HEPATITIS C UPDATE: A Quarter-Century Dramatic Journey. Steve T. Chen M.D. FACP, FACG

HEPATITIS C UPDATE: A Quarter-Century Dramatic Journey Steve T. Chen M.D. FACP, FACG

Hepatitis C Virus: Morphology and Characteristics Hepatitis C Virus Discovered in 1989 Nucleic Acid: 9.6 kb ssrna 40-60 nm Classification: Flaviviridae, Hepacivirus Genotypes: 1 to 6 In vitro model: primary hepatocyte and T cell cultures; replicon system In vivo replication: in cytoplasm, hepatocyte and lymphocyte; human and other primates

Hepatitis C Virus C E1 E2 NS 2 Hepatitis C Virus: Genome and Gene Products, pt.2 Genome and Gene Products NS3 NS4B NS5A NS5B 5 UTR P7 NS4A 3 UTR Structural protein coding region Nonstructural protein coding region C E1 E2 NS 2 Core Protease NS3 A NS4 NS5A NS5B B Protease Cofactor Envelope Serine protease Helicase RNA polymerase

HCV - Epidemiology Prevalence Prevalence Worldwide 230 million ( 3%) United States HCV positive 5.2 million (1.3%) 4 X more prevalent than HIV/HBV Most common cause (45%) of liver transplantation in the U.S..

Predictions by 2019: 193,000 HCV deaths 720,700 million years of advanced liver disease 1.83 million years of life lost $11 billion in direct medical care costs $21.3 and $54 billion societal costs from premature disability and mortality years of advanced liver disease.83 million

HCV - Epidemiology Risk Factors for Hepatitis C Long-Term Hemodialysis Clotting Factor Treatment Prior to 1987 Blood Transfusion or Organ Transplant Prior to 1992 Multiple Sexual Partners Risk Factors for Hepatitis C Injection Drug Use Mass Injections and Traditional Practices Birth from Infected Mother

The following patients should be screened for hepatitis C: A. Those who have elevated liver enzymes (ALT,AST). B. Those who have risk factors (blood products exposures, IVDA, hemodialysis, etc.) C. Those born between 1945 and 1965. D. All of the above. Those who have elevated... 0% 0% 0% 0% Those who have risk facto.. Those born between 194... All of the above.

2012 CDC and 2013 USPSTF guidelines for HCV birth-cohort screening Screen all baby boomers born 1945-1965 Rationale: 75% of HCV patients are undiagnosed Baby boomers: 3.27% HCV antibody positivity (5 X higher than other cohorts). 75% of all HCV positive Removes barriers of risk-based screening model Identifies 808,580 additional cases of chronic HCV Reduces deaths by 121,000 and cost by $35,700 per QALY (Rein et al, Ann Int Med 2012; 156(4):263-270)

Prevalence of hepatitis C virus antibody, by year of birth National Health and Nutrition Examination Survey, United States, 1988 1994 and 1999 2002 Source: Armstrong GL, Wasley A, Simard EP, et al. The prevalence of hepatitis C virus infection in the United States, 1999 through 2002. Ann Internal Med 2006;144:705 14. Alternate Text: The figure is a line graph that displays the prevalence of hepatitis C virus antibody in persons by year of birth during the 1988-1994 and 1999-2002 National Health and Nutrition Examination Survey.

Comparison of Birth-cohort screening with risk-based screening (Markov model) Screen additional 70 million Identify 1.07 million HCV positive Treat 552,000 Eradicate HCV in 364,000 Decrease decompensated cirrhosis 50,000 Decrease hepatoma 28,000 Decrease liver tranplantation 6,000 Decrease premature death by 121,000 (Reid, D et al, Annals Intern Med 156(4):263-270),2012.

HCV - Natural History Stages of Fibrosis In Chronic Hepatitis Stages of Fibrosis In Chronic Hepatitis Portal Periportal 1 2 3 4 Septal Cirrhosis

Hepatocellular Carcinoma Hepatocellular Carcinoma Incidence in HCV-Positive Cirrhosis 60 40 % Cumulative incidence 20 0 0 1 2 3 4 5 6 7 8 9 10 Years of follow-up

HCV - Diagnosis Diagnostic Tests Diagnostic Tests Hepatitis C antibody tests Qualitative/Quantitative HCV RNA tests Genotyping Liver biopsy or noninvasive Fibrosure/Fibroscan tests

Counseling advise for hepatitis C patients should include: A. Drink alcohol in moderation only. B. Avoid taking any acetaminophen. C. Complete sexual abstinence. D. Receive vaccination for hepatitis A and B (if not immune). Drink alcohol in moderati.. 0% 0% 0% 0% Avoid taking any aceta... Complete sexual abstine... Receive vaccination for...

Management of hepatitis C patients: PCP s role Counseling about complete alcohol abstinence Counseling to avoid potentially hepato-toxic medications (e.g. acetaminophen over 2000 mg/day) Vaccination for hepatitis A and B (if not immune) Evaluation for antiviral treatments For cirrhotic patients: Screening for liver cancer every 6 months (ultrasound) Screening for esophageal varices (EGD) Possible referral for liver transplantation evaluation

HCV - Diagnosis Genotype in hepatitis C HCV Genotypes Six major genotypes found throughout the world Major determinant of response to antiviral therapy In U.S., 75% genotype 1, 16% genotype 2, 11% genotype 3

HCV - Treatment Goals of Hepatitis C Treatment Goals of Hepatitis C Primary Treatment Eradicate the virus Secondary Prevent progression to cirrhosis Reduce incidence of HCC Reduce need for transplantation Enhance survival

The best measure of therapeutic efficacy for hepatitis C treatment is: A. Normalization of liver transaminase levels B. Normalization of liver ultrasound C. Negative HCV RNA at the end of treatment D. Negative HCV RNA 12 weeks after the end of treatment 0% 0% 0% 0% Normalization of liver tr... Normalization of liver ul... Negative HCV RNA at the... Negative HCV RNA 12 we...

HCV - Treatment Sustained virological response (SVR) Sustained Virological Response (SVR) 200 18 Treatment 150 12 ALT (IU) 100 HCV RNA (IU/ml) 50 ALT HCV RNA 6 0 0 0 24 48 72 Weeks

HCV - Treatment Patterns of response to treatment in hepatitis C Patterns of Response to Hepatitis C Treatment Baseline Treatment Nonresponder Relapser HCV RNA HCV RNA Negative Sustained Responder Time

HCV - Treatment Pegylated interferons Pegylated Interferons Interferon Pegylated interferon

Evolution of HCV therapy

Major adverse events reported with interferon alfa treatments Adverse Effects of Alfa - Flu-like symptoms Interferons Injection-site reactions Myalgia and arthralgia Nausea, anorexia, weight loss Neuropsychiatric side effects Bone marrow suppression Thyroid dysfunction Exacerbation of underlying autoimmune disease

Major side effects of ribavirin Adverse Effects of Ribavirin Teratogenic Hemolytic anemia Skin rash Cough Insomnia

HCV - Treatment Pegylated interferon alfa-2b plus ribavirin: impact of HCV genotype Genotype Impacts SVR 100 80 IFN alfa-2b/r PEG IFN alfa -2b 0.5/R PEG IFN alfa -2b 1.5/R 79 80 82 60 40 20 33 34 42 0 Genotype 1 Genotype 2/3 Manns MP, et al., Lancet 2001; 358:958

Hepatitis C Virus Genome and Gene Products C E1 E2 NS2 NS3 Hepatitis C Virus: Genome and Gene Products NS4B NS5A NS5B 5 UTR P7 NS4A 3 UTR Structural protein coding region Nonstructural protein coding region Host signal peptidase C E1 E2 NS2 NS3 A NS4 NS5A NS5B B Core Protease Protease Cofactor Envelope Serine protease Helicase RNA polymerase

HCV-specific enzymes as targets for future therapy HCV Enzymes Are Targets for New Therapies C E1 E2 NS2 NS3 NS4B NS5A NS5B 5 UTR 3 UTR P7 NS4A NS3 Protease domain NS3 Helicase domain NS3 Bifunctional protease / helicase NS5B RNA-dependent RNA polymerase

The currently available medications for treating hepatitis C include the following classes: A. Pegylated interferon and Ribavirin B. NS3/4A protease inhibitors C. NS5B polymerase inhibitor D. NS5A inhibitor E. All of the above 0% 0% 0% 0% 0% Pegylated interferon an... NS3/4A protease inhibitors NS5B polymerase inhibitor NS5A inhibitor All of the above

Direct-Acting Antiviral Agents: Key Characteristics C E1 E2 p7 NS2 NS3 NS4A NS4B NS5A NS5B NS3/4A Protease Inhibitors (PI) High potency Limited genotypic coverage Low barrier to resistance NS5A Inhibitors High potency Multigenotypic coverage Low barrier to resistance NS5B Nucleos(t)ide Inhibitors (NI) Intermediate potency Pangenotypic coverage High barrier to resistance NS5B Nonnucleoside Inhibitors (NNI) Intermediate potency Limited genotypic coverage Low barrier to resistance

Direct Acting Antivirals (DAA): First generation Protease Inhibitors Boceprevir(Victrelis) and Telaprevir(Incivek): FDA approved 2011 Only GT 1 patients are candidates. Only used with PEG-IF and Ribavirin (triple Rx). Both TID dosing with complex protocols. Response-guided therapy for 24-44 weeks. Multiple side effects and drug interactions. SVR up to 68-75% for treatment naïve patients. years of advanced liver disease.83 million

The evolution of hepatitis C therapies 2013: The Introduction of IFN-Free HCV Therapy IFN 6% IFN + RBV 36% 1991 1998 2001 PegIFN + RBV 55% GT1 GT2/3 BOC or TVR + P/R 68-75% SIM or SOF + P/R 80-90% 2011 2013 2013 SOF + RBV 91-94%

Direct Acting Antiviral (DAA): Simeprevir (Olysio) Second-generation protease inhibitor FDA Approved Nov. 2013 Dosage: 150 mg p.o. once daily Indicated for genotype 1 patients, in combination with PEG-IN and Ribavirin Duration of therapy: 24 weeks for Treatmentnaïve and prior relapser patients (including those with cirrhosis) 48 weeks for Prior non-responder patients (including partial and null responders)

QUEST-1: Simeprevir + P/R RGT in Treatment-Naive GT 1 HCV Randomized, double-blind, placebo-controlled phase III trial 12% to 13% had cirrhosis, 56% to 57% had GT 1a HCV Stratified by GT 1 subtype, IL28B genotype Wk 12 Wk 24 Wk 48 Treatment-naive pts with GT 1 HCV (N = 394) Simeprevir 150 mg QD + P/R* (n = 264) Placebo + P/R (n = 130) P/R P/R P/R *Response-guided therapy: Patients with HCV RNA < 25 IU/mL at Wk 4 and HCV RNA undetectable at Wk 12 received a total of 24 wks of therapy. Those not achieving this on-treatment response received 48 wks of therapy. Jacobson I, et al. EASL 2013. P/R, peginterferon Abstract 1425. alfa-2a 180 µg/wk + ribavirin 1000-1200 mg/day.

HCV RNA Undetectable (%) QUEST-1: Virologic Response to Simeprevir + P/R Treatment SVR12 (%) 100 80 60 Virologic Outcomes SMV + P/R 80 80 P/R 50 efficacy in combination with peginterferon alfa and ribavirin is substantially reduced in patients infected with HCV genotype 1a with an NS3 Q80K polymorphism 40 20 0 n/ N = 202/ 254 Wk 4 12 210/ 264 65/ 130 SVR12

NS5B Inhibitor: Sofosbuvir NS5B RNA-dependent RNA polymerase (RdRP) or RNA replicase is an enzyme that catalyzes the replication of RNA from an RNA template NS5B nucleoside and non-nucleoside inhibitors fall into two distinct classes: those that directly target the enzyme s active site and those that bind elsewhere on the protein and function as allosteric inhibitors..

Direct Acting Antiviral (DAA): Sofosbuvir (Sovaldi) NS5B Nucleotide polymerase inhibitor FDA Approved December 2013 Dosage: 400 mg p.o. once daily Genotype 1&4: Sofosbuvir plus PEG-IN and Ribavirin for 12 weeks Genotype 2: Sofosbuvir plus Ribavirin for 12 weeks (all oral regimen) Genotype 3: Sofosbuvir plus Ribavirin for 24 weeks Six trials with 1947 patients

NEUTRINO: Sofosbuvir + P/R for 12 Wks in Treatment-Naive GT 1/4/5/6 HCV Patients HCV RNA < LLOQ (%) Open-label, single-arm study of sofosbuvir 400 mg QD + P/R for 12 wks in treatment-naive patients with GT 1/4/5/6 HCV 17% had cirrhosis; 89% had GT 1, 9% had GT 4, < 1% had GT 5, 2% had GT 6 HCV 100 99 99 90 80 60 40 20 n/n = 0 321/325 326/327 295/327 Wk 4 EOTT SVR122 P/pegIFN alfa-2a 180 µg/wk + RBV 1000-1200 mgday Lawitz E, et al. EASL 2013. Abstract 1411..

FISSION: Sofosbuvir/RBV vs PegIFN/RBV in Treatment-Naive GT 2/3 HCV Patients Randomized, controlled, open-label phase III noninferiority trial 20% to 21% had cirrhosis; 72% had GT 3 HCV Stratified by HCV GT (2 vs 3), HCV RNA (< vs 10 6 IU/mL), cirrhosis (yes vs no) Wk 12 Wk 24 Treatment-naive patients with GT 2/3 HCV (N = 499) Sofosbuvir 400 mg QD + RBV 1000-1200 mg/day (n = 256) PegIFN alfa-2a 180 µg/wk + RBV 800 mg/day (n = 243) Gane E, et al. EASL 2013. Abstract 5.

SVR12 (%) FISSION: SVR12 According to Genotype and Fibrosis Level Genotype 2 Genotype 3 100 80 98 82 Sofosbuvir + RBV 91 PegIFN + RBV 60 40 62 61 71 34 30 20 0 n/n = 58/59 44/54 10/11 8/13 89/145 99/139 13/38 11/37 No Cirrhosis Cirrhosis No Cirrhosis Cirrhosis Genotype 2 Genotype 3 Gane E, et al. EASL 2013. Abstract 5. Reproduced with permission.

FISSION: Better Tolerability Profile With Sofosbuvir/RBV vs PegIFN/RBV Grade 3 AEs: 7% with SOF/RBV vs 19% for pegifn/rbv Discontinuations due to AEs: 1% for SOF/RBV vs 11% for pegifn/rbv AEs Occurring in 15% in Either Arm, % SOF/RBV (n = 256) PegIFN/RBV (n = 243) P Value Fatigue 36 55 <.0001 Headache 25 44 <.0001 Nausea 18 29.0057 Insomnia 12 29 <.0001 Rash 9 17.0052 Diarrhea 9 17.0075 Irritability 10 17.0328 Decreased appetite 7 18.0001 Myalgia 8 17.0060 Pruritus 7 17.0009 Influenzalike symptoms 3 18 <.0001 Chills 3 18 <.0001 Gane E, et al. EASL 2013. Abstract 5..

Sofosbuvir + Simeprevir ± RBV: All-Oral Regimen for Genotype 1 HCV NS3 NS5B RBV

COSMOS: Simeprevir + Sofosbuvir ± RBV in Genotype 1 HCV Patients Randomized phase IIa study Wk 12 Wk 24 SVR12, % Pts with GT1 HCV Cohort 2: naives and previous null responders, F3-F4 (N = 87) Simeprevir + Sofosbuvir + RBV (n = 30) Simeprevir + Sofosbuvir (n = 14) Simeprevir + Sofosbuvir (n = 16) Simeprevir + Sofosbuvir + RBV (n = 27) Simeprevir 150 mg QD; Sofosbuvir 400 mg QD (FDA-approved Nov.2014)weight-based RBV 1000-1200 mg/day. 93 100 93 93 Lawitz E, et al. EASL 2014. Abstract O165.

Launch for New IFN-Free Regimens 2014 SIM + SOF ± RBV SIM or SOF + P/R IFN s last hurrah DCV + ASV DCV/ASV/ BMS-791325 GT1 2013 2014 2015 2016-? SOF/LDV ± RBV ABT-450/RTV/OMB + DSV ± RBV MK-5172 + MK-8742 SOF + DCV SOF/GS-5816

Newer DAA under investigation NS3/4A Protease inhibitors: Vaniprevir, Asunaprevir, GS9451, GS9256, MK-5172, Danoprevir, ABT450(Peritaprevir) NS5B polymerase inhibitors: Togobuvir, BMS791325, Mericitabin, Dasabuvir(ABT333) NS5A inhibitors: Ledipasvir, Daclastavir, ABT267(Ombitasvir), MK8742 Future direction: combination DAA regiments MK2. responder, n Lead-in

Direct Acting Antivirals (DAA): third-generation interferon-free combination therapies Sofosbuvir and Ledipasvir (NS5A inh.) Paritaprevir (ABT450)/Ritonavir(Protease inh.), Dasabuvir (ABT333), Ombitasvir (ABT267)- NS5A inh. Daclastasvir (NS5A inh.) and Asunaprevir (NS3 protease inh.) MK5172 (NS3/4A Protease inh) and MK8742 (NS5A inh)

Sofosbuvir/Ledipasvir (Harvoni) FDA approved Oct. 2014 Ledipasvir (NS5A inh) high potency against GT1a and 1b HCV Once-daily, oral, 90 mg Ledipasvir/sofosbuvir FDC Once-daily, oral FDC tablet (90/400 mg) NS5B NS5A 1. Lawitz E, et al. EASL 2011. Abstract 1219.

Treat now or wait for newer therapy? million Treat Now Genotype 1: F3 or F4, treatment naive or previous relapse Genotype 2-6: F3 or F4, treatment naive Extrahepatic manifestations of HCV Wait for New Therapy Genotype 1: F0-F2 with previous null response Genotype 2/3: previous relapse or nonresponse Poor adherence to or tolerability of peginterferon/ribavirin Relative contraindication to peginterferon/ribavirin Unclear F3 or F4 with previous partial or null response Genotype 1: F0-F2, treatment naive or previous relapse Genotypes 2-6: F0-F2, treatment naive Issues to Consider Severity of liver fibrosis Previous response to and tolerability of treatment HCV genotype Age, comorbidities, social factors

Phase III Studies: SOF/LDV FDC ± RBV in GT1 Pts Wk 8 Wk 12 ION-1 [1] SOF/LDV (n = 214) Treatment-naive GT1 HCV; SOF/LDV + RBV (n = 217) cirrhosis in 15% to 17% per arm SOF/LDV (n = 217) (N = 865) SOF/LDV + RBV (n = 217) ION-2 [2] SOF/LDV (n = 109) Treatmentexperienced SOF/LDV + RBV (n = 111) GT1 HCV; 20% cirrhotics SOF/LDV (n = 109) (N = 440) SOF/LDV + RBV (n = 111) Wk 24 SVR12, % 99 97 98 99 94 96 99 99 ION-3 [3] Treatment-naive, SOF/LDV (n = 215) noncirrhotic pts SOF/LDV + RBV (n = 216) with GT1 HCV (N = 647) SOF/LDV (n = 216) 1. Afdhal N, et al. N Engl J Med. 2014;370:1889-1898. 2. Afdhal N, et al. N Engl J Med. 2014;370:1483-1493. 3. Kowdley KV, et al. N Engl J Med. 2014;370:1879-1888. 94 93 95

Direct Acting Antivirals (DAA): combination therapy Sofosbuvir and Ledipasvir (NS5A inh.) Paritaprevir (ABT450)/Ritonavir(Protease inh.), Dasabuvir (ABT333)-NS5B inh, Ombitasvir (ABT267)- NS5A inh. Daclastasvir (NS5A inh.) and Asunaprevir (NS3 protease inh.) MK5172 (NS3/4A Protease inh) and MK8742 (NS5A inh)

ABT-450/RTV/Ombitasvir + Dasabuvir ABT-450 (paritaprevir): potent NS3/4A protease inhibitor RTV boosting to increase peak, trough, and overall exposures of ABT- 450, enables once-daily dosing Ombitasvir: potent NS5A inhibitor Coformulated with ABT450/RTV Dasabuvir: nonnucleoside NS5B polymerase inhibitor Viekira Pak NS3 RBV NS5B NNI NS5A

Phase III Studies: ABT- 450/RTV/Ombitasvir + Dasabuvir SAPPHIRE-I Tx-naive noncirrhotic pts with GT1 HCV [1] (N = 631) + RBV in GT1 Pts ABT-450/RTV/OMB + DBV + RBV (n = 473) Placebo* (n = 158) Wk 12 Wk 24 SVR12, % 96 SAPPHIRE-II Tx-experienced noncirrhotic pts with GT1 HCV [2] (N = 394) TURQUOISE-II DAA-naive cirrhotic pts with GT1 HCV [3] ; 59% tx experienced, 36% null responders (N = 380) ABT-450/RTV/OMB + DBV + RBV (n = 297) Placebo (n = 97) ABT-450/RTV/OMB + DBV + RBV (n = 208) ABT-450/RTV/OMB + DBV + RBV (n = 172) 96 92 96 1S, et al. *Placebo recipients crossed over to active treatment regimen at Wk 12.

Direct Acting Antivirals (DAA): combination therapy Sofosbuvir and Ledipasvir (NS5A inh.) Paritaprevir (ABT450)/Ritonavir(Protease inh.), Dasabuvir (ABT333), Ombitasvir (ABT267)- NS5A inh. Daclastasvir (NS5A inh.) and Asunaprevir (NS3 protease inh.) MK5172 (NS3/4A Protease inh) and MK8742 (NS5A inh)

BMS Agent in Development: NS5A Inhibitor (BMS-790052, Daclatasvir) Shaw-Stiffel T. Reference to Hepatitis C Infection. 2004 Adapted from: Asselah T & Marcellin P. Liver Int 2011;31(s1):68 77. NS5A Protein that plays a central role in viral replication and assembly

Direct Acting Antivirals (DAA): combination therapy Sofosbuvir and Ledipasvir (NS5A inh.) Paritaprevir (ABT450)/Ritonavir(Protease inh.), Dasabuvir (ABT333), Ombitasvir (ABT267)- NS5A inh. Daclastasvir (NS5A inh.) and Asunaprevir (NS3 protease inh.) MK5172 (NS3/4A Protease inh) and MK8742 (NS5A inh)

Overall summary of treatment options for Genotype 1 SOF/LDV: 8 weeks, non-cirrhotic, treatment-naïve, viral titer < 6 million 12 weeks, non-cirrhotic, treatment- naïve or experienced 24 weeks, cirrhotic, treatment-experienced ABT450/r/OMB/DAS: 12 weeks, noncirrhotic, treatment naïve and experienced 24 weeks, cirrhotic, prior null responders RBV necessary for G1a, not G1b Other options: ASV/DCV for G1b for 24 weeks MK-5172 + MK-8472

Summary 2014 Current all-oral therapy: -- Sofosbuvir + ribavirin (G2, G3) Sofosbuvir + simeprevir (G1) Sofosbuvir/ledipasvir (G1) Additional all-oral therapies for GT1 will be approved in 2014 ABT-450/RTV/ombitasvir + dasabuvir (G1) Daclatasvir + asunaprevir (G1) Expect > 90% SVR, 12- to 24-wk duration Interferon will not be required RBV-free therapies also desirable G4 still requires P/R/Sofosbuvir for 12 weeks (94-96% SVR)

HCV: Future developments and challenges Effective screening yields 1-2 million patients Easier and more efficacious treatments cure majority of patients Primary care physicians may assume increased management roles Affordability of treatment may be main drawback ($100,000 to 150,000 x 12 weeks) Alternative and novel international funding sources may be needed to allow increased access to treatment HCV could become a rare disease in the coming decades (M. Kabiri, et al. AIM 161:3, 2014)