Evolving Role of Current & Emerging Therapies in the Management of (HCV)

David H. Winston, MD, FACP, AGAF Section Head, Gastroenterology & Hepatology CIGNA HealthCare of Arizona, Sun City

SUN CITY

1 2 HYBRID

Objectives

• Learn the current and future treatment strategies for HCV • Understand the epidemiology and natural history of HCV • Learn how to diagnose and screen for HCV

3 (HCV)

• Single-stranded RNA virus • Only member of genus Hepacivirus in the Flaviviridae family • Humans are the only known natural host • Unlike the DNA viruses HIV and HBV CURE of HCV is possible

Hepatitis C Differs from HIV and HBV: HCV can be Cured!

HBV HIV HCV

Host cell Viral RNA

cccDNA Proviral DNA

Host DNA

Nucleus

TREATMENTTREATMENT TREATMENT Long-term Long-term Viral Eradication = Cure suppression of viral suppression of viral replication replication2,3

1. Pawlotsky JM. J Hepatol 2006;44:S10-S13; 2. Siliciano JD, Siliciano RF. J Antimicrob Chemother 2004;54:6-9; 3. Lucas GM. J Antimicrob Chemother 2005;55:413-416

4 EPIDEMIOLOGY OF HCV

Chronic HCV: A Global Health Problem

FAR EAST ASIA 60 M WEST EUROPE U.S.A. 9 M EAST 3.2 M MEDITERRANEAN 20M SOUTH EAST ASIA 30 M AFRICA 32 M

SOUTH AMERICA 10 M AUSTRALIA 0.2 M

Weekly Epidemiological Record. N° 49, 10 December 1999, WHO

5 HCV Genotypes 6 HCV genotypes that differ from each other by 31-34% in their nucleotide sequences

1, 2, 3 1, 2, 3 1,2,3 6 4 1,3 4 1, 2, 3

1,2,3 5

Simmonds P. Curr Stud Hematol Blood Transfus. 1998;62:38-63.

Genotype and Viral Load in U.S. Patients

Genotype 4,5,6 HVL 2.7% Genotype 2,3 LVL Genotype 4,5,6 7.3% LVL 1.3% Genotype 2,3 HVL 14.7% Genotype 1 HVL Genotype 1 LVL 49.5% 24.5%

HIGH VIRAL LOAD:>800,000 IU/ML

Alter et al. N Engl J Med 1999;341;556-562. LOW VIRAL LOAD:<800,000 IU/ML Blatt et al. J Viral Hepatitis 2000;7(3):196-202.

6 Current Prevalence of HCV • 200 million persons have been infected with HCV worldwide (anti-HCV positive)1 • 170 million have chronic disease worldwide (HCV RNA positive)1 • 3.5 million Americans have been infected with HCV (anti-HCV positive)2 –True prevalence at least 5.2 million3 • 2.7 million Americans have chronic disease (HCV RNA positive)2

1. Edlin BR. Hepatology 2005:42(suppl 1):213A. 2. Denniston MM et al. Ann Intern Med 2014;160:293-300 3. Chak E, Talai AH, Sherman KE, Schiff ER, Saab S. Liver International 2011; 31:1090-1101

Chronic HCV Infection in the US

• Chronic HCV cases not included in NHANES estimate: – Homeless – Incarcerated – Veterans – Active military – Healthcare workers – Nursing home residents – Chronic hemodialysis – Hemophiliacs

Chak E, Talai AH, Sherman KE, Schiff ER, Saab S. Liver International 2011; 31:1090-1101

7 Prevalence of HCV in the U.S. (NHANES 2001-2010)

Overall prevalence: 1% (2.7 million), 81% were born between 1945 and 1965 (Baby Boomers)

3 2.7 2.5 2.2 2

1.5 1.3 1.0 1.0 1

0.5 Anti-HCV Positive Anti-HCV Positive % 0 White Black Hispanic Male Female

Denniston MM, et al. Ann Internal Med 2014;160(5):293-300.

Chronic HCV in U.S. (3.2M)

Undiagnosed ~2.4M (75%)

Diagnosed .8M (25%)

59% of diagnosed HCV 41% of diagnosed HCV patients UNTREATED ~590K patients TREATED ~410K (18% of all HCV) (13% of all HCV)

ALF @ www.liverfoundation.org/education/info/hepatitisc. Accessed April 8, 2014 CDC Hepatitis C fact sheet. @ www.cdc.gov. Accessed April 8, 2014 IOM. Hepatitis and liver cancer: a national strategy for prevention and control of hepatitis B and C. Washington, DC. 2010

8 Natural History of HCV: A Chronic Progressive Liver Disease

HCV Natural Disease Progression

Anti-HCV (+) Virus Cleared Cirrhosis HCV-RNA (-) •Connective tissues destroying hepatocytes 15% -25% (<6 months) •Generally irreversible

1%-4% 20-30% per year (20-30 years)

Acute Chronic Fibrosis HCV HCV 75%-85% 60%-70% (>6 months) Anti-HCV (+) Hepatocellular HCV-RNA (+) Carcinoma (HCC)

Chen SL and Morgan TR. Int. J. Med. Sci. 2006. 3:47-52.

9 HCV Disease Progression

Stage 0 Stage 1 Stage 2 No Fibrosis Portal Fibrosis Periportal Fibrosis

Few No Septa Septa Stage 4 Stage 3 Cirrhosis Bridging Fibrosis

Many Sepa

Razavi H, et al. Hepatology. 57(6):2164-2170

Chronic HCV: Progression to Cirrhosis

15%-30% of patients Mild

Moderate

Severe

Cirrhosis 50-65% of patients Decom. Cirrhosis 20%-30% of patients HCC

0 1020304050 Years

Shiffman ML. Viral Hepatitis Rev. 1999;5:27-43

10 Factors Associated With Disease Progression

• ETOH consumption: >30 g/day in males >20 g/day in females • Disease acquisition at > 40 years •Male • HIV or HBV co-infection • Hepatic Steatosis: obesity, metabolic syndrome

Ishida et al. Clin Gastro and Hepatol 2008;6:69-75 Swain et al. EASL 2005. Patton et al. J Hepatol 2004;40:484-490. Poynard et al. Lancet 1997; 349: 825-832.

Factors Associated With Disease Progression: ETOH

• > 30 g/day in male: 2-3 drinks > 20 g/day in females: 2 drinks

 

NIH Consensus Statement on Hepatitis C, 2002.

11 HCV and Alcohol

100

80

60 HCV 40 HCV + alcohol

Cirrhosis (%) 20

0 10 20 30 40 Years Following Exposure Excessive alcohol intake characterized as > 20 g/day for women and > 30 g/day for men

Wiley TE, et al. Hepatology. 1998:28:805-809.

Factors Associated With Disease Progression: Age

Patients infected with HCV when over 40 have a higher degree of fibrosis regardless of how long they have had the disease

12 HCV Fibrosis Progression: Effect of Age

4.0

3.0 Age at time of infection 2.0 > 40 years < 40 years 1.0 Fibrosis Score

0 < 10 11-20 21-30 31-40 > 40 Duration of Infection (Years)

Poynard T, et al. Lancet. 1997;349:825-832.

Factors Associated With Disease Progression: Obesity

Obesity-related insulin resistance can lead to fatty liver and NASH and accelerate the development of fibrosis in HCV

Clouston AD, Jonsson JR, Powell EE. Clin Liver Dis 2007;11:173-189.

13 Fibrosis Progression in HCV: Effect of Hepatic Steatosis

100 Steatosis: 80 <5% 5-10% 60 11-30% >30% 40 progression

20 % of patients with fibrosis withpatients of %

0 0 20406080100 Months

Fartoux L et al. Hepatology. 2005;41:82-87.

Factors Not Influencing Progression

• Transaminase level (ALT) • Viral load • Mode of transmission • Genotype

Swain et al. EASL 2005. Patton et al. J Hepatol 2004;40:484-490. Poynard T, et al. Lancet 1997;349:825-832.

14 Chronic HCV: The Epidemic has Just Begun

At least 2.7 million persons are chronically infected with HCV Between 2010-2030 if NO treatment is provided

1,040,000 will have developed cirrhosis 254,664 will have developed HCC 537,928 will die

Davis G, Alter MJ, El-Serag H, Poynard T, Jennings LW. Gastroenterology. 2010;138:513-521

Estimated Prevalence of Esee Chronic HCV and Cirrhosis Peak Prevalence

● Acute peaked between 1970 and 1990 The● The highest peak prevalence of chronic of HCV cirrhosis prevalence is projected was to2001 be ● The highest prevalence of cirrhosis is projected to be between 2010 and 2030

Davis G, Alter MJ, El-Serag H, Poynard T, Jennings LW. Gastroenterology. 2010;138:513-521

15 The Tsunami of HCV Cirrhosis Complications: Decompensation and HCC

Hepatic decompensation • Ascites • Variceal bleed • Encephalopathy

Davis G, Alter MJ, El-Serag H, Poynard T, Jennings LW. Gastroenterology. 2010;138:513-521

Diagnosis & Screening of HCV

16 Importance of Diagnosing HCV

• The Primary Care Provider (PCP) has a unique window of opportunity to make a diagnosis of HCV and refer for treatment prior to the development of cirrhosis and its complications –Improved survival –Improve quality of life –Will reduce the economic burden of HCV and result in cost savings

HCV Screening Is the First Step on the Road to a Cure

Treatment Cure

Counseling Evaluation

Screening

17 HCV Patients Are Undiagnosed Because of Screening Barriers to Diagnosis

Undiagnosed ~2.4M (75%)

Diagnosed .8M (25%)

59% of diagnosed HCV 41% of diagnosed HCV patients UNTREATED ~590K patients TREATED ~410K (18% of all HCV) (13% of all HCV)

ALF @ www.liverfoundation.org/education/info/hepatitisc. Accessed September 3, 2011 CDC Hepatitis C fact sheet. @ www.cdc.gov. Accessed September 3, 2011 IOM. Hepatitis and liver cancer: a national strategy for prevention and control of hepatitis B and C. Washington, DC. 2010

HCV Patients Are Undiagnosed Because of Screening Barriers to Diagnosis

• Patient Barriers –Persons infected with HCV are usually asymptomatic and unaware of their infection –Persons infected with HCV are usually unaware of the risk factors for HCV

IOM. Hepatitis and liver cancer: a national strategy for prevention and control of hepatitis B and C. Washington, D.C. 2010 Centers for Disease Control and Prevention. MMWR. 1998;47(RR-19):1-39

18 I hope I don’t have Hepatitis C

19 The Lack of Symptoms in Chronic HCV Infection

Symptomatic The most common symptom is fatigue 37% 100 Cirrhosis 80 80 7% 60

40

Patients (%) 20

0 56% Fatigue Asymptomatic

Alter MJ, et al. N Engl J Med 1999;341(8):556-62

HCV Patients Are Undiagnosed Because of Screening Barriers to Diagnosis

• Primary Care Provider Barriers1 – Routine HCV risk factor assessment not current PCP practice2 – Elevated LFTs, not risk factors, is current marker for PCPs ordering a liver panel3 • Normal ALT in males is up to 30 • Normal ALT in females is up to 19

1IOM. Hepatitis and liver cancer: a national strategy for prevention and control of hepatitis B and C. Washington, D.C. 2010 2Shehab, T et al. Viral Hepat. 2001;8(5):377-383. 3Rawls, R et al. J Clin Gastroenterol. 2005;39(2):144-151.

20 Common Risk Factors for HCV

HCV is spread through contact with infected blood

• IV drugs use now accounts for 2/3 of HCV in US • Received blood or blood products or solid organ transplant before 1992 • Hemodialysis patients before 1992 • Needle Sticks

Common Risk Factors for HCV

HCV is spread through contact with infected blood

• Intranasal cocaine with shared implements • Body piercing with contaminated needles • Tattooing with contaminated needles or ink • Incarceration

21 Less Common Risk Factors

• Sharing of household items that could carry infected blood: razors, toothbrushes, manicure implements • Traumatic contact with blood: cuts, nose- bleeds, menstrual blood • Perinatal transmission: 5% of deliveries from HCV positive mothers

NIH Consensus Statement on Management of Hepatitis C, 2002. Alter MJ, et al. N Engl J Med 1999;341:556-562. Resti M, et al. BMJ 1998;317:437-441. Vandelli C. Am J. Gastro 2004;99:855-859.

Less Common Risk Factors

• Sexual transmission: accounts for less than 5% of all cases: Seen in high-risk sexual behavior (multiple sex partners, prostitutes, man to man sex) where there is trauma to the mucosa) –The risk in monogamous partners is extremely low

NIH Consensus Statement on Management of Hepatitis C, 2002. Alter MJ, et al. N Engl J Med 1999;341:556-562. Resti M, et al. BMJ 1998;317:437-441. Vandelli C. Am J. Gastro 2004;99:855-859.

22 The Role of the PCP: Look for Risk Factors

It’s been up to the PCP to identify and screen all their patients with risk factors for HCV

Ask about Risk Factors when Asking about Alcohol and Tobacco

23 Risk-based Screening is not Working: You Can’t Treat What You Haven’t Diagnosed

Diagnosed HCV cases

Undiagnosed HCV cases

BABY BOOMERS

The CDC in 2012 and the US Preventive Services Task Force (USPSTF) in 2013 have recommended a 1-time screening for all persons born between 1945 and 1965 because of their high prevalence of HCV ● With Obamacare all screening tests recommended by the USPSTF will be free

24 81% of HCV found in BABY BOOMERS: THE ERA OF SEX, DRUGS AND ROCK AND ROLL

Screening Guidelines for Diagnosing Chronic HCV

• Screen all baby boomers and all patients with risk factors regardless of age and all patients with  LFT’s with EIA anti-HCV – >99% sensitivity • In patients with  LFT’s, look for other causes of  LFT’s: – HAAb, HBsAg, HBcAb, HBsAb – Iron, TIBC, ferritin – Antinuclear, antimitochondrial, and antismooth muscle antibodies

25 Diagnosis of HCV

• Confirm positive anti-HCV with quantitative HCV RNA PCR –Positive within 1-3 weeks after exposure –Denotes active disease and infectivity –Quantitative assays detect to low levels: Quest Heptimax (5 IU/ml) or LabCorp Quanta-Sure (10 IU/ml)

• Check HCV genotype at the same time

Serologic Pattern of Chronic HCV

anti-HCV Symptoms +/-

HCV RNA Titer

ALT

Normal 01 2 3 4 5 61234 Months Years Time after Exposure

26 Treatment of Hepatitis C: 2014

HEPATITIS C

Goals of Treatment of HCV

• Primary Goal: – Permanent eradication of virus from serum: Sustained Viral Response (SVR) • Undetectable HCV RNA 6 months after completion of treatment with current treatment regimes • Undetectable HCV RNA 3 months after treatment with the newer combinations in the future • SVR is synonymous with “cure”

27 Sustained Virologic Response (SVR) Leads to Improved Outcome

SVR

Viral Improved Clinical Improved Liver Eradication1 Outcomes2 Histology3

↓Decompensation ↓HCC ↓Mortality

1. Maylin S, et al. Gastroenterology. 2008;135:821-829. 2. Poynard T, et al. Gastroenterology. 2002;122:1303-1313. 3. Veldt BJ, et al. Ann Intern Med. 2007;147:677-684.

Improvements in Therapy of HCV

Standard INF INF/RBV PEG/INF PEG/INF/ DAA’s 2nd Gen INF 1991 1998 2001 RBV 2002 2011 DAA’s 2013 Free 90 + 90 80-81 68-75

54-56

42 39 34 SVR Rate (%) 16 6

IFN IFN IFN/RBV IFN/RBV PEG‐IFN PEG‐ PI/PEG‐ SMV + Peg‐ SOF/PEG‐ 6 mo 12 mo 6 mo 12 mo 12 mo IFN/RBV IFN/RBV IFN/RBV IFN/RBV 12 mo 6‐12 mo 6‐12 mo 3 mo

Year of publication Phase 3 NEUTRINO: Lawitz E, et al. APASL 2013. Singapore. Oral #LB-02 SVR12 rate of 90% among GT 1 patients in the Phase 3 NEUTRINO trial (12 weeks of SOF+PEG-IFN+RBV) Adapted from Strader DB, et al. Hepatology 2004;39:1147-71. Jacobson I, et al. EASL 2013. Amsterdam. The Netherlands. Poster # 1425. Manns M, et al. EASL 2013. Amsterdam. The Netherlands. Oral #1413. INCIVEK [PI]. Cambridge, MA: Vertex Pharmaceuticals; 2012. VICTRELIS [PI]. Whitehouse Station, NJ: Merck & Co; 2011.

28 Up to 2011, the Treatment of HCV GT1 was Pegylated and

• The unsatisfactory response rate in genotype 1 (54-56%) led to the development of a new class of HCV drugs called Direct Acting Antivirals (DAA’s) that directly inhibit viral replication

HCV Life Cycle and DAA Targets

Receptor binding and endocytosis Transport and release Fusion and uncoating Translation ER lumen Virion and (+) RNA LD polyprotein LD assembly processing

LD NS3/4 protease Membranous NS5B polymerase inhibitors web RNAinhibitors replication ER lumen Nucleoside/nucleotide Nonnucleoside

NS5A* inhibitors

*Block replication complex formation, assembly

Adapted from Manns MP, et al. Nat Rev Drug Discov. 2007;6:991-1000.

29 HCV Genome and DAA Targets

Scheel TKH, Rice CM. Nature Medicine 2013; 19:837-849

Emergence of Pre-existing Resistant Mutants During Treatment with DAA Monotherapy

Baseline HCV RNA Viral breakthrough

X X X X X

HCV RNA X X X X

Before Treatment Time on Treatment with DAA Alone

Resistant virus Sensitive virus

30 Use of Multiple Drugs Prevent Selection of Resistant Variants

Baseline HCV RNA All DAA’s now and in the future are used in combination with other HCV drugs to prevent viral resistance

X X X X X X

HCV RNA X X X X

Before Treatment Time on Treatment with DAA + PegIFN + RBV

Resistant virus Sensitive virus

The First DAAs were 2 Protease Inhibitors: and with PegINF and Ribavirin

Limitations: • They are only approved for genotype 1 • Efficacy: Many patients don’t achieve SVR • Tolerability Higher discontinuation rates • Complicated in real-world settings than in } clinical trials Regimens • Serious drug-drug interactions

31 Second Generation DAA’S

• Goal: –Increase genotype 1 SVR –Shorten the duration of treatment –Avoid serious side effects –Improve SVR in genotypes other than 1 • The first FDA approved 2nd generation DAAs are and

Sofosbuvir

• NS5B Polymerase Nucleoside Inhibitor • Potent antiviral activity against HCV GT1–6 • High barrier to resistance • Oral once a day tablet with no food effect • No clinically significant drug interactions • Generally safe and well-tolerated in clinical studies to date (> 3,000 patients) – Most common side effects are fatigue and headache

32 Sofosbuvir

• Treatment in genotypes 1 + 4 is 12 weeks with PEG/RBV – Sofosbuvir and RBV for 24 weeks if interferon contraindicated or patient intolerant • Treatment in genotype 2 is 12 weeks with RBV • Treatment in genotype 3 is 24 weeks with RBV • HCV-HIV-1 Co-infection: Safe with multiple antiretroviral agents

NEUTRINO: Sofosbuvir + P/R for 12 Weeks in Treatment-Naive GT 1/4/5/6

100 96 100 92 100 90 89 80 80 80

60 60

40 40 SVR12 (%)

20 20 n/N = 295/327 261/292 27/28 7/7 252/273 43/54 0 0 Overall GT1 GT4 GT5,6 No Cirrhosis Cirrhosis Lawitz E, et al. N Engl J Med. 2013;368:1878-1887

33 VALENCE: SVR12 With 12 or 24 Wks of SOF + RBV in GT2 and GT3

GT2 12-Wk Treatment GT3 24-Wk Treatment

97 100 100 100 94 91 88 92 87 80 80 60 60 60

40 40 SVR12 (%) SVR12 (%) 20 20 n/N = 29/30 2/2 30/33 7/8 n/N = 86/92 12/13 87/100 27/45 0 0 Naive, Naive, Exp’d Exp’d, Naive, Naive, Exp’d Exp’d, Noncirrhotic Cirrhotic Noncirrhotic Cirrhotic Noncirrhotic Cirrhotic Noncirrhotic Cirrhotic

Zeuzem S, et al. AASLD 2013. Abstract 1085.

Simeprevir

•2nd Generation once a day NS3/4A Protease Inhibitor • Effective in genotypes 1, 2, 4, 5, 6 • FDA approved for use in genotype 1 only • No Benefit if Q80K Positive: NS3 Q80K is a naturally occurring polymorphism that occurs in 48% of US genotype 1a • 61 drug-drug interactions (CYP3A4) • Adverse reactions: Photosensitivity, rash, pruritus, nausea, myalgia, and dyspnea • Mild-moderated bilirubin elevations

34 Simeprevir

• No dose recommendation for hepatic impairment: • 2.4-fold higher concentration in moderate hepatic impairment (Child-Pugh Class B) • 5.2-fold higher concentration in severe hepatic impairment (Child-Pugh Class C) • Treatment duration (Uses RGT and a PEG/RBV tail) • Treatment naïve and prior relapsers: 12 weeks SMV/PEG/RBV + 12 weeks PEG/RBV • Prior non-responders: 48 weeks (12 weeks SMV/PEG/PBV + 36 weeks PEG/RBV)

Simeprevir Naïve Genotype 1 SVR: Pooled Quest 1 and 2

100 No Benefit if Q80K Positive 85 80 84 80 75 58 60

40 SVR12 (%) 20

0 GT 1 GT 1a GT 1b GT 1a without GT 1a with Q80K Q80K

Simeprevir Package Insert November 2013 Lenz O, et al. 64th AASLD; Washington, DC; November 1-5, 2013. Abst. 1101.

35 Simeprevir Treatment Experienced Genotype 1 SVR (Promise Study)

No Benefit if Q80K Positive

100 86 79 78 80 70

60 47 40 SVR12 (%) 20

0 GT 1 GT 1a GT 1a without GT 1a with GT 1b Q80K Q80K

Simeprevir Package Insert November 2013

Response-Guided Therapy Paradigm with Simeprevir + Peg INF/RBV in Tx-Naïve + Relapse patients including Cirrhosis Week 0 4 12 24 48

HCV RNA Undetectable Undetectable Undetectable

SIM+ PEG/RBV PEG + RBV

HCV RNA Detectable Undetectable or Undetectable or (<25IU/ml) Detectable (<25IU/ml) Detectable (<25IU/ml)

SIM +PEG/RBV PEG + RBV

Simeprevir Package Insert November 2013

36 Treatment Recommendations www.hcvguidelines.org Genotype Recommended Alternative Not recommended 1 TVR + PEG/RBV SOF + PEG/RBV SMV x 12 wk + BOC + PEG/RBV INF-Eligible x 12 wk PEG/RBV x 24 wk in PEG/RBV Q80K neg patients Monotherapy with PEG, RBV, or a DAA 1 SOF + SMV ± RBV SOF + RBV x 24 wk x 12 wk INF-Ineligible “This regimen should “This regimen should be considered only be considered only those patients who those patients who require immediate require immediate treatment because it treatment because it is anticipated that is anticipated that safer and more safer and more effective INF-free effective INF-free regimens will be regimens will be available by 2015” available by 2015”

Treatment Recommendations

Genotype Recommended Alternative Not recommended 2 SOF + PEG/RBV None PEG/RBV x 24 wk x 12 wk Monotherapy with PEG, RBV, or a DAA Any regimen with TVR, BOC, or SMV 3 SOF + RBV x 24 wk SOF + PEG/RBV PEG/RBV x 24-48 wk x 12 wk Monotherapy with PEG, RBV, or a DAA Any regimen with TVR, BOC, or SMV 4 SOF + PEG/RBV SMV x 12 wk + PEG/RBV x 48 wk INF Eligible x 12 wk PEG/RBV x 24-48 wk Monotherapy with PEG, RBV, or a DAA INF Ineligible SOF + RBV x 24 wk None TVR or BOC regimens 5 or 6 SOF + PEG/RBV x PEG/RBV x 48 wk Monotherapy with PEG, 12 wk RBV, or a DAA TVR or BOC regimens

37 HCV Treatment

• Shorter treatment duration • SVR rates of 95+% • Fewer adverse events • All oral drug combinations for all genotypes

Interferon Free Treatment for HCV

The Holy Grail of Hepatology (Available starting fall 2014)

38 WHAT ARE THE PROBLEMS WITH

Peginterferon Side Effects

• Psychiatric symptoms: – Depression, anxiety, mood changes, suicidal ideation • Hematologic side effects: – Anemia, neutropenia, thrombocytopenia • Flu-like symptoms: – Headache, fatique, chills, myalgias, arthralgias • GI symptoms: – Nausea, diarrhea, dyspepsia • Retinopathy • Thyroid toxicity

39 Contraindications to Peginterferon

• History of/or ongoing poorly controlled psychiatric disease (depression, bipolar) • Decompensated cirrhosis • Autoimmune disease • Active substance abuse • Kidney and heart transplants

New HCV Drugs in Development

Non- NS3/4A NS5B Polymerase Nucleoside Host-Targeting Protease NS5A Inhibitors Nucleos(t)ide Inhibitors NS5B Antivirals Inhibitors Inhibitors ALS-2200 Tegobuvir Alisporovir Mirvirsen ABT-267 IDX184 NIM811 GSK-2336805 PSI-938 Lomibuvir SCY-635 BMS824393 Setrobuvir Cyclosporin A GS-9451 IDX719 GS-9669 ITX5061 GS-9256 PPI-461 BMS-791325 ABT-450 PPI-668 MK-3281 MK-5172 ACH-3102 TMC-647055 BILN-2061 MK-8742 ABT-333 ACH-2684 GS-9669

Dugum M, O’Shea R. Cleveland Clinic Journal of Medicine 2014; 81:159-172

40 Phase III Studies

Combination Sofosbuvir and Ledipasvir

• Sofosbuvir plus ledipasvir (NS5A inhibitor) – Single tablet • Three phase III studies: – Ion I: Genotype 1 naïve with and without cirrhosis – Ion II: Genotype 1 treatment experienced – Ion III: Genotype 1 naive

41 ION-1 (Treatment Naïve)

• Sofosbuvir/ ledipasvir for 12 weeks: SVR12 99%

– Cirrhosis present SVR12 94% Cirrhosis absent SVR12 99%

• Sofosbuvir/ledipasvir/RBV for 12 weeks: SVR12 97%

– Cirrhosis present SVR12 100% Cirrhosis absent SVR12 97%

• Sofosbuvir/ledipasvir for 24 weeks: SVR12 98%

– Cirrhosis present SVR12 94% Cirrhosis absent SVR12 98%

• Sofosbuvir/ledipasvir/RBV for 24 weeks: SVR12 99%

– Cirrhosis present SVR12 100% Cirrhosis absent SVR12 99% • Conclusion: Adding RBV and/or extending treatment to 24

weeks did not significantly increase SVR12 • Adverse events of fatigue, headache and insomnia higher with ribavirin Mangla A et al. EASL 2014 London, April 12, 2014, Afdhal N et al, NEJM Online April 12, 2014

ION-2 (Treatment-Experienced)

• Sofosbuvir/ledipasvir for 12 weeks: SVR12 94%

• Sofosbuvir/ledipasvir/RBV for 12 weeks: SVR12 96%

• Sofosbuvir/ledipasvir for 24 weeks: SVR12 99%

• Sofosbuvir/ledipasvir/RBV for 24 weeks: SVR12 99% • Conclusion: Adding RBV and/or extending treatment

to 24 weeks did not significantly increase SVR12 • No new adverse events with sofosbuvir and ledipasvir – Fatigue, nausea, insomnia consistent with ribavirin

Afdhal N et al. EASL 2014 London. April 11, 2014 Afdhal N et al. NEJM Online April 11, 2014

42 ION-3 (Treatment Naïve without cirrhosis)

• Sofosbuvir/ledipasvir for 8 weeks: SVR12 94%

• Sofosbuvir/ledipasvir/RBV for 8 weeks: SVR12 93%

• Sofosbuvir/ledipasvir for 12 weeks: SVR12 95% • Conclusion: Adding RBV and/or extending treatment

to 12 weeks did not increase SVR12 • Adverse events of fatigue, nausea, and insomnia were higher in the ribavirin group

Kowedley KV et al. EASL 2014 London, April 10, 2014 Kowedley KV et al. NEJM Online, April 10, 2014

3D plus Ribavirin Combination:

• ABT-450 (protease inhibitor boosted with ) • (NS5A inhibitor) • (non-nucleoside polymerase inhibitor) • 3 phase III studies: – SAPPHIRE-I: 12 week treatment in naïve genotype 1, non- cirrhotic patients – SAPPHIRE-II: 12 week treatment in treatment- experienced genotype 1, non-cirrhotic patients – TURQUOISE-II: Compensated cirrhotic genotype 1 patients

43 SAPPHIRE-I (Treatment Naïve)

• Overall: SVR12 96.2%

• Genotype 1a: SVR12 95.3%

• Genotype 1b: SVR12 98%

• Similar SVR12 rates in all subgroups (sex, race, age, fibrosis stage and viral load) • Adverse events were generally mild and included fatigue, headache, nausea, and pruritus

Feld JJ et al. EASL 2014 London, April 11, 2014 Feld JJ et al. NEJM Online April 11, 2014

SAPPHIRE-II (Treatment Experienced)

• Overall: SVR12 96.3%

• Genotype 1a: SVR12 96.0%

• Genotype 1b: SVR12 96.7%

• Prior relapsers: SVR12 95.3%

• Prior partial responders: SVR12 100%

• Prior null responders: SVR12 95.2% • Adverse events were generally mild and included fatigue, headache, nausea, and pruritus

Zeuzem S et al. EASL 2014 London, April 10, 2014 Zeuzem S et al. NEJM Online April 10, 2014

44 TURQUOISE-II (Compensated Cirrhosis)

• Genotype 1 compensated (Child-Pugh A) cirrhosis, naïve and treatment experienced • The overall efficacy of 12-week treatment (92%) and 24-week treatment (96%) did not differ significantly – 1a patients with a prior null response had a 12 week SVR of 80% and a 24 week SVR of 92.9% suggesting 24 weeks is more effective • The most common adverse events were fatigue, headache, nausea and pruritus

Poordad F et al. EASL 21014 London, April 12, 2014 Poordad F et al. NEJM Online, April 12, 2014

What Is the Ideal HCV Regimen?

Easy Dosing Once daily, low pill burden

All Oral Highly Effective PegIFN/RBV replaced High efficacy in all with alternate populations including backbone with low cirrhosis chance of resistance Simple Regimen Pan-Genotypic Safe and Tolerable Short duration, Regimen can be Few or easily simple, used across all manageable adverse straightforward genotypes effects stopping rules

45 The Price of a Cure: DAA is $1,000 a Pill SVR is Priceless

Increasing Health Care Costs Associated With Progressive Liver Disease in the Aging HCV-Infected Population

Prevalence Health Care Cost (95% CI) (95% CI) Prevalence (Million) Prevalence Health Care Cost (Billion)

. 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

Razavi H, et al. Hepatology 2013, 57(6):2164-2170

46 Healthcare Costs Associated with HCV are Substantial and Increase with Disease Severity

Estimated Mean Annual Costs

Retrospective analysis of demographics, healthcare utilization and healthcare costs of 33,309 chronic HCV patients in a large, US private insurance database (1/2002 – 8/2010)

Gordon SC, et al. Hepatology. 2012;56;1651-1660.

HCV is a Progressive Disease and HCV-Related Healthcare Costs are Directly Related to Disease Severity

PPPM Costs

Retrospective analysis of demographics, healthcare utilization and healthcare costs of 33,309 chronic HCV patients in a large, US private insurance database (1/2002 – 8/2010) Numbers in parentheses are +SD. *P<.001 vs non-cirrhotic liver disease. Gordon SC, et al. Hepatology. 2012;56:1651-1660.

47 HCV Therapy Is Associated with Lower Healthcare Costs and Curing HCV Should Lower Downstream Health Care Costs

Mean follow-up per patient per month (PPPM) by treatment history and liver disease severity HCV-related costs Medical costs Total cost s 6000 P<0.001 P<0.001 P<0.001 P<0.001P<0.826 P<0.001 P<0.001 P<0.057 P<0.001 5137

5000 4656 31% lower

4000 3634 3547

3186 3000 Treated 24% 2389 lower 35% Untreated lower 2000 1802 1370 1369 1224 1193 1007 1023 885 1000 591 729 543 225 Predicted cost (2010 $US PPPM) 0 NCD CC ESLD NCD CC ESLD NCD CC ESLD Retrospective analysis of demographics, healthcare utilization and healthcare costs of 33,309 chronic HCV patients in a large, NCD=non-cirrhotic disease US private insurance database (1/2002 – 8/2010) CC=compensated cirrhosis ESLD=end-stage liver disease Gordon S.C., et al. Aliment Pharmacol Ther. 2013; 38:784-793.

SVR is Priceless and Cost Effective

• SVR in non-cirrhotic HCV patients prevents the development of cirrhosis and its complications • SVR in compensated cirrhosis lowers the rate of complications, liver cancer, and transplant • SVR improves all-cause mortality in all patients • SVR improves quality of life in all patients • SVR increases life expectancy

Reau NS, Jensen DM. Hepatology 2014; 59:1246-1249

48 Treatment with Oral IFN-free Regimens will be the Most Cost-Effective Strategy

• Treatment is short term and curative in almost all patients • Although DAA is $1,000 a pill ($84,000/12 weeks), the cost is similar to previous 12 week protease inhibitor regimes which have a lower SVR (telaprevir $68,000, PEGINF $12,340) • There are not as many costs associated with INF-free treatment compared to INF treatment (cost of managing side effects plus $5,000/12 weeks for visits, labs, etc)

Younossi ZM et a. J Hepatology 2014;60:530-537 Pockros P. 29th Annual New Treatments in Chronic Liver Disease, La Jolla, March 29, 2014 Reau, NS, Jenson DM. Hepatology 2014;59:1246-1249

Treatment with Oral IFN-free Regimens will be the Most Cost-Effective Strategy

• The cost of not treating patients is higher than $84,000 – Patients with compensated cirrhosis may live for over a decade accruing over $270,000 in expense prior to developing end-stage liver disease – It markedly reduces the national cost of treating cirrhosis and HCC ($30,000-$70,000 annual cost x 5-10 years/patient) – It markedly reduces need for liver transplantation ($350,000/transplant + $145,000 year)

Younossi ZM et a. J Hepatology 2014;60:530-537 Pockros P. 29th Annual New Treatments in Chronic Liver Disease, La Jolla, March 29, 2014 Gordon SC, et al. Hepatology. 2012;56;1651-1660

49 Conclusions

• HCV is a major cause of chronic liver disease, cirrhosis and hepatocellular carcinoma • Suspect HCV on the basis of risk factors, not symptoms or lab tests • Screen all patients with risk factors, and all baby boomers for HCV • We are about to undergo a dramatic paradigm shift in HCV treatment with new DAA combinations that promise higher cure rates, shorter duration and fewer side effects

Questions ?

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