOF+RBV for GT 2,3

Cure Rate* Rising Cure Rates for Chronic HCV 100% 80% Telaprevir or Boceprevir + PegIFN/RBV 70% 2 nd Gen DAAs IFN-Free Regimens >90% 3 rd Gen DAAs IFN-Free Regimens >95% 60% 40% 20% IFN 16% IFN/RBV 35% PegIFN/RBV 44% 0% 1991 1998 2001 2011 2013 2014+ *Cure rates based on data from clinical trials Year

Characteristics of HCV DAA Classes Characteristic Protease inhibitors (SMV, PAR/r, GRZ) Nucleos(t)ide Polymerase inhibitors (SOF) Nonnucleoside Polymerase inhibitors (DAS) NS5A inhibitors (LDV, OMB, DCV, ELB) Potency High; Variable among genotypes Moderate-high Pangenotypic Variable; variable among genotypes High; variable among genotypes Barrier to Resistance Low 1a < 1b High 1a = 1b Very Low 1a < 1b Low 1a < 1b Drug Interaction CYP3A4 OATP1B1/3 P-gp UGT1A1 Minimal CYP2C8 UGT1A1 OATP1B1/3, BCRP, P-gp UGT1A1 Dosing QD QD QD to BID QD

HCV Treatment Paradigm Shift Then Difficult regimens 24-48 weeks of treatment Moderately successful Support patients to manage extensive side effects and drug-drug interactions Now Easier regimens 8-12 weeks of treatment Highly successful Prepare patients for treatment and a cure 44

When and in Whom to Initiate HCV Therapy Treatment is recommended for patients with chronic HCV infection (Class I, Level A) Treatment is assigned the highest priority for those patients with advanced fibrosis (METAVIR F3), those with compensated cirrhosis (METAVIR F4), liver transplant recipients, and patients with severe extrahepatic HCV (cryoglobulinemia, DM, debilitating fatigue) Based on available resources, treatment should be prioritized as necessary so that patients at high risk for liverrelated complications (those with HIV, HBV) and severe extrahepatic hepatitis C complications are given high priority AASLD, IDSA, IAS USA. Recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org. Accessed August 12, 2014.

Initial Tx Recommendations Genotype 1a/b Regimen Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 8-12 weeks. Daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) plus twice-daily dosed dasabuvir (250 mg) and weightbased RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]) for 12 weeks (no cirrhosis) or 24 weeks (cirrhosis)

Initial Tx Recommendations Genotype Regimen 2 Daily sofosbuvir (400 mg) and weightbased RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]) for 12 weeks is recommended for treatment-naive patients (consider 16 weeks in cirrhotics) 3 Daily sofosbuvir (400 mg) and weightbased RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]) for 24 weeks

Initial Tx Recommendations Genotype Regimen 4, 6 Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks (Geno 4 and 6) Daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) and weightbased RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]) for 12 weeks (Geno 4) 5 Daily sofosbuvir (400 mg) and weightbased RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]) plus weekly PEG-IFN for 12 weeks

New HCV Treatment: SOF/LDV Indicated for the treatment of chronic hepatitis C (CHC) genotype (GT) 1 infection in adults SOF/LDV The first and only once-daily, single-tablet regimen containing ledipasvir (90 mg), a hepatitis C virus (HCV) NS5A inhibitor, and sofosbuvir (400 mg), an HCV nucleotide analog NS5B polymerase inhibitor Is an interferon (IFN)-free and ribavirin (RBV)-free regimen Pill not actual size

New HCV Treatment: SOF/LDV Sofosbuvir An inhibitor of the HCV NS5B RNA-dependent RNA polymerase, which is required for viral replication Ledipasvir An inhibitor of the HCV NS5A protein, which is required for viral replication

Background Ledipasvir Potency against HCV GT 1a and 1b 1 Effective against NS5B RAV S282T 2 Once-daily, oral, 90 mg LDV NS5A inhibitor Sofosbuvir Potent antiviral activity against HCV GT 1 6 High barrier to resistance Once-daily, oral, 400-mg tablet approved for use with other agents to treat HCV infection SOF nucleotide polymerase inhibitor Ledipasvir/Sofosbuvir FDC Once-daily, oral fixed-dose (400/90 mg) combination tablet No food effect >2000 patients treated LDV NS5A inhibitor SOF nucleotide polymerase inhibitor 1. Lawitz E, et al. EASL 2011, poster 1219; 2. Cheng G, et al. EASL 2012, poster 1172.

New HCV Treatment: Harvoni The recommended dosage of HARVONI for adults is one tablet taken orally once daily with or without food RECOMMENDED REGIMEN AND TREATMENT DURATION IN GT1 CHC PATIENTS 1 Treatment-naïve HARVONI TABLET DAILY patients with or without cirrhosis Treatmentexperienced patients b without cirrhosis Treatmentexperienced patients b with cirrhosis 12 weeks a 12 weeks 24 weeks a HARVONI for 8 weeks can be considered in treatment-naïve patients without cirrhosis who have pre-treatment HCV RNA less than 6 million IU/mL. b Treatment-experienced patients who have failed treatment with either peginterferon (Peg-IFN) alfa + RBV or an HCV protease inhibitor (PI) + Peg-IFN alfa + RBV. Relapse rates are affected by baseline host and viral factors and differ between treatment durations for certain subgroups No dose recommendation can be given for patients with severe renal impairment (estimated Glomerular Filtration Rate [egfr] <30 ml/min/1.73m 2 ) or with end stage renal disease (ESRD) due to higher exposures (up to 20-fold) of the predominant sofosbuvir metabolite 4

SVR12, % HARVONI Provided High SVR12 Rates in CHC GT 1 Subjects Regardless of the inclusion of RBV OVERALL SVR12 RATES ACROSS ION STUDIES 1-4 100 80 94% 96% 99% 93% 97% 99% 94% 96% 99% 60 40 20 0 202 215 201 216 208 216 210 211 213 a 217 102 109 107 111 108 109 110 111 ION-3 8 Weeks ION-3 12 Weeks ION-1 12 Weeks b ION-2 12 Weeks ION-2 24 Weeks HARVONI HARVONI + RBV a Excluding 1 subject with GT 4 infection. 1 b SVR rates for all treatment-naïve subjects enrolled in the 24-week treatment groups (N = 434) were not available at the time of the interim analysis. HCV RNA analyzed by COBAS TaqMan HCV Test v2.0 HPS, with lower limit of quantification (LLOQ) of 25 IU/mL. 1 1. HARVONI US full Prescribing Information. Gilead Sciences, Inc. Foster City, CA. March 2015. 2. Afdhal N, et al. N Engl J Med. 2014;370:1889-1898. 3. Afdhal N, et al. N Engl J Med. 2014;370:1483-1493. 4. Kowdley KK, et al. N Engl J Med. 2014;370:1878-1888.

Adding RBV to HARVONI resulted in an increased incidence of adverse reactions 2-4 IMPORTANT SAFETY INFORMATION: ADVERSE REACTIONS 1 Most common ( 10%, all grades) adverse reactions were fatigue and headache ADVERSE REACTIONS (ALL GRADES) REPORTED IN SUBJECTS RECEIVING 8, 12, OR 24 WEEKS OF TREATMENT WITH HARVONI ± RBV 2-4 HARVONI 8 Weeks N = 215 HARVONI + RBV 8 Weeks N = 216 HARVONI 12 Weeks N = 539 HARVONI + RBV 12 Weeks N = 328 HARVONI 24 Weeks N = 326 HARVONI + RBV 24 Weeks N = 328 Fatigue 21% 35% 22% 38% 24% 40% Headache 14% 25% 21% 23% 24% 30% Nausea 7% 18% 11% 17% 11% 17% Insomnia 5% 12% 8% 19% 9% 20% Diarrhea 7% 6% 7% 7% 10% 9% The majority of adverse reactions with HARVONI alone occurred at a severity of grade 1 1 Direct comparison across studies should not be made due to differing study designs. 1. HARVONI US full Prescribing Information. Gilead Sciences, Inc. Foster City, CA. March 2015. 2. Afdhal N, et al. N Engl J Med. 2014;370:1889-1898. 3. Afdhal N, et al. N Engl J Med. 2014;370:1483-1493. 4. Kowdley KK, et al. N Engl J Med. 2014;370:1878-1888.

HARVONI, a once-daily single-tablet regimen, Delivered High SVR12 Rates in the treatment of adults with CHC GT 1 Subjects Without Cirrhosis Subjects with Compensated Cirrhosis Treatment-Naïve 96%-99% SVR12 with 12 weeks of treatment 97% SVR12 with 8 weeks of treatment (baseline HCV RNA <6 million IU/mL) 94% SVR12 with 12 weeks of treatment Treatment-Experienced a 95% SVR12 with 12 weeks of treatment 100% SVR12 with 24 weeks of treatment Coadministration with amiodarone may result in serious symptomatic bradycardia. Use of HARVONI with amiodarone is not recommended Rifampin and St. John s wort are not recommended for use with HARVONI as they may significantly decrease ledipasvir and sofosbuvir plasma concentrations HARVONI is not recommended for use with other products containing sofosbuvir (SOVALDI) a Treatment-experienced patients who have failed treatment with Peg-IFN alfa + RBV ± HCV PI. HARVONI US full Prescribing Information. Gilead Sciences, Inc. Foster City, CA. March 2015.

AbbVie HCV Program Viekira Pak

AbbVie HCV Clinical Development Program Phase 2a Phase 3 Special Patient Populations PILOT GT1 naïve N=11 ABT-450/r + ABT 072 + RBV CO-PILOT GT1 naïve/experienced, N=50 ABT-450/r + ABT-333 + RBV Phase 2b AVIATOR GT1 naïve/experienced, N=571 ABT-450/r ABT-267 +/- ABT-333 +/- RBV NAVIGATOR GT1, 2, 3 naïve, N=60 ABT-450/r + ABT-267 +/- RBV SAPPHIRE I GT1 naïve, N= 631 ABT-450/r/ABT-267 + ABT-333 + RBV SAPPHIRE II GT1 experienced, N=394 ABT/450/r/ABT-267 + ABT-333 + RBV PEARL-II GT1b experienced, N= 179 ABT-450/r/ABT-267 + ABT-333 +/- RBV PEARL-III GT1b naïve, N=419 ABT-450/r/ABT-267 + ABT-333 +/- RBV TURQUOISE I (HIV/HCV) GT1 naïve/experienced, N= 300 ABT-450/r/ABT-267 + ABT-333 + RBV TURQUOISE II (Compensated Cirrhosis) GT1 naïve/experienced, N= 380 ABT-450/r/ABT-267 + ABT-333 + RBV M12-999 (Liver Transplant Recipients) GT1 naïve/experienced, N= 30 ABT-450/r/ABT-267 + ABT-333 + RBV Comparative Trials MALACHITE I GT1 naïve, N= 314 ABT-450/r/ABT-267 + ABT-333 + RBV Compared to TPV+ PegIFN + RBV PEARL I GT1b, 4 naïve/experienced N=320 ABT-450/r +ABT-267 +/- RBV PEARL-IV GT1a naïve, N=305 ABT-450/r/ABT-267 + ABT-333 +/- RBV MALACHITE II GT1 experienced, N= 150 ABT-450/r/ABT-267 + ABT-333 + RBV TPV + PegIFN + RBV Source: www.clinicaltrails.gov; Data on File, AbbVie.

VIEKIRA PAK Label

HCV Treatment Genotype 2 and 3

SVR12 (%) SOF/RBV GT 2 or 3 Treatment-Naive and Experienced: VALENCE 100 94 91 92 93 85 75 68 50 25 0 No cirrhosis Cirrhosis Overall SOF/RBV x 12w (GT2, n = 73) or 24 W (GT3, n = 250) G2 (blue); G3 (red) Zeuzem et al, N Engl J Med 2014; 370:1993

Genotype 3 Ally-3 ALLY-3 0 Weeks 12 24 EOT SVR Treatment-naive 19% w/ cirrhosis N = 101 Daclatasvir + sofosbuvir 99% 90% Prior treatment 25% w/ cirrhosis N = 51 Daclatasvir + sofosbuvir 99% 86% SVR F0-F3 = 96% (105/109) SVR F4 = 63% (20/32) No SAEs related to treatment, no premature D/C due to AEs Most AEs mild: fatigue, headache, nausea, diarrhea Longer duration being examined for cirrhotics Nelson D et al, Hepatology 2015;61:1127

SVR12 for SOF + GS-5816 (pangenotypic NS5A) ± RBV for 12 Wk in Treatment-Naive Patients with GT 1-3 HCV 12 weeks w/o RBV GT 1, 2, 3 Noncirrhotic SOF + GS-5816 25mg SOF + GS-5816 100mg 100 96 100 100 91 93 93 80 60 40 20 0 GT 1 GT 2 GT 3 Tran, Abst # 80, AASLD 2014

HCV - Beginning of the end? Or the end of the beginning? Can we engage the epidemic s base? Even more new agents on the way SVR just about 100% Regimens safer, shorter, easier IFN and liver biopsy gone Infrastructure? Cost? 65

Conclusion Need to diagnose more patients infected with HCV and link them into care Recently updated screening guidelines are expected to identify more cases of HCV but we need to improve our screening practices Dramatic improvement in antiviral therapies that yield 90-100% cure using well tolerated regimens Decrease rates of liver cancer, liver failure and mortality with better therapies Continued follow up needed in cirrhotic patients even with SVR including HCC surveillance

QUESTIONS?