presentation at the 2015 liver summit

Cholangitis

The CLDF and IC-HEP would like to thank our supporters for providing an educational

grant to support this program:

AbbVie, Bristol-Myers Squibb, Gilead, Intercept Pharmaceuticals, and Merck

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Disclaimer

In accordance with the ACCME Standards for Commercial Support of CME, the speakers for this course have been asked to disclose to participants the existence of any financial interest and/or relationship(s) (e.g., paid speaker, employee, paid consultant on a board and/or committee for a commercial company) that would potentially affect the objectivity of his/her presentation or whose products or services may be mentioned during their presentation. The following disclosures were made:

Planning Committee MemberJohn Bayliss, VP, Business Development, Spouse -Employee of Amgen, Inc

Lisa D. Pedicone, PhD-No Relevant Relationships

Faculty

Robert Gish, MDMedical Director, Professor

Hepatitis B Foundation, San Diego and Stanford University

Catherine Frenette, MDMedical Director of Liver Transplantation

Scripps ClinicLa Jolla, CA

Disclosures

• Consultant/Speaker Bureau: Contravir, Genentech, Janssen, MedImmune, Eiger, Novira, Presidio, Bayer, Gilead Sciences, Inc., Onyx, Salix, AbbVie, Bristol-Myers Squibb

• Advisory Board Membership: AbbVie, Merck, Arrowhead, Contravir, Novira, Isis, Presidio, Eiger Enyo, Janssen, MedImmune

• Stockholder: Kinex, Synageva, Arrowhead

Educational Objectives

• Identify the risk factors and overall disease processes in chronic liver diseases

• Describe current and evolving treatment strategies for chronic liver diseases in order to optimize patient outcomes

• Effectively adhere to long-term surveillance recommendations outlined in the AASLD guidelines

Primary Biliary Cholangitis (PBC)

What is PBC?

• Chronic cholestatic disease with a progressive course which may extend over many decades

• Rate of progression varies greatly• Asymptomatic in early disease• Often leads to fatigue, pruritus and Sicca syndrome (dry

eyes and/or dry mouth)• Primary biliary cholangitis (PBC) affects about 1/1000

women age >40 years and is a leading indication for liver transplantation1

1. Kumagi T, Heathcote EJ. Orphanet J Rare Dis. 2008;3:1.

Causes and Markers of PBC

• Autoimmune disease thought to be due to a combination of genetic predisposition and environmental triggers

• High degree of specificity for involvement of the small intrahepatic bile ducts

• Serologic hallmark of PBC is the AMA, a highly disease-specific autoantibody found in 90-95% of patients and less than 1% of controls.

AASLD Suggested Diagnostic Algorithm for Patients With Suspected PBC

Elevated serum alkaline phosphatase (ALP) activity

Exclude other causes of liver disease including alcohol and drugs

Cross sectional imaging of liver to exclude biliary obstruction

AMA (Antimitrochondrial antibody), ANA (antinuclear antibody), ASMA (anti-smooth muscle antibody)

Consider liver biopsy, especially if AST>5x ULN or AMA -

Ursodeoxycholic Acid (UDCA)

• Orally administered nontoxic bile acid

• Replaces the bile acids normally produced by the liver, which are more toxic and can harm the liver

• UDCA in a dose of 13-15 mg/kg/day is the only currently FDA approved therapy for PBC

• UDCA is initiated gradually and given BID

• Improvement in liver tests will be seen within a few weeks and 90% of the improvement usually occurs within 6-9 months

AASLD Guidance Document

• Safe, may improve clinical symptoms, delay progression of disease and survival, and improve QOL

• However, up to 40% of PBC patients treated with UDCA have a suboptimal response

Pares A, Gastroenterology, 2006; Marschall HU, Gastroenterology, 2005.

Lammers, EASL, AASLD. 2013.

ALP <1.67 x ULN and Normal Bilirubin after 1 Year of UDCA is Highly Predictive of Outcome

Global PBC Study Group (N=4845)

Non-Responder

Responder

• Backbone of therapy in PBC in the past 20 years• Early treatment provides the most benefit• Can improve the outcome but does not cure PBC• Up to 40% have a suboptimal response to URSO

defined by AP parameters

Obeticholic Acid (OCA): A Modified Bile Acid and FXR Agonist

FXR EC50= 8.6 µM

CDCAchenodeoxycholic acid

6-α ethyl substitution

OCA (6E-CDCA)obeticholic acid

= 90 nMFXR EC50~100x increased potency

Obeticholic Acid (OCA): A Modified Bile Acid and FXR Agonist

OCA in Patients with PBC: POISE Study Design

• OCA Titration at 6 Months: Subjects in OCA titration arm titrated from 5 mg to 10 mg at Month 6 if they met any of the following criteria at the Month 6 assessment:

1. The primary endpoint (ALP <1.67x ULN or bilirubin ≤ULN) was not achieved

2. No evidence of tolerability issues, e.g. pruritus

Randomization StrataSubjects stratified 1:1:1 by: 1) ALP >3x ULN and/or AST >2x ULN and/or total bilirubin >ULN (Paris I) 2) Not receiving UDCA treatment

OCA 10 mg (n=73)

Placebo (n=73)

M3 M12 M6W20 M9

If on UDCA: Continue UDCA

OCA 5 mg

Titrate to OCA 10 mg (n=33)

Remain at OCA 5 mg (n=36)

Primary Objective and Patient Population

1. Corpechot, Hepatology 2008.

• To assess the proportion of patients achieving ALP <1.67 xULN and a decrease of ≥ 15% and total bilirubin ≤ULN

• Inclusion– PBC diagnosis (EASL and AASLD guidelines)– ALP ≥1.67 xULN and/or total bilirubin >ULN to <2 xULN– Stable UDCA or unable to tolerate UDCA

• Exclusion– Concomitant liver diseases, decompensation, severe pruritus requiring treatment

• Randomization Strata– UDCA (yes/no)– Paris I1

Demographic and Baseline Characteristics

Placebo

(N=73)

OCA Titration

(N=70)

OCA 10 mg

(N=73)

Age, y 55.5 ± 10 55.8 ± 11 56.2 ± 11

Sex, Female, n (%) 68 (93) 65 (93) 63 (86)

Race/Ethnicity, n (%)

White 66 (90) 67 (96) 70 (96)

Non-White 7 (10) 3 (4) 3 (4)

BMI (kg/m2) 26.2 ± 4 25.6 ± 5 26.3 ± 5

ALP, U/L 327 ± 115 326 ± 116 316 ± 104

Bilirubin, umol/L 12 ± 7 10 ± 6 11 ± 7

UDCA use, n (%) 68 (93) 65 (93) 67 (92)

Daily UDCA dose, mg/kg 15 ± 4 17 ± 5 16 ± 5

Pretreatment Liver Biopsy Performed 7 (10) 13 (19) 9 (12)

Age at PBC diagnosis, y 47.3 ± 9.3 47.6 ± 11.7 47.1 ± 10.6

Duration PBC, y 8.3 ± 5.4 8.3 ± 5.8 9.2 ± 6.9

Data are mean ± SD where applicable.

Disposition of OCA Titration Group

70 Subjects Randomized to Titration

69 Completed Month 6 Visit

37 Eligible for Titration to 10 mg OCA

32 Ineligible for Titration Remained at 5 mg OCA

21 Reached Primary Endpoint

8 Pruritus Tolerability

3 Other/Other AE

33 Titrated from 5 mg to 10 mg OCA

4 Remained at 5 mg OCA

3 Reached Primary Endpoint at Month 12

Percent Achieving Primary Endpoint

*p<0.0001 vs. placebo

Response:Achieving ALP <1.67x ULN with bilirubin ≤ULN and ≥15% reduction in ALP

p values obtained using Cochran-Mantel-Haenszel stratified by randomization strata factorTitration OCA group: 5 mg OCA for 6months 10 mg OCA if well tolerated & ALP >1.67x ULN or bilirubin >ULN

OCA Treatment Significantly Reduced ALP

***p<0.0001 vs. placebo for all post baseline values of Titration OCA and 10 mg OCA groups Baseline values (mean ± SE, U/L): Placebo 327 ± 13; Titrated OCA: 326 ± 14; 10 mg OCA: 316 ± 12; N=216Titration OCA group: 5 mg OCA for 6 months then titrated to 10 mg OCA if tolerated & ALP ≥1.67x ULN or bilirubin >ULN

A Significantly Greater Proportion of OCA-treated Subjects Had a ≥10, 20 or 40% ALP Reduction

***p<0.0001 vs. placebo; p values obtained using Cochran-Mantel-Haenszel stratified by randomization strata factor Titration OCA group: 5 mg OCA for 6 months then titrated to 10 mg OCA if tolerated & ALP ≥1.67x ULN or bilirubin >ULN

OCA Treatment Resulted in Significant Decreases in Markers of Hepatobiliary Damage

***p<0.001 vs. placeboTitration OCA group: 5 mg OCA for 6 months then titrated to 10 mg OCA if tolerated & ALP ≥1.67x ULN or bilirubin >ULN

OCA Treatment Decreased Bilirubin Over Time

*p<0.05 vs. placeboBaseline Direct Bilirubin (mean ± SE, µmol/L): Placebo 5.5 ± 0.7; Titrated OCA: 4.5 ± 0.5; 10 mg OCA: 4.9 ± 0.5Baseline Total Bilirubin (mean ± SE, µmol/L): Placebo 11.8 ± 0.9; Titration OCA: 10.3 ± 0.7; 10 mg OCA: 11.3 ± 0.8Titration OCA group: 5 mg OCA for 6 months then titrated to 10 mg OCA if tolerated & ALP ≥1.67x ULN or bilirubin >ULN

Adverse Events

• Pruritus, generally mild to moderate, was the most common and dose related AE– Few subjects treated with OCA withdrew due

to pruritus (<6%)

• The incidence of AEs other than pruritus was no worse with OCA (Placebo, 90%, 5/10 mg OCA, 89%, 10 mg OCA, 86%)

Overall Findings

• The effect of OCA was consistent independent of age at diagnosis, duration of PBC and baseline ALP.

• Titration from 5 to 10 mg based on clinical response improved tolerance, minimized dropouts due to pruritus, and showed comparable efficacy to 10 mg OCA after 1 year. Thus, starting patients on OCA 5 mg with titration to 10 mg based on the clinical response appears to be an appropriate dosing strategy.

• OCA given to individuals with PBC with an inadequate response to or unable to tolerate UDCA produced a significant clinically meaningful improvement in liver biochemistry, which have been shown to correlate strongly with clinical benefit.

Long-term Management of Patients with PBC (AASLD Guidance)

• Liver tests every 3-6 months• Thyroid status (TSH) annually• Bone mineral densitometry every 2-4 years• Vitamins A, D, K annually if bilirubin >2.0• Upper endoscopy every 1-3 years if cirrhotic or Mayo

risk score >4.1• Ultrasound ± AFP every 6 months in patients with known

or suspected cirrhosis

Nonalcoholic Fatty Liver Disease (NAFLD)and Nonalcoholic Steatohepatitis (NASH)

Adult Obesity in America 2014

Percent of Obese Adults(Body Mass Index of 30+)

http://stateofobesity.org/adult-obesity/

20 - 24.9% 25 - 29.9% 30-34.9% 35%+

Adult Obesity in America 2011-12

Obese Overweight or Obese

34.9% 68.5%

16.9% 31.8%

Childhood Obesity in America 2011-12

Visceral Obesity

Non-alcoholic Fatty Liver Disease

(NAFLD)

Endothelial DysfunctionAtherosclerosis

Insulin ResistanceType 2 Diabetes

DyslipidemiaHypertension

Polycystic Ovarian Syndrome(PCOS)

CoronaryArtery Disease

NAFLD is Closely Associated with Visceral Obesity and Insulin Resistance

Diseases Associated with Visceral Obesity

The Spectrum of NAFLD

Normal Simple Steatosisor “NAFL”

NAFLD Spectrum

Ludwig 1980, Diehl 1988, Lee 1989, Powell 1990, Bacon 1994, Younossi 1997, Matteoni/Younossi 1999, Angulo 1999, Caldwell 1999, Ponawala 2000, Contos 2001, Ong/Younossi 2001, Bugianesi 2002, Ratziu 2002, Saddeh/Younossi 2002, Harrison 2003, Marchesini 2003, Younossi 2004, Gramlich/Younossi 2004, Fassio 2004, Sanyal 2004, Ong/Younossi 2005, Adams 2005, Ong/Younossi 2008, Mishra/Younossi 2008, Rafiq/Younossi 2010, Hossain/Younossi 2009, Kim/Younossi 2010, Stepanova/Younossi 2010, Hossain/Younossi 2010, Stepanova, Younossi 2012, Younossi 2012, Chalasani, Younossi 2012.

• Exclusion of liver diseases (HCV & ETOH)• Requires specific pathologic criteria for NASH• Important for prognosis

Prevalence of NAFLD & NASH

Torres DM. Clin Gastro Hepatol. 2012;32:30-38.

44.4%35.1%

29.9%30%

33%24%

San Antonio, Texas(Williams, et al. Gastroenterology. 2011;140:124-31.)

Dallas Heart Study Prevalence Numbers(Browning, et al. Hepatology. 2004;40:1387-95.)

Prevalence of NAFLD in Children

• Using surrogate markers, prevalence of NAFLD in children is 2.6-17.3%

• Autopsy study from UCSD (N=742)– Prevalence: 9.6%, rates

increasing with age– More common in boys– Highest rate in Hispanics

Schwimmer JB 2006, Argo C 2009

Isolated Fatty Liver

NASHCirrhosis

Decompensation

~70-75%

~11% over 15 years, but significant variability

~7.2% over 6.5 years

19-45% over 7-10 years

Fatty Liver with Mild Inflammation

Possible sampling variability withsome risk of progression

~20-25%

Natural History of NAFLD

Modified from Torres DM, et el. Features, diagnosis, and treatment of NAFLD. Clin Gastro Hepatol. 2012;10:837-858.

1. ↑ risk of death compared with general population1. Cardiovascular2. Malignancy3. Liver-related

2. NASH with fibrosis portends worse prognosis 1. Fibrosis progression a/w DM, severe IR,

weight gain >5kg, rising ALT, AST

1. None to very minimal progression to fibrosis

2. No ↑ risk of death compared with the general population

NASHCirrhosis HCC

10-15% 2-3%

OverallAnnual

Incidence

Summary of Outcomes of NASH

Ludwig 1980, Diehl 1988, Lee 1989, Powell 1990, Bacon 1994, Matteoni 1999, Angulo 1999, Caldwell 1999, Ponawala 2000, Contos 2001, Ong 2001, Bugianesi 2002, Ratziu 2002, Harrison 2003, Marchesini 2003, Younossi 2004, Fassio 2004, Sanyal 2004, Ong 2005, Adams 2005, Ong 2006, Rafiq 2008, Stepanova 2010, Younossi 2012.

Harrison SA. Clin Gastro Hepatol. 2014.

Predicting Advanced Fibrosis

20% (7)

100% (100)

33% (33)

Fibrosisprogression

Rapid Fibrosis progression

Progression from stage 0 to stage 3-4 over a mean of 5.9 years

• NAFLD with liver biopsy (N=432)

• In multivariate analysis, elevated AST and ALT, presence of diabetes mellitus, male gender and Caucasian ethnicity were associated with moderate to severe fibrosis (p-value<0.0001)

Positive

Negative

Hossain N, et al. Gastro and Hepatology. 2009.

NAFLD Patients With Components of Metabolic Syndrome are at Highest Risk for Advanced Fibrosis

DM HTN DM+HTN DM+HTN+Visceral obesity*

• 209 NAFLD patients with liver biopsy slides, clinical data and mortality data were included – Median follow up = 146 months (max 342 months)– During follow-up, 31% of patients died with 9% dying of LRM

• Regardless of the pathologic criteria used, NASH patients had higher LRM than non-NASH NAFLD– (13.0% vs. 1.3% for Original NAFLD NASH, p = 0.0047)

• On multivariate analysis, only significant fibrosis (Stage > 2) was an independent predictor of LRM

Predicting Liver Related Mortality (LRM)

Younossi Z, et al. Hepatology. 2011.

*Average follow up = 10 yearsYounossi et al. Clin Gastro and Hepatology 2004

Long-term Outcomes of Diabetics with NAFLD

• NAFLD & DM (n=44) vs. NAFLD alone (n=88)

• Patients with NAFLD and DM have*:– Higher rate of cirrhosis (25% vs. 10.2%, p=0.04)

– Higher liver-related mortality (RR=22.83, p=0.003)

– Higher mortality (RR=3.3, p=0.002)

Clinical Presentation&

Routine Laboratory Data

New Radiologic Modalities

(Transient Elastography, LMS MRI/MRE)Predictive Panels

Based on Clinical and Lab Data

Liver Biopsy&

Pathologic Protocols

New Biomarkers(NASH or Fibrosis)

Routine Radiologic Tests

(Ultrasound, CT, MRI)

Diagnostic & Prognostic

Tests for NASH

• NAFLD Fibrosis Score is a clinically useful tool for identifying NAFLD patients with higher likelihood of having bridging fibrosis and/or cirrhosis (Strength - 1, Evidence - B)

• Although serum/plasma CK18 is a promising biomarker for identifying steatohepatitis, it is premature to recommend in routine clinical practice (Strength - 1, Evidence - B)

NAFLD Guideline RecommendationsNon-invasive Assessment

NAFLD Guideline RecommendationsRole of Biopsy

• Liver biopsy should be considered in patients with NAFLD who are at increased risk to have steatohepatitis and advanced fibrosis (Strength - 1, Evidence - B)

• Liver biopsy should be considered in patients with suspected NAFLD in whom competing etiologies for hepatic steatosis and co-existing chronic liver diseases cannot be excluded without a liver biopsy (Strength - 1, Evidence - B)

Who Would You Biopsy?

Hepatologists (N=75)

Gastroenterologists (N=75)

Endocrinologists (N=64)

Internists/PCP (N=75)

Total Physician Sample (N=289)

53%41%*

29%** 31%**39%**

Diagnosed NASH Patients Who Received a Liver Biopsy

A Minority (39%) of Patients Have a Liver Biopsy to Confirm Their Diagnosis of NASH; Hepatologists Performed the Greatest Percentage of Biopsies vs. Other Specialties

Compared with Hepatologists. *denotes p=0.027, **denotes p<0.001, Tukey’s HSDHarrison SA, Abstract AASLD. 2014.

Goals of Liver Biopsy

• Identify NASH (ballooning, inflammation, etc)

– Establish diagnosis

– Clinical trials

• Stage fibrosis

• Rule out concomitant liver disease (iron loading, etc)

• Prognosis

No lab test or imaging study will be able to predict with 100% accuracy

The more risk factors… the more concern

Red Flags for NASH

• Age• Gender• Hispanic• HT• Obesity• Diabetes• ALT and AST level• AST/ALT ratio• Insulin level• PNPLA3

1. Friedrich Rust, et al. Gastroenterology. 2008; 2. Sasso, et al. Journal of Viral Hepatitis. 2011.

Transient Elastography

• Allows painless and simultaneous measurement oftwo quantitative parameters:

• Liver stiffness expressed in kPa– Correlated to liver fibrosis [1]

• Controlled Attenuation Parameter (CAP™)expressed in dB/meter

– Correlated to liver steatosis [2]

• Both quantitative parameters are assessed on thesame volume of liver tissue

• 100 times bigger than liver biopsy

Transient Elastography

Castera L. Nat Rev Gastroenterol Hepatol. 2013.

• Measures velocity of a low-frequency (50 Hz) elastic shear wave propagating through the liver

– Normal liver: ~5.5 kPa

• Good performance for excluding advanced stage disease (stage 3-4)

• User-friendly, short procedure time

• Problems still with severe obesity, ascites, operator experience

• False positives: acute hepatitis, extrahepatic cholestasis and congestion

• Fibroscan VCTE, one method of TE, has an XL probe: ~25% unreliable results; cut-off concerns

• ****Not very good in our hands at predicting fibrosis in NAFLD patients****

A threshold of 3.63 Kpa discriminates

advanced fibrosis

Stage 4

Loomba, et al. Abstract DDW, 2013.

MRE Can Identify Advanced Fibrosis in NAFLD

The first non-invasive test to clearly identify even early fibrosis

AUROC is 0·94 (95% CI 0·89 – 0·99) to detect any disease; sensitivity 86%, specificity 93%Journal of Hepatology Jan 2014

Multi-parametric MRI Stages Adult Patients with Chronic Disease

Certified by: Sponsored by: Endorsed by:

Inflammation & fibrosis (T1) Fat

Iron (T2*)

Comparison of NASH stage 0-2 Vs 3-4

ROC Analysis:

FIB-4: 0.86AST/ALT:0.83NAFLD Fib Score:0.81BARD: 0.77APRI:0.67

FIB-4:95%BARD:95%AST/ALT:93%NAFLD Fib Score:92%APRI:84%

British study of 145 NAFLD patients

McPherson S et al. Gut 2010;59:1265-1269.

Treatment and Intervention

NASH Resolution(64-90%)*

Ballooning/

Inflammation(41-100

Steatosis(35-100%)*

Weight Loss ≥ 10%1

Weight Loss ≥ 7%1

Weight Loss ≥ 5%1,2,3

Weight Loss ≥ 3%1,2,3,4

Weight Loss Pyramid

1. Vilar-Gomez. Gastroenterology 2015; 2. Promrat. Hepatology 2010; 3. Harrison. Hepatology 2009; 4. Wong. J Hepatol 2013 *Depending on degree of weight loss

NAFLD Guideline Recommendations

• Weight loss generally reduces hepatic steatosis, achieved either by hypocaloric diet alone or in conjunction with increased physical activity (Strength - 1, Evidence - A)

• Loss of at least 3-5% of body weight appears necessary to improve steatosis, but a greater weight loss (up to 10%) may be needed to improve necroinflammation (Strength - 1, Evidence - B)

• Exercise alone in adults with NAFLD may reduce hepatic steatosis but its ability to improve other aspects of liver histology remains unknown (Strength - 1, Evidence - B)

• Metformin has no significant effect on liver histology and is not recommended as a specific treatment for liver disease in adults with NASH. (Strength - 1, Evidence - A)

• Pioglitazone can be (?) used to treat steatohepatitis in patients with biopsy-proven NASH. (Strength - 1, Evidence - B)

– However, the majority of patients who participated in clinical trials that investigated pioglitazone for NASH were non-diabetic

– Long term safety and efficacy of pioglitazone in patients with NASH is not established

Treatment: Vitamin E

Therapy Author N Design Duration(Months) ALT Improve Histo

Vitamin E Lavine 11 Open 4-10 Yes N/A

Vitamin E Kawanaka 10 Open 6 Yes N/A

Vitamin E Sanyal 10 RCT 6 Yes N/A

Vitamin E Hasegawa 12 Open 12 Yes Yes

Vitamin E Vajro 14 RCT 5 No N/A

Vitamin E Bugianesi 25 RCT 6 No N/A

Vitamin E/Ex Kugelmas 8 Open 3 Yes N/A

Vitamins E+C Harrison 23 RCT 6 No ? Yes

Vitamins E+C Ersoz 28 RCT 6 Yes N/A

Vitamin EPIVENS (Sanyal)

84 RCT 24 Yes Yes

• Vitamin E (a-tocopherol) administered at daily dose of 800 IU/day improves liver histology in non-diabetic adults with biopsy-proven NASH and therefore should be considered as a first-line pharmacotherapy for this patient population. (Strength - 1, Quality - B)

• Until further data supporting its effectiveness become available, vitamin E is not recommended to treat NASH in diabetic patients, NAFLD without liver biopsy, NASH cirrhosis, or cryptogenic cirrhosis (Strength - 1, Quality - C)

Competitive Landscape in NASHClinical development pipeline

Company Product MoA Phase Condition Timeline Endpoint

GENFIT GFT505 PPAR / agonist 3 NASH Beginning late 2015

INTERCEPT(NIDDK)

OCAFXR agonist (bile acid)

3 NASH Beginning 2015

Co=primary1. Reversal of NASH

without worsening of fibrosis

2. Improvement in fibrosis without worsening of NASH

CENTAUR CenicrivirocInhibitor of ligand binding to CCR2/CCR5

2a Liver fibrosis/NASH Enrollment completeImprovement of NAS (by 2 points) and no worsening of fibrosis

GILEAD Simtizumab Mab against LOXL2 2b Liver fibrosis/NASH Enrollment completeChange in morphometric quantitative collagen

NGM Biopharm NGM282 FGF 19 agonist 2a NASH EnrollingChange in hepatic fat by MRI

Immuron IMM-124EHyperimmune bovine colostrum

2a NASH EnrollingChange in hepatic fat by MRI

GALMED AramcholSynthetic Fatty Acid/ bile acid conjugate

2b NASH EnrollingChange in hepatic fat by MRI

GALECTIN GR-MD-02 Galectin-3 inhibitor 2a Liver fibrosis/NASH EnrollingSafety (+ elevation of liver in enzymes)

FLINT Trial Design- Obeticholic Acid (OCA)

Primary endpoint: liver histological improvement defined as decrease in NAFLD Activity Score (NAS) of ≥2 points with no worsening in fibrosis

Placebo QD

Screening (Biopsy)

Follow-up

OCA 25 mg QD Follow-up

72-week treatment period 24 week off treatment

N=283Patients w/

Histological Evidence of NASH*

*Entry was based upon histologic diagnosis of nonalcoholic steatohepatitis (NASH) based on local CRN site pathologist’s read (end-of-study blinded central read of baseline biopsies revealed 80% of patients enrolled had definite NASH); interim analysis was conducted when ≥50% of patients completed treatment and had repeat liver biopsy; NAFLD: nonalcoholic fatty liver disease; Neuschwander-Tetri B, et al. Lancet. 2014:S0140-6736(14)61933-4.Neuschwander-Tetri B, et al. Presented at EASL, 50th annual meeting; 2015; Vienna, Austria (Poster LB18).

• Improvement in NAFLD activity score* (NAS) ≥ 2 pts– * NAS = steatosis grade (0-3) + inflammation grade (0-3) + ballooning grade (0-2)

• No worsening of fibrosis• Results:

Series10%

p = 0.0002

21%(23/109)

46%(50/110)

Placebo OCA25 mg/day

FLINT primary endpoint

Neuschwander-Tetri et al, The Lancet, http://dx.doi.org/10.1016/S0140-6736(14)61933-4.

Series10%

p = 0.004

Placebo OCA

Improvement in Fibrosis and NASH ResolutionP

dFibrosis NASH Resolution

Series1-1.0-0.6-0.20.20.61.0

Placebo OCACh

ore p = 0.01

Series10%

p = 0.08 (NS)

Placebo OCA

13% 22%19%35%

+0.1 -0.2

Neuschwander-Tetri et al, The Lancet, http://dx.doi.org/10.1016/S0140-6736(14) 61933-4.

Lipid Concentrations

1Data from Tetri et al. The Lancet and Supplementary Appendix. Published online November 7, 2014.2All p-values compared to placebo. *p<0.05 3Converted mean values using factor of 38.6 for cholesterol and 88.5 for triglycerides.

Adverse Events

• 6 severe adverse events in obeticholic acid group– 4 severe pruritus (1 stopped treatment)– 1 hypoglycemia– 1 possible cerebral ischemia (dysarthria and dizziness)

• Moderate or severe pruritus– 23% in obeticholic acid – 6% in placebo

P < 0.0001

Placebo OCA0

10203040

MildModSevereP

Neuschwander-Tetri et al, The Lancet, http://dx.doi.org/10.1016/S0140-6736(14) 61933-4.

Patients at High Risk for Disease Progression

• Established fibrosis is the best predictor of liver-related mortality1,2 – Hazard ratio (HR) = 20.4 for histologic documentation of fibrosis stage ≥2

• Various factors have been shown to be associated with higher rates of fibrosis progression3-5:

– Diabetes– Elevated body mass index (BMI)– Elevated ALT

• Based on the literature, we defined the following high-risk FLINT subgroup: – Fibrosis stage 2 (perisinusoidal and portal/periportal) or stage 3 (bridging); or – Fibrosis stage 1 (perisinusoidal or periportal) if accompanied by one or more of:

• Diabetes• Obesity (BMI ≥30 kg/m2)• Elevated ALT (ALT ≥60 U/L)

1. Younossi ZM, et al. Hepatology. 2011;53(6):1874-82; 2. Ekstedt M, et al. Hepatology. 2014 Aug. doi:10.1002/hep.27368 [epub ahead of print]; 3. Adams LA, et al. J Hepatol. 2005;42(1):132-8; 4. Ekstedt M, et al. Hepatology. 2006;44(4):865-73; 5. Singh S, et al. Clin Gastroenterol Hepatol. 2015;13(4):643-654.Neuschwander-Tetri B, et al. Presented at EASL, 50th annual meeting; 2015; Vienna, Austria (Poster LB18).

NASH Resolution in High-Risk Subgroup†

Overall Subgroup Subgroup by Baseline Fibrosis Stage

*p=0.014; †NASH resolution as defined by NASH CRN pathologists; High-risk subgroup: patients with NAS ≥4 and fibrosis stage 2 or stage 3 or stage 1 with diabetes, BMI ≥30 kg/m2 or ALT ≥60 U/L; Intercept post hoc analyses.Neuschwander-Tetri B, et al. Presented at EASL, 50th annual meeting; 2015; Vienna, Austria (Poster LB18).

Fibrosis Improvement in High-Risk Subgroup†

Overall Subgroup Subgroup by Baseline Fibrosis Stage

*p=0.014; †NASH resolution as defined by NASH CRN pathologists; High-risk subgroup: patients with NAS ≥4 and fibrosis stage 2 or stage 3 or stage 1 with diabetes, BMI ≥30 kg/m2 or ALT ≥60 U/L; Intercept post hoc analyses.Neuschwander-Tetri B, et al. Presented at EASL, 50th annual meeting; 2015; Vienna, Austria (Poster LB18).

NAFLD and NASH

• NAFLD is a complex disease tied closely to obesity and diabetes• NASH patients with fibrosis most likely to progress

– NAFLD/NASH in the setting of DM/MS has adverse outcomes

• Personalized targeted treatment may be the best future option to treat NASH

• Some considerations for current patients with NASH:– Life style modifications for all– Vitamin E for non-DM NASH – ??Pio for DM with NASH but be aware of safety concerns– Clinical trials (OCA and others) – Consider bariatric surgery for morbidly obese+/-DM with NASH

• More than XXX clinical trials underway in the USA to treat NASH

Hepatitis B

More Than 2 Billion People Show Evidence of Hepatitis B (HBV) Infection1

240 million people are chronically infected with HBV worldwide1,3, 4

≥8% HBsAg prevalence2–7% HBsAg prevalence<2% HBsAg prevalence

1. World Health Organization. Hepatitis B. http://www.who.int/mediacentre/factsheets/fs204/en/.2. Map: Adapted from Liaw Y-F et al. Antiviral Therapy. 2010; 15 (suppl 3): 25–33.3. Hepatitis B Foundation Statistics. Accessed on 4 March 2011. Available at http://www.hepb.org/hepb/statistics.htm.4. WHO 2015

Global Burden of Disease Study 2010:Causes of Death From Chronic Liver Disease

Global 2010

Liver Cancer

30%28%

HCV ETOH Other HBV

CirrhosisHCV ETOH Other

USA 2010

Liver Cancer

HCV ETOH Other HBV

CirrhosisHCV ETOH Other

Increase in liver-cancer deaths (past 20 years): Globally (from 1.25 to 1.75 million/year); USA (45,000 to 70,000/year).Lancet 2012

• Consider delta testing in all HBV patients with anti-HDV blood test

Immunoprophylaxis Failure

Overall(n=1242)

Maternal HBV DNA(log10 copies/mL)

<6(n=174)

6-6.99(n=298)

7-7.99(n=531)

>8(n=531)

Risk Factors Associated With Perinatal HBV Infection Due to Immunoprophylaxis Failure

• Immunoprophylaxis failure rate– Overall: 4.9%

– Maternal HBV DNA >6 log10 copies/mL: 5.7%

• Independent risk factor for vertical transmission of HBeAg positive mothers

– Maternal HBV DNA levels

• Immunoprophylaxis failure occurred in a significant proportion of infants born to mothers with anti-partum hemorrhage, meconium-stained amniotic fluid, independently

Han G, et al.; Hepatology 2011; 54(suppl): 444A, Abstract 170.

Alignment of HBV Screening Recommendations From USPSTF, CDC, and AASLD

AASLDCDCUSPSTF

• People born in regions with prevalence of HBV infection of ≥2%1-3• US-born people not vaccinated as infants whose parents were born in regions with prevalence of HBV infection of

≥8%1-3• Household and sexual contacts of persons with HBV infection1-3• All pregnant women2-4• Men who have sex with men1-3• Injection drug users1-3• Individuals infected with human immunodeficiency virus (HIV)1-3• People with certain medical conditions2,3,5

– Needing immunosuppressive therapy– Undergoing hemodialysis

For a complete list of screening recommendations, please see:LeFevre ML; USPSTF. Ann Intern Med. 2014;161:58-66.CDC. Morb Mortal Wkly Rep. 2008;57:1-20.Lok ASF, McMahon BJ. Hepatology. 2009;50(3):1-36.USPSTF. Ann Intern Med. 2009;150:869-873.USPSTF. Consumer Fact Sheet. May 2014. http://www.uspreventiveservicestaskforce.org/uspstf/uspshepb.htm. Accessed August 12, 2015.

AASLD=American Association for the Study of Liver Diseases.CDC=Centers for Disease Control and Prevention. USPSTF=United States Preventive Services Task Force.

HBV ACUTE /CHRONICHEPATITIS B

CIRRHOSISESLD

HEPATOCELLULAR CARCINOMA

PRIMARY PREVENTION

CHEMO PREVENTION

CANCER Surveillance

Vaccination

CytokinesIFN-α, Peg-IFN-α

AntiviralsLMV, ADV, ETV, LdT

Tumour MarkerUltrasound

Transplantation

Time 20-30 YearsCirrhosis HCCNormal Cirrhosis

Liver Disease Progression

Hepatocellular Carcinoma: Incidence and Risk for Patients with Family History of HCC• Study in Taiwan of 22,472 individuals with

18 year f/u and linkage to national cancer registry

• 374 cases of HCC identified during

362,000 person/yrs of follow-up

• Family history of HCC and HBsAg-positive had

synergistic interaction with the risk of HCC in

multivariable-adjusted analysis

(age-sex-BMI-alcohol-smoking-ALT-DM)

(HR: 32.33, 95% CI [20.8-50.3],

p-value <0.01)

• Conclusion: HBV patients with family history

of HCC should be considered very high risk

for HCC.

0 2 4 6 8 10 12 14 16 18

0.45 No/HBsAg(-)

Yes/HBsAg(-)

No/HBsAg(+)/HBeAg(-)/HBV DNA<10,000

Yes/HBsAg(+)/HBeAg(-)/HBV DNA<10,000

No/HBsAg(+)/HBeAg(-)/HBV DNA>10,000

Yes/HBsAg(+)/HBeAg(-)/HBV DNA>10,000

No/HBsAg(+)/HBeAg(+)

Yes/HBsAg(+)/HBeAg(+)

Follow-up Time (years)

Family History of HCC, HBsAg and HBeAg Serostatus, HBV DNA level, and Risk of Incident HCC

19.1%17.6%

5.4%2.5%

0.64%0.62%

Loomba R, et al. Clinical Gastroenterology and Hep Dec 2013.

Phases of Chronic HBV Infection

Optimal treatment times

Anti-HBeHBV DNA

ALT activity

Yim HJ, et al. Hepatology. 2006;43:S173−S181.

Phase Immune Trained Immune Clearance Inactive Carrier State Reactivation

Liver Minimal inflammation and fibrosis

Chronic activeinflammation

Mild hepatitis and minimal fibrosis

Active inflammation

HBV: Who to Treat

• Active viremia– >2,000-20,000 IU/ml

• Some evidence of liver injury– Elevated ALT

– Histologic injury

• Family history HCC

• Special populations

• Elevated HCC biomarkers

• Always treat patients with cirrhosis and any HBV DNA (+)

FDA Approved Therapies

First Line Therapy

Peginterferon alfa-2a PEGASYS® Roche Laboratories 2005

Entecavir BARACLUDETM Bristol-Myers Squibb 2005

Tenofovir VIREAD® Gilead Sciences 2008

Second Line Therapy

Adefovir dipivoxil HEPSERA™ Gilead Sciences 2002

Telbivudine TYZEKA™ Idenix and Novartis 2006

Third Line Therapy

Lamivudine EPIVIR-HBV® GlaxoSmithKline 1998

Ishak Fibrosis Scores

Liver Fibrosis in Regression over 5 Years of Treatment with TDF• Patients with Ishak score ≥4: 38% at Baseline, 12% at Year 5• Patients with cirrhosis (Ishak score ≥5): 28% at Baseline, 8% at Year 5

Marcellin P, et al. Lancet; Vol 381, No. 9865, pp 468-475.

ETVr = LVDr (M204V ± L180M) + T184, S202, and/or M250 substitutions

1n=663

2n=278

3n=149

4n=120

5n=108

0.2 0.5 1.2 1.2 1.2 1.2

Nucleoside-naïve Cohort (HBeAg+ and HBeAg-): Cumulative Probability of ETV Resistance Through 6 Years

• HBV DNA <300 copies/mL in 94% of patients (n=99) in Year 6Kitrinos. Hepatology 2014

Treatment: How Long?

• HBeAg positive– Seroconversion– Consolidation 6-12 months after

• HBeAg negative– “until patient has achieved HBsAg clearance”– Indefinite?

Immune trained

HBeAg(+), anti-HBe(-) HBeAg(-), anti-HBe(+)

HBsAg+ HBsAg-

ALT level

HBsAg status

Undetectable level of HBV DNA

HBeAg/anti-HBe status

HBV DNA >109 copies/mL

HBV DNA level

Immune clearance Inactive carrier state

Milestone 1:

Start of decline

of HBV DNA

Milestone 2:

HBeAg/ anti-

HBe sero-

conversion

Milestone 3: HBV

DNA decreased

to undetectable

Milestone 4: Clearance of

Low HBV DNA (<2000 IU/mL) for reduced progression risk

This is where we would like our patients to be

Immune control

Milestone 5: Clearance of cccDNA

Functional cure

Milestone 6:

Clearance of

cells with

integrated HBV

DNA sequences

Absolute cure

6 Endpoints in HBV Treatment

Slide courtesy R Gish

Trying to Stop Treatment

• APASL guidelines recommend discontinuing if undetectable HBV-DNA on 3 occasions >6 months apart

• Study tested stopping rule in patients treated with entecavir– 95 patients (39 with cirrhosis)– Treated median of 721 days (395-1762 days) and

then monitored off therapyJeng WJ et al Hepatology 2013 Dec; 58(6): 1888-96

Time to Relapse: ETV vs LAM or LdT

• Clinical relapse defined as ALT >2X ULN + HBV DNA >2000 IU/mL)

• Overall relapse: 45% (43/95)• Relapse in cirrhotics: 43% (17/39) and 1

developed decompensation• Median duration until relapse:

230 days (74% >6 months)• HBV DNA <2 x 105 IU/mL only

independent factor for response (29% vs 53% relapse)

• Consolidation therapy >64 weeks appropriate for those with higher BL HBV DNA

Jeng WJ et al Hepatology 2013 Dec; 58(6): 1888-96

Rejinders et al

Even When You Seroconvert…Relapse May Happen Over Time

Number of patients without serological recurrencea

Total number of patientsb in follow-up

Block and Gish, et al, AVR 2013

What is Really a Cure?

• Natural Cure– Clearance of HBsAg without therapy and serum HBV DNA is undetectable

• Functional Cure– Based on the clinical outcome, in which the patient’s life expectancy becomes the same

as that of an individual who has resolved his HBV infection without therapy

• Apparent Virologic Cure– Based on the stable off-drug suppression of HBV viremia and antigenemia and the

normalization of ALTs and other laboratory tests

• Absolute Cure– In which an individual with chronic hepatitis B completely resolves the infection, and is

then at the same risk of death from liver disease as someone the same age who has never been infected

Cure Will Include

• Clearance of all cells with cccDNA

• Elimination of cells with integrated HBV DNA

• Prevent risk of HBV reactivation in anti-HBc(+) patients

• Remove integrated HBV DNA to completely eliminate risk of HCC

Rituximab-Associated HBV Reactivationin Lymphoproliferative Disorders• Meta-analysis and review of FDA

safety profiles– Case reports (n=27)– Case series reports (n=156)

• Onset post last rituximab dose– Median: 3 months (range: 0-12

months)– >6 months: 29%

• Reactivation in anti-HBc positive patients receiving rituximab versus no rituximab

– Odds ratio: 5.73 (P=0.0009)

Hui(n=233)

Tsutsumi(n=47)

Targhetta(n=319)

Yeo(n=50)

Fukushima(n=48)

Overall(n=697)

HBV Reactivation Risk:Rituximab-Treated Lymphoma Patients

0.32 1.0 3.16 31.62Odds Ratio

5.64(2.18-14.54)

Evens AM, et al. Ann Oncol. 22:1170-1180, 2011

DysfunctionalT-cell response

cccDNA reservoir

Insufficient B-cell response

CD8+ T cell

HBV Virion~10 ng/ml

HBV Sphere~100 g/ml

HBV Filament~1 g/ml

LHBsAg

MHBsAg

HIGH COPY #

LOW COPY #

HBV Virion~10 ng/ml

HBV Sphere~100 g/ml

HBV Filament~1 g/ml

LHBsAg

MHBsAg

HIGH COPY #

LOW COPY #

HBV Virion~10 ng/ml

HBV Sphere~100 g/ml

HBV Filament~1 g/ml

LHBsAg

MHBsAg

HIGH COPY #

LOW COPY #

HBV Virion~10 ng/ml

HBV Sphere~100 g/ml

HBV Filament~1 g/ml

LHBsAg

MHBsAg

HIGH COPY #

LOW COPY #

HBV Virion~10 ng/ml

HBV Sphere~100 g/ml

HBV Filament~1 g/ml

LHBsAg

MHBsAg

HIGH COPY #

LOW COPY #

HBV Virion~10 ng/ml

HBV Sphere~100 g/ml

HBV Filament~1 g/ml

LHBsAg

MHBsAg

HIGH COPY #

LOW COPY #

HBV Virion~10 ng/ml

HBV Sphere~100 g/ml

HBV Filament~1 g/ml

LHBsAg

MHBsAg

HIGH COPY #

LOW COPY #

HBV Virion~10 ng/ml

HBV Sphere~100 g/ml

HBV Filament~1 g/ml

LHBsAg

MHBsAg

HIGH COPY #

LOW COPY #

HBV Virion~10 ng/ml

HBV Sphere~100 g/ml

HBV Filament~1 g/ml

LHBsAg

MHBsAg

HIGH COPY #

LOW COPY #

HBV Virion~10 ng/ml

HBV Sphere~100 g/ml

HBV Filament~1 g/ml

LHBsAg

MHBsAg

HIGH COPY #

LOW COPY #

HBV Virion~10 ng/ml

HBV Sphere~100 g/ml

HBV Filament~1 g/ml

LHBsAg

MHBsAg

HIGH COPY #

LOW COPY #

HBV Virion~10 ng/ml

HBV Sphere~100 g/ml

HBV Filament~1 g/ml

LHBsAg

MHBsAg

HIGH COPY #

LOW COPY #

HBV Virion~10 ng/ml

HBV Sphere~100 g/ml

HBV Filament~1 g/ml

LHBsAg

MHBsAg

HIGH COPY #

LOW COPY #

HBV Virion~10 ng/ml

HBV Sphere~100 g/ml

HBV Filament~1 g/ml

LHBsAg

MHBsAg

HIGH COPY #

LOW COPY #

HBV Virion~10 ng/ml

HBV Sphere~100 g/ml

HBV Filament~1 g/ml

LHBsAg

MHBsAg

HIGH COPY #

LOW COPY #

HBV Virion~10 ng/ml

HBV Sphere~100 g/ml

HBV Filament~1 g/ml

LHBsAg

MHBsAg

HIGH COPY #

LOW COPY #

HBV Virion~10 ng/ml

HBV Sphere~100 g/ml

HBV Filament~1 g/ml

LHBsAg

MHBsAg

HIGH COPY #

LOW COPY #

HBV Virion~10 ng/ml

HBV Sphere~100 g/ml

HBV Filament~1 g/ml

LHBsAg

MHBsAg

HIGH COPY #

LOW COPY #

HBV Virion~10 ng/ml

HBV Sphere~100 g/ml

HBV Filament~1 g/ml

LHBsAg

MHBsAg

HIGH COPY #

LOW COPY #

HBV Virion~10 ng/ml

HBV Sphere~100 g/ml

HBV Filament~1 g/ml

LHBsAg

MHBsAg

HIGH COPY #

LOW COPY #

HBV Virion~10 ng/ml

HBV Sphere~100 g/ml

HBV Filament~1 g/ml

LHBsAg

MHBsAg

HIGH COPY #

LOW COPY #

HBV Virion~10 ng/ml

HBV Sphere~100 g/ml

HBV Filament~1 g/ml

LHBsAg

MHBsAg

HIGH COPY #

LOW COPY #

HBV Virion~10 ng/ml

HBV Sphere~100 g/ml

HBV Filament~1 g/ml

LHBsAg

MHBsAg

HIGH COPY #

LOW COPY #

HBV Virion~10 ng/ml

HBV Sphere~100 g/ml

HBV Filament~1 g/ml

LHBsAg

MHBsAg

HIGH COPY #

LOW COPY #

B cell

Barriers to Resolution of Chronic HBV Infection

Treatment Challenges: Barriers to Curing Chronic Hepatitis B

• Reservoir of cccDNA• Dysfunctional T-cell Response

– T cell exhaustion

• Insufficient B-cell Response

Strategies to overcome these barriers• Deplete or Silence cccDNA• Activate Antiviral Immunity

Current Treatment Challenges

• If use low genetic barrier NAs, drug resistance a serious problem

• Long term therapy with NAs (> 3 years) affects patient compliance and typically has little effect on HBsAg levels

• Peg-IFN has substantial toxicity

New Treatment Approaches: Future Developments

Strategy Target Agents/Company

HBV life cycle

HBV Pol TAF

Viral entry Myrcludex-B

cccDNA Zinc finger nucleases cccDNA conversion inhibitors

mRNA transcription/ stability Zinc finger proteins Epigenetic silencers - Ribozymes

Viral assembly HAPs Phenylpropenamides

HBV antigen secretion REP 9AC’Small molecule inhibitors of HBsAg secretion (e.g. glucovirs, triazolo-pyrimidines)

mRNAAntisenseiRNA

ISIS OAS product 3rd Gen DNA, Arrowhead iRNA, Tekmira iRNA, Analym siRNA (formally Merck now Arrowhead)

Capsid Multiple Novorio, Emery

Immuno-therapeutic

PegIFN-λ1a (IL29) BMS, Nanogen

Cytokines rIL-7 rIL-21

TLR agonists TLR7 (GS-9620) Gilead

Therapeutic vaccinesAdeno-virus approaches (TG1050)

Tarmogen(GI-13020)

Abivax

Blocking T cell inhibitory receptors

Anti-PD-1 moAB (BMS936558)(MedImmune)

Anti-PD-L1 moAb (BMS936559)

Intrahepatic blocking of suppressive cytokines / regulatory T cells

TGF-βinhibitors

T reg depletion (e.g. α-CD25, daclizumab)

R. Gish

Summary

• Viral suppression is successful but limited– Regression of fibrosis can occur

– Cancer risk still exists

• Special populations– Prevention of MTCT, mother to baby

– Prevention of reactivation

• Chance for a cure?– Multiple viral replication cycle targets

– Immune modulators

– Still early in development

Chronic Hepatitis C Infection is a Major Concern in the US

DiagnosedUndiagnosed

2.7 to 5 Million1,3,4

75% Unaware of Infection

1.1 Million1

~800,000 to 2 Million1,3

HIV HBV HCV

Prevalence of Chronic Viral Infections

HCV is Nearly 4 Times as Prevalent as HIV and HBV

• A 2011 study estimated that as many as 5.2 million persons are living with HCV in the United States2

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. 3. Gish Hepatology 2015 4. Edlin Hepatology 2015

By 2007, Deaths From HCV Surpassed Those From HIV

Change in Mortality Rates From 1999 to 2007

01999 2000 2001 2002 2003 2004 2005 2006 2007

Hepatitis C

Hepatitis B

15,10612,734

Ly KN, et al. Ann Intern Med. 2012;156(4):271-278.

Fibrosis Cirrhosis Hepatocellular Carcinoma

(with cirrhosis)

Chronic HCV Infection May Lead to Chronic Liver Disease and Liver Cancer

• ~75% of patients infected with HCV will develop a chronic infection and approximately 65% of those are expected to develop chronic liver disease

Factors Associated With Accelerated Fibrosis Progression in HCV• Modifiable

– Alcohol consumption– Nonalcoholic fatty liver disease– Obesity– Insulin resistance– THC (2 prospective studies)*

• Non-modifiable– Fibrosis stage– Inflammation grade– Older age at time of infection– Male sex– Organ transplant

• Viral– Genotype 3– Coinfection with HBV or HIV

*As modified from: AASLD, IDSA, IAS–USA. Recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org. Accessed July 15, 2015.

Projected Number of Cases of Hepatocellular Carcinoma and Decompensated Cirrhosis Due to HCV

1950 1960 1970 1980 1990 2000 2010 2020 2030Year

160,000

140,000

120,000

100,000

80,000

60,000

40,000

20,000

Decompensated cirrhosis

Hepatocellular carcinoma

Complications Due to HCV-Related Cirrhosis Expected to Rise Over the Next 10 Years

Davis GL, Gastroenterology. 2010;138:513-521.

Does Chronic Hepatitis C Increase Rates of Cancers Other Than Liver Cancer?

• Retrospective cross-sectional study from Kaiser Permanente Southern CA

• Adults diagnosed with CHC (ICD-9 code) or positive HCV RNA test between JAN08-DEC12

• Excluded patients with HIV or history of solid organ/bone marrow transplant

Nyberg AH et al., EASL Conference 2015.

Patient Demographics

HCV/Cancer HCV/No Cancer Non HCV

N (%) 1831 33881 5297191

Age Years Mean (SD) 62.6 (9.25) 59.4 (8.40) 71.9 (14.59)

Gender

Female 679 (37.1%) 13789 (40.7%) 2695862 (50.9%)

Male 1152 (62.9%) 20092 (59.3%) 2601142 (49.1%)

Asian 137 (7.5%) 2188 (6.5%) 377248 (7.5%)

Black 358 (19.6%) 4236 (12.5%) 412310 (7.8%)

Hispanic 425 (23.2%) 9670 (28.5%) 1862557 (35.2%)

White 871 (47.6%) 14040 (41.4%) 1543486 (29.1%)

Unknown 14 (0.8%) 2949 (8.7%) 928943 (17.5%)

Baseline Comorbidities and Health Status

Charlson Index (N)

1504 25161 2834195

Mean (SD) 2.1 (2.30) 1.50 (1.93) 0.5 (1.22)

Tobacco Smoking

Never 469 (25.8%) 10798 (33.7%) 3087355 (70.3%)

Ever 1351 (74.2%) 21247 (66.3%) 1307074 (29.7%)

Missing 11 (0.6%) 1836 (5.4%) 902763 (17%)

Alcohol Abuse

Never 1488 (81.3%) 29370 (86.7%) 5184626 (97.9%)

Ever 343 (18.7%) 4511 (13.3%) 112566 (2.1%)

Baseline Comorbidities and Health Status

Diabetes

Never 1262 (68.9%) 26962 (79.6%) 4898006 (92.5%)

Ever 569 (31.1%) 6919 (20.4%) 399186 (7.5%)

Cirrhosis 1312 (71.7%) 11766 (34.7%) 352294 (6.7%)

N 1825 32459 4319284

Mean 28.1 (6.30) 29.0 (6.25) 26.4 (7.18)

Missing 6 (0.3%) 1422 (4.1%) 977907 (18.4%)

Forest Plot: Crude HCV vs. Non-HCV Cancer Rates

HCV Can Now Be Cured in Most Patients

• Unlike HIV and HBV infection, HCV infection is a curable disease– HCV does not archive its genome, no integration

• What does cure mean?– Undetectable HCV RNA 12 weeks after completion of

antiviral therapy for chronic HCV infection

– SVR12 is almost invariably durable

Ghany MG, et al. Hepatology. 2009;49(4):1335-1374.

Birth Year Group

1,600,000

1,400,000

1,200,000

1,000,000

800,000

600,000

400,000

200,000

1990+1980–1989

1970–1979

1960–1969

1950– 1959

1940– 1949

1930– 1939

1920–1929

Estimated Prevalence by Age Group

Majority of Persons Chronically Infected With HCV Are Baby Boomers (Those Born Between 1945-1965)

Centers for Disease Control and Prevention. MMWR. 2012;61(RR-4):1-32.

CDC and USPSTF Recommendations for HCV Screening

• Regardless of risk factors, one-time testing for HCV of adults born between 1945–1965– Testing of persons of all ages at risk for HCV infection

• CDC also recommends for those identified withHCV infection– Brief alcohol screening and intervention as clinically indicated– Referral to appropriate care and treatment services for HCV

infection and related conditions

Centers for Disease Control and Prevention (CDC). MMWR. 2012;61(4):1-18Moyer VA; on behalf of the U.S. Preventive Services Task Force. Ann Intern Med. 2013;159(1):51-60.

US population with chronic HCV infection5 million

HCV detected1.6 million (<<50%)

Referred to care1.0 – 1.2 million (32%-38%)

HCV RNA test630,000 – 750,000 (20-23%)

Treated220,000 – 360,000 (7-11%)

Successfully treated170,000 – 200,000 (5-6%)

Liver biopsy380,000 – 560,000 (12%-18%)

Current Status of HCV in the US: Screening and Linkage to Care Rates Remain Low

Holmberg SD et al, New Engl J Med. 2013; 1859-1861, Gish Hepatology, 2015.

Diagnosisand treatment

All HCVpatients

PEG-IFN/RBV

95% SVR

95% SVR and higher rates of diagnosis/treatment

Highly Efficacious Treatments Are Not Enough: Higher Rates of Screening, Diagnosis and Treatment Are Necessary

Slide courtesy of Prof. Michael Manns

Rising Cure Rates for Chronic HCV

1991 1998 2001 2011 2013 2014+0%

35%44%

>90%>95%

IFN/RBV

PegIFN/RBV

Telaprevir orBoceprevir +PegIFN/RBV

2nd Gen DAAsIFN-Free

Regimens

3rd Gen DAAsIFN-Free

Regimens

*Cure rates based on data from clinical trials

Global Distribution and Prevalence of HCV Genotypes

Messina JP et al, Hepatology, 2015; 61: 77-87.

3’UTR5’UTR Core E1 E2 NS2 NS4B NS3 NS5A NS5Bp7

Ribavirin

Polymerase

DaclatasvirLedipasvirOmbitasvir

Sofosbuvir Dasabuvir

NS5BNUC

Inhibitors

NS5AReplication

Complex Inhibitors

NS5BNon-NUC

Inhibitors (NNI)

SimeprevirParitaprevir/r

NS3Protease Inhibitors

Protease

Note the common root name for each drug class

Approved Direct-Acting Antiviral Agents from Multiple Classes: Combination Regimens for HCV

Principles of All Oral Regimens for HCV

• Combine drugs from different classes– Target multiple targets to increase efficacy– Decrease risk of viral resistance

• If done properly– Near universal efficacy– Shortened duration of therapy– Adverse events have minimal impact on patient’s

quality of life

General Concepts About Selecting HCV Regimens

• Choice of regimen, treatment duration, and use of ribavirin depends on: – Presence of cirrhosis– Prior treatment experience

• PEG-RBV failure• Prior protease inhibitor failure• Prior sofosbuvir failure

– Genotype• Genotype 1a vs 1b• Genotypes 2-6

Important Information Needed at Diagnosis: Consultation With a Liver Specialist• Making sure the patient is not cirrhotic: Accurate staging of liver

disease is important– History, physical exam– Laboratory data:

• Focus on platelets• Subtle clues: Decreased albumin

– Hepatic imaging may be suggestive of cirrhosis– Non-invasive testing

• Fibrosure or equivalent serum tests• Fibroscan or equivalent

• Use clinical judgment to reconcile conflicting results

Excluding Cirrhosis is Important

• Presence of cirrhosis– Triggers routine cirrhosis care

• Evaluation for varices• Surveillance for hepatocellular carcinoma

– Impacts SVR– May affect treatment duration– May impact use of ribavirin

Is the patient taking any drugs that could have a potentialdrug:drug interaction with a DAA?

Antiarrhythmics e.g. digoxin, amiodarone

PPIs/acidreducing agents

Herbal supplementsHIV antiviralse.g. tenofovir,

lopinavir/ritonavir

Drugs that arerenally cleared

Is a co-medication contraindicated or is a dose adjustment required?

Can plasma levels of co-medications be easily monitored to ensure they remain within the established therapeutic range?

Reviewing Potential Drug: Drug Interactions is Important

PPI = proton pump inhibitor

Approved Treatments for Patients with GT 1 Infection

see AASLD and EASL guidelines for regular

updates

Paritaprevir/r (protease inhibitor/ritonavir) + ombitasvir (NS5A inhibitor) + dasabuvir

(non-nucleoside polymerase inhibitor) + RBV

(PTV/RTV/OMV + DSV + RBV)

All Patients Treatment Naïve0

10090 90

PlaceboRibavirin

Logistic regression: baseline BMI and treatment regimen(+/- RBV) were significant variables for not achieving SVR

Integrated Efficacy: SVR12 in GT 1a Non-cirrhotic Patients Treated with PTV/RTV/OMV + DSV for 12 Weeks (+/- RBV) (SAPPHIRE-I and –II, PEARL-IV)

Re-lapse

Partial Null

Prior PegIFN/RBV Response

p=0.004 p=0.006

182/202

569/593

182/202

403/420

Everson G, et al. Abstract #83, AASLD 2014

All Patients Treatment Naïve

Relapse Partial Respon-

Null Re-sponder

10089 92 93

95 95100 100

9312 weeks

24 weeks

Integrated Efficacy: SVR12 in GT 1a Cirrhotic Patients Treated with PTV/RTV/OMV + DSV + RBV for 12 vs 24 Weeks (TURQUOISE-II)

Logistic regression: IL28B TT, prior null, North American region and history of IDU were significant variables for not achieving SVR

p=0.08 p=0.73 p=0.13

126/142

115/121

Prior PegIFN/RBV ResponseEverson G, et al. Abstract #83, AASLD 2014

0102030405060708090

100100 100 100 100 10098.3 98.9 98.5 98.1 95.6

SVR12 in GT 1b Non-cirrhotic Patients Treated with PTV/RTV/OMV + DSV for 12 Weeks (+/- RBV)

• Pooled analysis of Phase 3 trials

Treatment-experienced*Includes 1 treatment-naive G1b pt who was enrolled in PEARL-IV study

301/301

562/572

210/210

357/361

+ RBV - RBV

Colombo M, et al. AASLD 2014, Boston. #1931

• Pooled analysis of Phase 3 trials • All treated with RBV

10098.5 100 100

100100 100 100 100 100

Treatment-experienced

SVR12 in GT 1b Cirrhotic Patients Treated with PTV/RTV/OMV + DSV + RBV for 12 vs 24 Weeks

12 Weeks 24 Weeks

Colombo M, et al. AASLD 2014, Boston. #1931

Do GT 1b Cirrhotics Really Need RBV? NO

• Phase 3 program included RBV for all cirrhotics• TURQUOISE III trial

– 60 GT 1b patients with cirrhosis received PTV/RTV/OMV + DSV (no RBV) for 12 weeks

– 100% SVR4 (SVR12 results expected at AASLD 2015)– AASLD/IDSA guidance document updated in August 2015: 12

week duration WITHOUT RBV for GT 1b cirrhotics

Feld J, et al. J of Vir Hep. 2015 (suppl 2); pp. 134-135

Paritaprevir/r (PTV/r) + ombitasvir (OMV) + dasabuvir (DSV) + RBV: GT 1

• Interferon not necessary; ribavirin necessary for some patients (GT1a to increase SVR from 90 to 99%)

• Very manageable safety profile

• Two tablets once daily + one tablet twice daily

• Approved regimens– 12 weeks for noncirrhotic GT1a + RBV

– 24 weeks for cirrhotic GT1a + RBV

– 12 weeks for noncirrhotic GT1b

– 12 weeks for cirrhotic GT1b + RBV (interim SVR4 from TURQUOISE III suggests RBV not necessary; AASLD/IDSA guidance document recommends 12 weeks without RBV)

• No dose adjustment necessary in patients with severe or ESRD requiring dialysis

• Drug:drug interactions (e.g., drugs cleared by CYP3A, omeprazole, statins)

AASLD, IDSA, IAS–USA. Recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org. Accessed August 6, 2015

Ledipasvir (LDV) (NS5A inhibitor) + sofosbuvir (SOF) (nucleotide

polymerase inhibitor)(LDV/SOF)

10099 97 98 99

179/180

178/184

181/184

179/181

12 Weeks 24 Weeks

LDV/SOF + RBV

LDV/SOF LDV/SOF

Non-Cirrhotic

LDV/SOF + RBV

LDV/SOF LDV/SOF

12 Weeks 24 Weeks

LDV/SOF ± RBV for 12 vs 24 Weeks: SVR12 in GT 1 Treatment-naïve Patients (ION-1)

Cirrhotic

Afdhal et al. N Eng J Med. 2014;370:1889-98.

GT 1 Treatment Naïve Non-Cirrhotics With BL Viral Load <6 Million IU/mL: 8 Weeks Can Be Considered But May Impact Insurance Coverage

Ledipasvir/sofosbuvir (HARVONI™) Prescribing Information. Gilead Sciences, Foster City, CA. March, 2015 (Adapted from Table 6).

LDV/SOF8 Weeks(N=215)

LDV/SOF12 Weeks(N=216)

SVR12 (Overall)

SVR12 (BL viral load <6M IU/mL)

94% (202/215)

97% (119/123)

96% (208/216)

96% (126/131)

Relapse Rates (Overall)

<6M IU/mL>6M IU/mL

5% (11/215)

2% (2/123)10% (9/92)

1% (3/216)

2% (2/131)1% (1/85)

No cirrhosis

Cirrhosis

12 Weeks 24 Weeks

LDV/SOF + RBV LDV/SOF + RBVLDV/SOF LDV/SOF

95 86 10082

1009910099

LDV/SOF ± RBV for 12 vs 24 Weeks:SVR12 in GT 1 Treatment-experienced Patients (ION-2)

Afdhal EASL Abst O109

Ledipasvir (LDV) + Sofosbuvir (SOF): GT 1

• Interferon and ribavirin not necessary• Very manageable safety profile• One pill once a day• Duration

– 12 weeks for patients without cirrhosis (consider 8 weeks for some patients)

– 12 weeks with ribavirin or 24 weeks without ribavirin for patients with cirrhosis

• Potential drug:drug interactions (e.g., PPI, P-gp inducers, amiodarone)• Not recommended in patients with severe or ESRD

requiring dialysis

Simeprevir (SMV) (protease inhibitor) + sofosbuvir (SOF)

(nucleotide polymerase inhibitor)

(SMV/SOF)

GT1a GT1a GT1a GT1b0

100 97 96 97 97

Treatment-naïve Treatment-experienced0

10097 95

SMV+SOF 12 weeks SMV+SOF 8 weeks

112/115 88/103 38/40 40/52

112/116 92/116 44/46 36/49 68/70 56/67 38/39 36/39

with Q80k without Q80k

SMV/SOF x 12 WeeksSVR12 in GT 1 Non-cirrhotics (OPTIMIST-1)

Kwo et al. Abstract #LP-14, EASL 2015.

SVR12: SMV + SOF 12 weeks

Treatment-_x000d_naive

Treatment-experienced0

100 8879

44/50 42/53

Implication: SMV+SOF insufficient for GT1 cirrhotics

SMV/SOF x 12 WeeksSVR12 in GT 1 Cirrhotics (OPTIMIST-2)

Lawitz E, et al. EASL 2015, Vienna. #LP04

Simeprevir (SMV) + Sofosbuvir (SOF): GT 1

• Interferon not necessary; ribavirin may be necessary for some patients• Manageable safety profile• One tablet and one capsule once daily• Regimens (+/- RBV)

– SMV/SOF x 12 weeks for patients without cirrhosis– SMV/SOF x 24 weeks for patients with cirrhosis

• Not recommended in patients with moderate or severe hepatic impairment (Child-Pugh Class B and C)

• No dosage adjustment of SMV required in patients with mild, moderate or severe renal impairment (remember SOF warning in severe renal impairment)

• Drug:drug interactions (e.g., moderate/strong inducers or inhibitors of CYP3A, amiodarone due to the SOF component)

DAC SOF for GT1

• In AASLD guidelines

Approved Treatments for Patients with GT 2 or GT 3 Infection

GT 3 Is Associated With a Significantly Higher Risk of Cirrhosis and HCC vs GT 1

Conclusion: GT 3 is associated with a significantly higher risk of cirrhosis and HCC vs GT 1, independent of age, diabetes, BMI or antiviral treatment

• VA HCV Clinical Case Registry (2000-2009)– 88,348 patients with genotype 1 (80%)– 13,077 genotype 2 (12%)– 8,337 genotype 3 (7.5%)– Mean follow-up 5.4 years

• After adjustment for demographic, clinical and antiviral treatment factors, comparison between genotypes 3 and 1

Kanwal F et al, Hepatology 2014;60:98-105

Hazard Ratio Confidence Interval

Cirrhosis 1.31 1.22-1.39

HCC 1.80 1.61-2.03

SOF+PEG/RBV x 12 Wks vs SOF + RBV x 24 Weeks: SVR12 in GT 2 vs GT 3 Patients (BOSON Study)

SOF + RBV 16 weeks SOF + RBV 24 weeks SOF + PEG/RBV 12 weeks

94/112 83/100 10/11

Series10

100 87

17/17 128/181

15/16 153/182 168/181

GT 3Error bars represent 95% confidence intervals.Foster et al., Abstract #L-05, EASL 2015

SOF + RBV 16 weeks SOF + RBV 24 weeks SOF + PEG/RBV 12 weeks

94/112 83/100 10/11

TN no cirrhosis TN cirrhosis TE no cirrhosis TE cirrhosis0

100 83

90 82 8277

96 91 9486

Treatment Naïve Treatment Experienced

No Cirrhosis Cirrhosis No Cirrhosis Cirrhosis

SOF+PEG/RBV x 12 Wks vs SOF+RBV x 24 Weeks: SVR12 in GT 3 Patients By Subgroup (BOSON Study)

Foster et al., Abstract #L-05, EASL 2015

100 90 86

Treatment-naive Treatment-experienced

91/101 44/51

Daclatasvir/Sofosbuvir for GT 3: SVR12 in Treatment-naïve and Treatment-experienced Patients Treated for 12 Weeks (ALLY-3)(FDA Approval: July 2015)

Nelson DR et al., Hepatology 2015; 61: 1127-1135.

96 97 94

63 58 69SV

CirrhosisYesNo YesNo

Overall Tx-naive Tx-experienced

Daclatasvir/Sofosbuvir for GT 3: SVR12 in Patients With and Without Cirrhosis Treated for 12 Weeks (ALLY-3) (FDA Approval: July 2015)

Nelson DR et al., Hepatology 2015; 61: 1127-1135.

AASLD/IDSA Guidance Document on GT 2 Patients

• Treatment-naïve (HCV has never been treated)– SOF + RBV for 12 weeks (extend to 16 weeks in patients

with cirrhosis)

• Treatment-experienced (HCV was previously treated)– SOF + RBV for 12 weeks (extend to 16 weeks in patients

with cirrhosis)

– SOF + PEG/RBV for 12 weeks (alternative)www.hcvguidelines.org (accessed July 15, 2015)

Treatment of GT 3 Patients

• In July 2015, daclatasvir (DCV) + sofosbuvir (SOF) x 12 weeks was approved by the FDA for patients without cirrhosis

• Recommended regimens in guidance document– SOF + PEG/RBV x 12 weeks

– DCV + SOF x 12 weeks

• GT 3 infected patients with cirrhosis remain the biggest challenge to cure, EASL guidelines rec: DAC SOF Riba for 24 weeks

www.hcvguidelines.org (accessed August 27, 2015)

SVR and All-cause Mortality in CHC Patients with Advanced Fibrosis

Baseline factors significantly associated with all-cause mortality:• Older age• GT 3 (2-fold increase

in mortality and HCC)• Higher Ishak

fibrosis score• Diabetes• Severe alcohol use

SVR patients Non-SVR patients

All-cause mortality

Liver-related mortality or

liver transplant

HCC Liver failure

530 patients followed for a median of 8.4 years

Van der Meer A, et al. JAMA 2012; 308:2584‒2593.

Years Years Years0 1 2 3 4 5 6 0 1 2 3 4 5 6 0 1 2 3 4 5 6

Genotype 1(n=12,166)

Non-SVR

P<.0001

SVR rate: 35%

Genotype 2(n=2904)

Non-SVR

P<.0001

SVR rate: 72%

Genotype 3(n=1794)

Non-SVR

P<.0001

SVR rate: 62%

SVR Reduced Risk of All-Cause Mortality in a Retrospective VA Study

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.

• Targeted screening programs are effective in increasing HCV testing, detection of HCV cases and referrals to specialist care1

– But, insufficient data to show impact on patient outcomes

• 40–85% of infected persons are unidentified2

– Varies greatly by setting, documented risk level in population, and site-specific screening practices

Population Screening

Birth Cohort Screening

Risk Factor- Based Screening

3 Approaches

HCV Screening: The Hidden Problem in Linkage to Care

1. Guidelines for the screening, care and treatment of persons with hepatitis infection. WHO, 2014. Available at http://www.who.int/hiv/pub/hepatitis/hepatitis-c-guidelines/en/ (accessed April 2015)2. Smith BD, Yartel AK. Am J Prev Med 2014;47:233–41WHO: World Health Organization

GT 4, 5, 6

• Discuss treatment options

• GT4 Harvoni 12 weeks no ribavirin

• GT 5 and 6, multiple options

Conclusions

• Who to test– One time testing of all baby boomers

is essential – Test all patients with ALT over 20 (women), 30 (men)– Any history of blood exposure– Immigrant populations

• Linkage to infectious / liver experts that can assess disease progression and treatment options

• Highly efficacious, short duration regimens with favorable safety profiles are available

• Rapidly evolving field…

www.hcvguidelines.org

AASLD/IDSA Guidance Document Remains Current

Managing the Complications of Cirrhosis

Compensated Cirrhosis May Be Difficult to Recognize

• Asymptomatic (compensated)– Subtle clues may be overlooked

• Thrombocytopenia

• Muscle wasting

• AST>ALT without alcohol consumption

• Liver enzymes may not be abnormal

• Albumin < 3.5 mg/dL

• Bili > 1.0-1.2

– Etiology may be remote• Prior alcohol use

• Uncontrolled diabetes mellitus and obesity

• Decompensated (Symptomatic)– Portal hypertension: ascites, overt hepatic encephalopathy, variceal bleeding– Hepatic failure: jaundice, coagulopathy

From http://digestive.niddk.nih.gov/ddiseases/pubs/cirrhosis/. Accessed July 2015.Trichrome stain micrograph from http://en.wikipedia.org/wiki/Cirrhosis. Accessed July 2015.

Cirrhosis: Symptoms and Signs

However…..often asymptomatic

• Anorexia, weight loss• Weakness, fatigue• Muscle loss, cramps• Nausea• Vague (RUQ) abdominal pain• Pruritus• Easy bruising, epistaxis• GI bleeding• Confusion, sleep disturbance• Amenorrhea or irreg menses

• Spider angiomata• Palmar erythema• Gynecomastia, testicular atrophy• Abdominal distention, edema• Parotid hypertrophy• Dupuytren’s contractures• Clubbing, leukonychia• Jaundice, icterus• Caput medusa• Splenomegaly• Enlarged left or caudate lobe• Asterixis, fetor hepaticus• Cachexia

Cirrhosis: Diagnosis

• Gold standard remains liver biopsy• Biopsy not required for all, “Clinical or radiologic cirrhosis”• Clues: physical exam, abdominal imaging, low platelet

count, AST:ALT ratio >1, cholestasis, low albumin, prolonged INR

• Non-invasive assays (FibroTest=FibroSure, APRI, FIB-4)• U/S Elastography (FibroScan, Aixplorer), Magnetic

Resonance Elastography

Non-invasive Markers of Fibrosis

NONE ARE ACCURATE IN THE MIDDLE FIBROSIS RANGES

FibroTest / FibroSure Bili, gGT, g-globulin, haptoglobin, a2 M, apolipoprotein

FibroSpect Hyaluronic acid, TIMP-1, a2 M

ELF HA, Procollagen III amino terminal peptide (PIIINP),TIMP1

HepaScore Hyaluronic acid, gGT, a2 M

Forns GGT, cholesterol, platelets, age

APRI AST /ULN X 100 / platelets (109/ L)

SHASTA; (HIV/HCV) AST, HA, albumin

FIB-4 AST, ALT, platelets, age

Non-Invasive Alternative: Hepatic Elastography

The probe induces an elastic sound wave

through the liver

The velocity of the sound wave is evaluated in a region located from 2.5 to 6.5 cm below the skin

surface

Sampled volume:1:500

Explored volume

Technical Limitations of Transient Elastography

Afdhal NH. Gastroenterol Hepatol (NY) 2012;8:605-607.

• Ascites• Morbid obesity• Adipose tissue within the chest wall• Acute hepatitis• Congestive hepatopathy• Post-prandial variability• Breath hold, patient movement, targeting liver

Prevalence of Cirrhosis

• Experts estimate that 5.5 million people in the United States have cirrhosis

• Many cirrhotics remain undiagnosed

– 40% of cases of cirrhosis “latent”

• Twelfth leading cause of death in US

Khungar V, Poordad F. Clin Liver Dis 2012;16:73-89.

2004 2005 2006 2007 2008 2009 2010 20110

100000

200000

300000

400000

500000

600000

700000

403,665 411,029 436,901 444,883 459,496498,181

526,096576573

10% increase

*ICD-9-CM diagnosis codes 571.2. 571.5, 571.6; all listed diagnoses. HCUPnet, Healthcare Cost and Utilization Project. Agency for Healthcare Research and Quality, Rockville, MD. http://hcupnet.ahrq.gov. Accessed January 2014

US Hospital Discharges Due to CirrhosisAre Increasing

Annual Prevalence Rates Between 1996 and 2006 Among HCV-Infected Veterans

El-Serag HB. Gastroenterology 2012;142:1264–1273.

Progressive Increase in Incidence of HCV-Related Cirrhosis and HCC in US

Stage Definition 1-year mortality

1 Compensated without varices 1%

2 Compensated with varices 3%

3 Decompensated with ascites without variceal hemorrhage

4 Decompensated with or w/out ascites with variceal hemorrhage

D’Amico G et al. J Hepatol. 2006;44:217-231.

Stages of Cirrhosis

Stage 1

Stage 2

Stage 3

Stage 4

4.4%7%

6.6% 4%

Baveno IV International Consensus Workshop Staging System for Cirrhosis: 1-Year Outcome Probabilities

NO VARICESNO ASCITES

VARICESNO ASCITES

ASCITES VARICES

BLEEDING ASCITES

Pts at risk 806 513 402 302 243 217

months 0 24 48 72 96 120

Half of patients decompensated over 5 years

Cumulative Proportion of Patients Transitioning from Compensated to Decompensated Cirrhosis Over Time

Points

Encephalopathy None Grade 1 – 2 (or precipitant-induced) Grade 3 – 4 (or chronic)

Ascites None Mild/Moderate (diuretic-responsive) Severe (diuretic-refractory)

Bilirubin (mg/dL) <2 2-3 >3

Albumin (g/dL) >3.5 2.8 - 3.5 <2.8

INR <1.7 1.7-2.3 >2.3

Total Numerical Score Child-Pugh Class

5 - 6 A

7 - 9 B

10 - 15 C

Class A considered “compensated”Class B/C considered “decompensated”

Adapted from Garcia-Tsao G et al. Am J Gastroenterol. 2009;104:1802-1829.

Classification of Cirrhosis:Child-Turcotte-Pugh (CTP)

Classification of Cirrhosis Severity Model for End Stage Liver Disease Score• Calculated from 3 variables:

– INR– Bilirubin– Serum creatinine

• The MELD score equation: – [9.6 x loge creatinine (mg/dL) + 3.8 x loge bilirubin (mg/dL) + 11.2 x loge

INR + 6.4]

• Eliminates subjectivity of HE and ascites evaluation used in CTP• Etiology removed without affecting predictive ability

Murray KF, Carithers RL. Hepatology 2005;41:1-26.Wiesner R et al. Gastroenterology 2003;124:91-96.

< 9 10 to 19 20 to 29 30 to 39 > 40

MELD Score

n=124 n=1800 n=1098 n=295 n=120

2.9 7.7

Wiesner, R et al. Gastroenterology 2003; 124:91-96

MELD Score: 3 Month Mortality**

**Mortality includes death on waitlist and removed for “too sick”

Liver-Related Mortality in the US is Underestimated

Updated Es-timate

3025.7

Deaths Due to Liver-Related Causes in US, 2008

Asrani, SK et al. Gastroenterology 2013;145:375-382.

• Liver related mortality in the US is underestimated by the National Center for Health Statistics (NCHS), in part, as a result of incomplete inclusion of liver-related deaths

• Use of an updated definition of liver mortality (includes other specific liver diagnoses such as hepatorenal syndrome, viral hepatitis and hepatobiliary cancerns) increased the estimated death rate by >2 fold from 11.7 to 25.7 deaths/100,000

Hospital Readmissions Among Patients with Decompensated Cirrhosis are Common

• Retrospective study of 402 patients from an academic transplant center

• Follow-up time censored at death, elective admissions such as transplant or post-procedure observation, or the date of last clinic note; median follow-up was 203 days

• Included cirrhotic patients hospitalized for ascites, SBP, renal failure, hepatic encephalopathy, or variceal hemorrhage

• Median time to readmission was 67 days• Median number of readmissions was 2

(range 0-40); overall rate was 3 hospitalizations/person-year

Within 1 wk Within 1 mo Overall0

Hospital Readmissions

Volk ML et al. Am J Gastroenterol 2012;107:247-252.

Costs for Readmissions Among Patients with Decompensated Cirrhosis

• The mean costs for readmissions within 1 week and between Weeks 1 and 4 were $28,898 and $20,581 respectively.

Volk ML et al. Am J Gastroenterol 2012;107:247-252.

Liver insufficiency

Variceal hemorrhage

Cirrhosis Ascites,Hydrothorax

Encephalopathy

Portal hypertension

Hepatorenal syndrome

“Coagulopathy”JaundiceHypoalbuminemia

Portopulmonary hypertensionHepatopulmonary syndrome

Complications of Cirrhosis: Distinguish Portal Hypertension from Liver Insufficiency

General Management Guidelines - Cirrhosis

• Surveillance for hepatocellular carcinoma– Abdominal US (or CT/MRI) every 6 months– Alfa-fetoprotein (AFP) no longer recommended by AASLD but many experts still

utilize, AFPL3% and DCP are FDA cleared for HCC risk

• Vaccinate for HAV, HBV, influenza (annual), Pneumovax; consider Zoster and HPV

• Avoid non-steroidals; acetaminophen preferred but in limited quantities (consider < 2-3gm/day)

• Cautious use of benzodiazepines and opioids; contraindicated in decompensated cirrhosis w/ HE

• Beware of raw shellfish (Vibrio vulnificus)• Dietary considerations: adequate protein intake (1-1.2gm/kg/day), careful

sodium intake (ideally <2gm/day)

General Management Guidelines - Varices• Screening and surveillance endoscopy

– All cirrhotic patients at diagnosis (Class IIa, Level C) – Every 2-3 years in Childs A with no or small varices – Annually in Childs B/C (or at time of decompensation)

• Non-selective beta-blocker (NSBB: propranolol, nadolol, carvedilol)*– Childs B/C with small varices or Childs A with small varices with red signs (Class IIa, Level C)– Childs A with medium/large varices without red signs (Class I, Level A)– Childs A with small varices without red signs (optional) (Class III, Level B)

• NSBB or Esophageal Variceal Ligation (EVL, “banding”)– Medium/large varices in Childs B/C or Child A with red signs (Class I, Level A)

• EVL– Acutely bleeding varices– Medium/large EV in Childs A, intolerant or non-compliant with NSBB (Class I, Level A)– All patients with previously bleeding varices (in combination with NSBB, secondary prophylaxis)

(Class I, Level A)

*Stop beta-blockers in patients with cirrhosis and ascites to avoid acute kidney injury and cardiac events

AASLD Guidelines, Updated 2009

Small varicesLower risk of bleeding

Large varicesHigher risk of bleeding

No varices

7-8%/year 7-8%/year

Varices Increase in Diameter Progressively

Merli et al. J Hepatol 2003;38:266

Inflammation

Proinflammatory Cytokines

Nitric Oxide & Oxidative Stress

Glutamate& NH3

Glutamine

Increased brain water,deterioration in

neuropsychologicalfunction & hepatic

encephalopathy

CerebralBlood FlowAstrocyte

Swelling

Astrocyte

Hepatic Encephalopathy: Pathophysiology

Adapted from Mullen KD et al. Semin Liver Dis. 2007;27(Suppl 2):32-47.

Normal “Covert” HE I II III IV

“Overt” HE Stages

Categorization is often arbitrary and varies between raters

ClinicalDiagnosis

Worsening cognitive dysfunction

Bajaj JS, et al. Hepatology. 2009;50:2014-2021.

Characterization of HE Stages

Clinical Classification of HE

• Hepatic encephalopathy should be classified according to the type of underlying disease, severity of manifestations, time course, and precipitating factors (GRADE III, A, 1).

Role of Ammonia Testing in HE

• “Increased blood ammonia alone does not add any diagnostic, staging, or prognostic value for HE in patients with CLD. A normal value calls for diagnostic reevaluation (GRADE II-3, A, 1)”

Specific Approach to Overt HE Treatment

• Four-pronged approach to management of HE (GRADE II-2, A, 1):

– Initiation of care for patients with altered consciousness

– Alternative causes of AMS should be sought and treated

– Identification of precipitating factors and their correction

– Commencement of empirical HE treatment

Management of Overt HE (OHE)

• Lactulose is the first choice for treatment of episodic OHE (GRADE II-1, B, 1)

• Rifaximin is an effective add-on therapy to lactulose for prevention of OHE recurrence (GRADE I, A, 1)

• Oral BCAAs can be used as an alternative or additional agent to treat patients nonresponsive to conventional therapy (GRADE I, B, 2).

• IV LOLA can be used as an alternative or additional agent to treat patients nonresponsive to conventional therapy (GRADE I, B, 2).

• Neomycin is an alternative treatment (GRADE II-1, B, 2)

• Metronidazole is an alternative treatment (GRADE II-3, B, 2)

• Probiotics and PEG cathartics appear to be equivalent to lactulose for HE therapy*

*As modified from: AASLD Practice Guideline, 2014.

Prevention of Overt HE (OHE)

• Lactulose is recommended for prevention of recurrent episodes of HE after the initial episode (GRADE II-1, A, 1)

• Rifaximin as an add-on to lactulose is recommended for prevention of recurrent episodes of HE after the second episode (GRADE I, A, 1)

• Routine prophylactic therapy (lactulose or rifaximin) is not recommended for the prevention of post-TIPS HE (GRADE III, B, 1)

• Under circumstances where the precipitating factors have been well controlled (i.e., infections and VB) or liver function or nutritional status improved, prophylactic therapy may be discontinued (GRADE III, C, 2)

• Probiotics and PEG cathartics appear to be equivalent to lactulose for HE therapy*

* As mofdifed from : AASLD Practice Guideline, 2014.

Sharma BC et al. Am J Gastroenterol 2013;108:1458-1463.

Treatment Approach for Episodic OHE: Lactulose + Rifaximin vs. Lactulose

172 Cirrhotic Patients Screened

120 Patients Enrolled

Randomization

Lactulose (30-60 mL TID) + Rifaximin (one 400 mg capsule TID)n=63 (10 grade 2, 20 grade 3, 33 grade 4)

Lactulose (30-60 mL TID) + Placebo (one sugar capsule TID)n=57 (12 grade 2, 20 grade 3, 25 grade 4)

Treatment Approach for Episodic OHE: Lactulose + Rifaximin vs. Lactulose

Sharma BC et al. Am J Gastroenterol 2013;108:1458-1463.

• Given via nasogastric tube until recovery of HE or a maximum of 10 days

• Hospital stay was shorter with Lactulose+ Rifaximin than with Lactulose + Pbo (5.8±3.4 vs. 8.2±4.6 days, P=0.001)Reversal of HE Death

80 76%

44%49%

Lactulose + RifaximinLactulose + Placebo

48/63 25/57 15/63 28/57

P=0.004

P=<0.05

Summary

• Cirrhosis is increasing in prevalence in the US and recognition with

accurate diagnosis is critical for patient care

• Histologic or clinical diagnosis

• Be familiar with the various staging and prognostic tools

• Recognize the clinical importance of transition from compensated to

decompensated cirrhosis

• HE is a frequent complication of cirrhosis

– Familiarize yourself with new guidelines for its diagnosis, classification,

and treatment

Hepatocellular Carcinoma

The Incidence and 5-Year Survival of HCC in United States

El-Serag HB. N Engl J Med 2011

GLOBOCAN 2002

Seroprevalence of HBsAg, antiHCV-Ab, Both and Neither in Patients with HCC in the US in Three Time Periods

De Martel C et al, Hepatology 2015; online version (July)

Risk Factors for HCC in Chronic HCV:Host Factors• Older age• Duration of HCV infection• Male sex• Race• Alcoholism• Obesity• Diabetes• HBV co-infection esp if they have Delta infection• HIV co-infection

Hazard Ratio Confidence Interval

Cirrhosis 1.31 1.22.-1.39

HCC 1.80 1.61-2.03

Conclusion: Genotype 3 is associated with a significantly higherrisk of cirrhosis and HCC vs genotype 1, independent of age, diabetes, BMI or antiviral treatment

Kanwal F et al, Hepatology 2014;60:98-105

HCV Genotype 3 in the VA HCV Clinical Case Registry 2000-2009: Cirrhosis and HCC• 88,348 patients with genotype 1 (80%)• 13,077 genotype 2 (12%)• 8,337 genotype 3 (7.5%)• Mean follow up 5.4 years• After adjustment for demographic, clinical and antiviral treatment factors,

comparison between genotypes 3 and 1:

Viral factors Host Factors External Factors

HBV: Risk Factors for Progression to HCC

• Persistently high HBV DNA levels

• HBV CP variant

• HBV genotype (C > B)

• Delta infection

• Older age

• Male gender

• Asians??

• Advanced fibrosis

• Persistent ALT elevation

• Recurrent hepatitis flares

• HDV, HCV coinfections

• HIV coinfection

• Family history of HCC

• Increased or increasing: AFP, AFPL3% and DCP

• Alcohol

• Aflatoxin

• Smoking

Chuang SC , et al. Cancer Epidemiol Biomarkers Prev . 2010;19:1261–1268

Tobacco Smoking

• Smoking alone– Positive associations and no associations reported in

different studies

• Smoking PLUS HBV and HCV infection– More than additive interaction between HBV infection

and cigarette smoking

– More than multiplicative interaction between HCV infection and cigarette smoking

NAFLD and Risk of HCC

• No evidence from population based data• Possible increase in HCC risk in clinic based cohorts

of NASH– ? Magnitude– ? Risk factors

• Consistent evidence from clinic based cohorts with NAFLD/NASH cirrhosis– Magnitude < HCV cirrhosis

White D, Kanwal F, El-Serag. Clin Gastro Hep 2012

DiabetesN=173,643

No Diabetes N=650,620

P<0.0001

Years of Follow up0 2 4 6 8 10 12 14

) 0.25

El-Serag HB, et al, Gastroenterology 2004

Diabetes Is Associated with a Two-fold Increase in Risk of HCC

El-Serag HB et al. DDW 2014

HCC in the Absence of Cirrhosis in United States Veterans

• ~13% of 1500 HCC cases developed in absence of cirrhosis

• These cases were more likely than HCC in cirrhosis to have – NAFLD or idiopathic compared to HCV or alcohol– Co-morbidities associated with metabolic syndrome

• While a small proportion, this poses logistical problems for HCC surveillance

Prevention of HCC

Ashahina et al., Hepatology 2010

Non-SVR

SVRNon-SVR

HCC and Hepatitis C Treatment

HBV Vaccination and HCC:Taiwan Experience• National HBV immunization program was launched in July 1984.

• Results

– Incidence rate of HCC in children 6-19 years of age was statistically significantly reduced for those born after initiation of vaccination program

– HCC prevention extended from childhood to early adulthood

• Higher risk of development of HCC in those who received incomplete vaccination (fewer than 3 doses) or who were born to HBsAg or HBeAg-seropositive mothers

Chang et al., J Natl Cancer Inst 2009;101:1348-1355

Year of follow-up

00 1 2 3 4 5 6 7 8 9 10 11 12 13

13.50%

0.89%0.74%

Adapted from Chen CJ et al. JAMA. 2006;295:65–73

Baseline HBV DNA Level (copies/ml)

≥106

105–<106

104–<105

300–<104

HBeAg negative, normal ALT, no liver cirrhosis at entry (n=2,925)

Hepatitis B: Association Between Viral Load and Incidence of HCC>> treatment guidelines

Chen CJ et al. JAMA. 2006;295:65–73

Singh S, et al Gastroenterology 2009

Statins and HCCSystematic Review

• Ten studies– 7 observational, 3 clinical trials

• Pooled OR: 0.63 (0.52-0.76) – Not in the 3 clinical trials

• Not other lipid lowering medications• Unclear

– Dose, duration, type

Metformin and Reduced Risk of HCC in Diabetic Patients: a Meta-analysis

• Seven studies: – Three cohort studies

– Four case-control studies

• Significantly reduced risk of HCC in metformin users versus nonusers in diabetic patients – RR: 0.24, 95% CI 0.13–0.46, p < 0.001

Zhang H et al. Scand J Gastroenetrol 2013

• Epidemiologic studies: coffee consumption is inversely related to – Serum liver enzyme activity– Liver cirrhosis– HCC

• For each additional 1 cup of coffee:– Case-control studies

• (0.77, 0.72-0.83)

– Cohort studies • (0.75, 0.65-0.85)

Coffee and Hepatocellular Carcinoma

Population Group

Threshold Incidence for Efficacy ofSurveillance

(>0.25 LYG)(%/year)

Incidence of HCC(%/year)

Asian male hepatitis B carriers > age 40 0.2 0.4–0.6

Asian female hepatitis B carriers > age 50 0.2 0.3–0.6

Hepatitis B carrier with family history of HCC 0.2 Incidence higher than without family history

African/North American Blacks 0.2 HCC occurs at a younger age

Cirrhotic hepatitis B carriers 0.2-1.5 3–8

Hepatitis C cirrhosis 1.5 3–5

Recommended Groups for HCC Surveillance

Sherman M. Semin Liver Dis. 2010;30(1):3-16.

AFP and Des-gamma-carboxy Prothrombin (DCP) in the Early Diagnosis of HCC• 1031 patients randomized in the Hepatitis C Antiviral Long-term

Treatment Against Cirrhosis (HALT-C) Trial

– Nested case-control study of 39 HCC cases and 77 controls

• Testing within one month prior to HCC diagnosis

• DCP: sensitivity (74%) and specificity (86%) at a cutoff of 40 mAU/mL

• AFP: sensitivity (61%) and specificity (81%) at a cutoff of 20 ng/mL

• Combining both markers increased the sensitivity to 91% at month 0 but the specificity decreased to 74%

Lok, et al. Gastroenterology 2009 AFPl3% and DCP are FDA cleared as risk markers for HCC

HCC Surveillance Recommendations

• The target population for surveillance are those with liver cirrhosis (and HBV-infected patients without cirrhosis in special circumstances)

• US and AFP are the recommended screening tests for HCC in patients at the highest risk – US is central– Not AFP alone

Roberts Gastro 2015

HCC Surveillance Recommendations

• Premature to recommend dropping AFP

– RCTs used AFP + US

– Only population based cohort used AFP

– Approximately 20% of HCC cases are detected based only on an increase in AFP (with normal results from US analysis)

– Most of the current community-based surveillance is either nothing or AFP

– Adjust AFP for ALT and plt count

Singal, Clin Gastro Hep 2015, El-Serag Gastro 2014

Very early stage1 HCC <2 cm

Carcinoma in situ

Early stage1 HCC or 3 nodules

<3 cm, PS 0

Intermediate stageNo portal vein

thrombosisMultinodular, PS 0

Advanced stagePortal invasion

Metastases,PS 0-2

Terminal stage

1 HCC 3 nodules<3 cm

Portal pressure / bilirubin Associated

diseasesNormal

OLTResection PEI / RFAChemo-

embolization Sorafenib

Potentially curative treatments Palliative treatments Symptomatic Therapy

Barcelona-Clinic Liver Cancer (BCLC) Staging Classification and treatment Schedule for Hepatocellular Carcinoma

El-Serag HB, et al. Gastroenterology 2008

Patients at risk Sorafenib:

Placebo:

274 241 205 161 108 67 38 12 0276 224 179 126 78 47 25 7 2

299303

Time (months)

Hazard ratio (Sorafenib/Placebo): 0.69(95% CI, 0.55-0.87) P = 0.00058*

SorafenibMedian: 10.7 months(95% CI, 40.9-57.9)

PlaceboMedian: 7.9 months(95% CI, 29.4-39.4)

Phase III SHARP Trial in Advanced HCC: Overall Survival Benefit with Sorafenib

*O’Brien-Fleming threshold for statistical significance was P = 0.0077; CI=confidence intervalLlovet JM et al. NEJM. 2008; 359(4):378

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

HCC in the United States

• HCC fastest rising cause of cancer related death– #1 cause of cancer death in VN and SE Asian men– NASH, HCV and HBV

– Modifiable risk factors (alcohol, obesity, diabetes) for individual management

• Non modifiable risk factors (age, duration, sex) • Likely to continue for the near future

– Possible role for NAFLD with and w/o cirrhosis

• Prevention– HBV vaccination– Antiviral treatment

• Detection: Surveillance in high risk groups

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