4/30/2015

1

Formatted:04-24-2015

Marion G. Peters, MDJohn V. Carbone, Endowed Chair

Professor of MedicineChief of Hepatology Research

University of California San FranciscoSan Francisco, California

Overview of Liver Disease

Associated With HCV

Los Angeles, CA: April 28, 2015 (ADVANCED)

Slide 2 of 35

Learning Objectives

Describe HCV in 2015

Describe how to diagnose advanced liver disease

and cirrhosis

Identify the clinical presentation and risks

associated with decompensated cirrhosis

Describe HCV treatment 4-2015

After attending this presentation, participants will

be able to:

Slide 5 of 35

Worldwide prevalence of each HCV genotype by GBD

Region. Size of pie charts proportional to the number of

seroprevalent cases estimated by Hanafiah et al 2014: Messina 2015

HCV genotype 1 (83.4 million cases: 46.2%)- one-third of which are in East Asia.

Genotype 3 (54.3 million: 30.1%); genotypes 2, 4, and 6 (22.8%); genotype 5 <1%.

While genotypes 1 and 3 dominate in most countries irrespective of economic

Status: largest proportions of genotypes 4 and 5 are in lower-income countries.

4/30/2015

2

Future Burden of Hepatitis C Related Morbidity

and Mortality in the US Markov model of health outcomes

– Of 2.7 M HCV infected persons in primary care 1.47 M will develop cirrhosis

350,000 will develop liver cancer

897,000 will die from HCV-related complications

Rein D, et al. Dig Liver Dis 2010.

0

5000

10000

15000

20000

25000

30000

35000

40000

20

10

20

13

20

16

20

19

20

22

20

25

20

28

20

31

20

34

20

37

20

40

20

43

20

46

20

49

20

52

20

55

20

58

Deaths

DCC

HCC

Num

ber

Effects of SVR on the risk of liver transplant,

hepatocellular carcinoma, death and re-infection:

meta analysis, 129 studies, 34,563 patients

Hill AASLD 2014

2.95.3

0.9

9.3

13.9

10

02468101214161820

General Cirrhotic Co-infected

Patients after 5 years (%) SVR No SVR

5-year risk of hepatocellular

carcinoma

by SVR

General: 21 stud

n=12,496

Avg. FU=6.1 years

Cirrhotic: 18 stud

n=4,987

Avg. FU=6.6 years

HIV/HCV: 3 studies

n=2,085

Avg. FU=4.7 years

Benefits may be offset by re-infection over 5 years

0.9% in ‘low-risk’ persons

8.2% in persons who inject drugs

23.6% in persons coinfected with HIV

4.5 3.61.3

10.5 11.310

02468101214161820

General Cirrhotic Co-infected

Patients after 5 years (%) SVR No SVR

5-year risk of death (all-cause)

by SVR

Gen 18 stud

n=29,269

Avg. FU=4.6 years

Cirr 9 stud

n=2,734

Avg. FU=6.6 years

HIV/HCV: 5 stud

n=2,560

Avg. FU=5.1 years

Slide 7 of 37

Slide 8 of 35

HCV SVR and All Cause Mortality

Backus CGH 2011: VAMC 22,942 PEG-IFN/RBV treated 2001-2007: mortality thru 2009

12,166: SVR 35%1,119 died over 3.8y f/u

4/30/2015

3

Slide 9 of 35

Steps in Assessing Fibrosis

1. Clinical evidence of cirrhosis• Labs (elevated INR, low albumin, bilirubin)

• Radiology evidence of portal HTN

• Exam (ascites, varices, encephalopathy)

2. Transient elastography

3. Noninvasive markers• E.g. APRI Fib 4- uses AST, platelets, ALT

4. If further deliniation is needed Liver biopsy• Not needed in many/ most situations with HCV

Slide 10 of 35

Transient Elastography

Slide 11 of 35

TRANSIENT ELASTOGRAPHY• Measures elasticity using sound waves

• Stiffness determined by multiple factors

– Degree of Fibrosis

– Degree of Inflammation- not good for AVH, high ALT

• Degree of Steatosis

– Not effective in morbidly obese patients >3.5cm

• Approved in U.S. 4-2013

– now have XL probes

J Gastrointestin Liver Dis. 2008 Jun;17(2):155-163

4/30/2015

4

Slide 12 of 35

Elastography: HCV Fibroscan

2.5 kPa

Affected by weight, access of probe (2 cm), steatosis

Slide 13 of 35

Diagnosing Cirrhosis – Labs

EXAM:

Spider nevi, splenomegaly

Most labs not helpful

• 50% Child’s A normal

• AST: ALT often >1

Synthetic dysfunction

• Hypoalbuminemia

• Prolonged PT/ INR

• Hyperbilirubinemia

Portal Hypertension

• Thrombocytopenia

• Leukopenia

• Anemia

Renal dysfunction

• Elevated creatinineremember depends on muscle mass

Hyponatremia with ascites

Slide 14 of 35

Survival Time from First Liver Decompensation to Death in HCV

Pineda, Hepatology 2005

54

74

40

61

25

44

0

10

20

30

40

50

60

70

80

Perc

ent o

f p

atie

nts

1 2 5

Year survival

HIV+

HIV-•Death during study

•366/1037 HCV

•100/180 HIV/HCV

• Risk factors for death:

•HIV

•Baseline CTP

•MELD >13

•Age

Decompensation with AscitesEncephalopathyVariceal bleedSynthetic dysfunction (INR, Bili, Alb)

4/30/2015

5

Slide 15 of 35

Prognosticating Decompensated Cirrhosis

http://hepatitisc.uw.edu/go/management-cirrhosis-related-complications/liver-transplantation-referral/core-concept/all

Slide 16 of 35

3-Month Mortality Based on CTP

Wiesner R, Edwards E, Freeman R, et al. Model for end-stage liver disease (MELD) and allocation of donor livers. Gastroenterology. 2003;124:91-6.

Slide 17 of 35

MELD and Liver Transplantation

• MELD

– Prioritization on liver transplant list

– Most IMPORTANT single value in

prognostication

– Easy to calculate prior to referral

• MELD = 15 or greater

– Benefit from OLT

• Important predictor of liver-related outcomes

4/30/2015

6

Slide 18 of 35

MELDINRBilirubinCreatinine

Slide 19 of 35

3-Month Survival Based on MELD

http://hepatitisc.uw.edu/go/management-cirrhosis-related-complications/liver-transplantation-referral/core-concept/all

Slide 20 of 35

Cirrhosis

Prevalence

35%-80%

25%-40%

Die

30%-50%50%-70%Survive

Rebleed

70%

Risk of

Bleeding

Risk of Bleeding from Esophageal Varices

4/30/2015

7

Slide 21 of 35Variceal Surveillance

All cirrhotics require

Esophagogastroduodenoscopy

Garcia-Tsao G, et al. Hepatology. 2007;46:932-938.

Novarices

Repeat endoscopy in 3 years (well

compensated); in 1 year if

decompensated

No beta-blocker prophylaxis

Small varices (< 5 mm),

Child B/C

Nonselective

Beta-blocker

prophylaxis

Medium or large varices

Child Class A, no red

wales: beta blockers

Child class B/C, red

wales: beta blockers

or band ligation

Slide 22 of 35

Hepatic Venous Pressure to Predict Portal Hypertension

Robic J Hep 2011: 100 pts followed for 2y: ETOH 38; v hep 28: 75 F3-4

71 events in 41 patients

Slide 23 of 35

Liver Stiffness to predict Portal Hypertension

Robic J Hep 2011

4/30/2015

8

Slide 24 of 35

Hepatocellular Carcinoma (HCC)

• Late complication of end-stage liver disease– Exceptions: HBV seen in non cirrhotics

• Diagnosis by US, CT scan, MRI– Histology is not essential

• Alpha-fetoprotein level may be elevated– 20-40% with HCC have normal AFP

– 20-30% without HCC have abnormal AFP

– The higher the AFP, the more likely the diagnosis of HCC

Slide 25 of 35

Hepatocellular Carcinoma (HCC)

• Surveillance

– Screen all patients with cirrhosis for HCC

• Up to 8% risk of HCC/year

– Also male HBV carriers >40 and female HBV >50 (even if they don’t have cirrhosis)

• Up to 0.6% risk of HCC/year

• If recertifying…”screen with ultrasound q 6 months”

– No benefit to shortening interval

– No benefit to screening with AFP

– In practice many still use cross-sectional imaging and AFP to screen as well

Bruix et al Hepatology 2010

Slide 26 of 35

Quad phase CT Appearance of HCC

Arterial Phase

Arterial Phase Portal venous Phase washout

Hypervascular lesion that washes out on portal venous phase

4/30/2015

9

Slide 27 of 35

Treatment of HCC

• Resection

• Local-regional therapy

– TACE

– RFA

– Ethanol ablation

• Liver transplantation

• Systemic

– Sorafenib

Slide 28 of 35

LOCAL REGIONAL THERAPIES FOR HCC

CHEMOEMBOLIZATION

– Conventional and Drug-eluting beads

ABLATION

• CHEMICAL

– Percutaneous ethanol injection (PEI)

• THERMAL

– Radiofrequency ablation (RFA)

(Laparoscopic, percutaneous or open)

– Microwave/ Cryo- ablation

RADIOEMBOLIZATION (YITTRIUM - 90)

Slide 29 of 35

Take Home: HCC

• Screen ALL patients with u/s q6 months if they have cirrhosis

• Usually radiographic diagnosis

– Biopsy rarely needed if classic imaging

– Cross-sectional imaging look for “arterial enhancement” and “washout”

• Treatment:

– Possibly “curative”: ablation, resection, transplant

– Palliative: TACE, sorafenib

4/30/2015

10

Slide 30 of 35

HCV treatment in cirrhotics

• 5% to 7% of Child’s A cirrhotics decompensate per year

• Diagnosis of Child’s A, even B cirrhosis may

be subtle

• Screen for HCC

• Perform EGD

• Monitor closely on therapy

• Child’s B can be treated- OLT back up plan

Slide 31 of 35Treatment of HCV: 4-2015 USANo cirrhosis Cirrhosis

Genotype Regimen wk Regimen TN TE

1a SOF+LDV (<6M) 12 (8) SOF+LDV 12 24

SOF+LDV +RBV 12

3D +RBV 12 3D +RBV 24 24

SMV +SOF±RBV 12 SMV +SOF±RBV 24 24

1b SOF+LDV (<6M) 12 (8) SOF+LDV 12 24

SOF+LDV +RBV 12

3D 12 3D +RBV 12 12

SMV + SOF±RBV 12 SMV + SOF±RBV 24 24

Slide 32 of 35

Treatment of HCV: 4-2015 USA

No cirrhosis Cirrhosis

Geno Regimen wk Regimen TN TE

2 SOF+RBV 12 SOF+RBV 16 16

SOF + RBV TE 12-16

SOF + PEG/R 12

3 SOF+RBV 24 SOF+RBV 24 24

SOF+PEG/R 12 SOF+PEG/R 12 12

(DAC + SOF) 12 (DAC + SOF) 12