IMPACT OF HCV THERAPY ON METABOLISM AND PUBLIC HEALTH …€¦ · IMPACT OF HCV THERAPY ON METABOLISM AND PUBLIC HEALTH Mitchell L Shiffman, MD ... • Demonstrate that these metabolic

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IMPACT OF HCV THERAPY ON METABOLISM AND PUBLIC HEALTH

Mitchell L Shiffman, MDDirector

Liver Institute of VirginiaBon Secours Health System

Richmond and Newport News, VA

Bon SecoursLiver Institute of Virginia

DISCLOSURESCONFLICTS OF INTEREST

Company RolesAbbvie Advisor meetings, Grant support, SpeakerAmerican Regent SpeakerBayer SpeakerBeckman-Colter Grant supportBristol Myers-Squibb Advisor meetings, grant support, SpeakerConatus Grant supportCymaBay Grant supportGalectin Grant supportGenfit Grant supportGilead Advisor meetings, Grant support, SpeakerIntercept Grant support, Advisor meetings, Speaker, Immuron Grant supportMerck Grant support, Advisor meetings, Speaker, NGMBio Grant supportNovartis Grant support


CHRONIC HCVA GLOBAL HEALTH PROBLEM

Chronic HCV is a significant health burden

– USA 4 M– EU 14 M– Worldwide 185 M

LIVER

CIRRHOSISLIVER CANCER


CHRONIC HCVEXTRAHEPATIC TARGETS

Hepatitis C Virus

EXTRAHEPATIC TARGETS

IMMUNE RESPONSE

Cryoglobulinemia

METABOLISM

LIVER


CHRONIC HCVEFFECTS ON METABOLISM

• Estimated 47 M persons have T2DM from HCV

• T2DM is 4x more common in patients with HCV

• HCV proceeds appearance of 2TDM by 10-20 years

• HCV induced 2TDM is a significant public health problem

HEPATITIS C VIRUS

INSULIN RESISTANCE

TYPE 2 DM

Chronic Kidney DiseaseCoronary Artery DiseaseCerebral Vascular Disease


HEPATITIS C VIRUSGENETIC SEQUENCE

NS5B

C E1 E2 P7 NS3NS4A

NS4B

NS5A

Structural Proteins

Non-Structural ProteinsPrimary role:Replication Translation

HCV Core ProteinSuppress immune Response

Alters glucose metabolism


CHRONIC HCVINSULIN RESISTANCE

HCV General0

20

40

60

80

IR (

%)

Population

S Harrison. Hepatology 2006; 43:1168.S Harrison et al. Clin Gastroenterol Hepatol 2008; 6:864-876.

IR No IR0

1

2

3

4

5

Log

HC

V R

NA

(IU

/ml x

10

)


CHRONIC HCV AND IRIMPACT OF OBESITY

<30 >300

100

200

300

Yes

Pla

sma

Insu

lin (

pm

ol/L

) HCV

S Mehta et al.Hepatology 2003; 38:50-56.

<30 >300

2

4

6

8

10

12

Yes

HO

MA

-IR

HCV

BMIBMI


CHRONIC HCVASSESSING INSULIN RESISTANCE

Basal Insulin Clamp0

5

10

15

20

Control

EG

P

• 7 Normal weight controls• 14 Normal weight HCV• No features of metabolic

syndrome• Endogenous glucose

production measured at:● Basal state ● During insulin clamp

• Higher EGP indicative of insulin resistance

E Vanni et al.Hepatology 2009; 50:697-707.


CHRONIC HCVDEVELOPMENT OF DM

0 5 10 15 20 25 300

4

8

12

16

20

Yes

YEARS

Ris

k of

DM

(%

)

HCV (+)

REVEAL Study Cohort930 HCV (+)16,928 HCV (-)Monitored prospectively for development of DM

YJ Lin et al.Liver Intl. 2016; 37:179-186.


CHRONIC HCVOTHER METABOLIC COMPLICATIONS

• Since chronic HCV is a risk factor for T2DM

• T2DM is associated with metabolic syndrome

• HCV may contribute to other metabolic complications:– Coronary artery disease Acute coronary syndrome– Cerebral vascular disease Stroke– Chronic kidney disease End Stage Renal Disease


CHRONIC HCVCORONARY ARTERY DISEASE

0 1 2 3 4 5 6 7 8 990

92

94

96

98

100

Yes

YEARS

Fre

e o

f C

AD

(%

)

HCV (+)

• US VA hospital system• 82, 083 with HCV• 89, 582 without HCV• HCV associated with

significantly higher rate of CAD after adjusting for standard risk factors.

• Standard risk factors increased CAD risk in both groups.

AA Butt et al.Clin Infect Dis. 2009; 49:225-232.


HCV CORE PROTEINCAROTID ARTERY PLAQUE

0 1 2 3 40

20

40

60

80

100

Log HCV CoreProtein (pg/ml)

CA

Pla

que

(%

)

Y Ishizaka et al.Circ J 2003; 67:26-40.

Yes No0

20

40

60

80

100

HCV CoreProtein

CA

Pla

que

(%

)


CHRONIC HCV CAROTID VASCULAR INJURY

HCV No HCV1000

1200

1400

1600

PW

V (

cm/s

)

H Tomiyama et al.Atherosclerosis. 2003; 166:401-403.

• Vascular injury, atherosclerosis and plaque leads to increased carotid artery stiffness

• 87 patients with HCV

• 7,427 without HCV or HBV

• Assessed by Pulse Wave Velocity

• This was not increased with HBV

P< 0.01


CHRONIC HCVCEREBROVASCULAR DISEASE

0 5 10 15 20 25 30 35 400

1

2

3

4

Yes

YEARS

De

ath

fro

m S

trok

e (%

)

HCV (+)• 1,037 patients with HCV• 22,358 negative for HCV• Ages 30-65 years• All anti-HCV positive

confirmed by HCV RNA• Enrollment 199092• HCV associated with 2.6

fold increased risk for stroke

MH Lee et al.Stroke. 2010; 41:2894-2900.


CHRONIC HCVALBUMINUREA

20-39 40-59 >600

10

20

30

40

50

HCV (-)

AGE RANGE (Years)

% o

f Pat

ient

s

JI Tsui et al.JASN 2006; 17:1168-1174.


CHRONIC HCVIMPACT OF DM ON ESRD

0 2 4 6 8 10 12 140

1

2

3

4

5HCV (+)

YEARS

Inci

denc

e (

%)

Patients: 19,57450% with HCVDiabetes for 3.9 yearsHypertension: 39%CAD: 11%Hyperlipidemia: 16%Factors associated with development of ESRD• Hypertension• Chronic HCV

JC Hwang et alMedicine 2016; 95:e2431.


CHRONIC HCVIMPACT OF TREATMENT

• The best way to demonstrate that HCV does cause alterations in metabolism and other downstream effects

• Treat and cure HCV

• Demonstrate that these metabolic effects can be prevented or reversed

• Only data available so far is based on interferon therapy


IMPACT OF HCV TREATMENT HOMA AND IR

Baseline EOF0

0,20,40,60,8

11,21,41,61,8

2

SVR

Mea

n H

OM

A

SVR NR0

5

10

15

20

De

No

vo I

R (

%)

A Aghemo et alHepatology 2012; 56:1681-1687.


IMPACT OF HCV TREATMENT DEVELOPMENT OF DM

0 5 10 15 20 25 30 35 400

10

20

30

40

YEARS

Ne

w T

2D

M (

%)

Y Arase et al.Hepatology. 2009; 49:739-744.

AGE>50 Yrs

0 5 10 15 20 25 30 35 400

20

40

60

80

YEARS

Ne

w T

2D

M (

%)

NR

SVRSVR

NR

Cirrhosis


IMPACT OF HCV TREATMENTEXTRAHEPATIC DISEASE

Lymphoma DM ESRD0

5

10

15

20

25

30

35

SVR% OF PATIENTS

Y Kawamura et al. Am J Med 2007; 120: 1034–1041.Y Arase et al. Hepatology 2009; 49: 739–744.YC Hsu et al. Hepatology 2014; 59: 1293–302.

TreatmentNo Treatment

IN PTS WITH DM


HCV TREATMENTIMPACT ON CARDIAC DISEASE

Baseline EOF0

1

2

3

4

5

SVR

Ca

rdia

c S

eve

rity

Sco

re

• 210 HCV patients without over cardiac disease

• Evaluated with:● ECG● Echocardiogram● Serum tests of myocardial

injury● Thallium myocardial

perfusion scan• Cardiac severity score

calculated• Patient treated with PEGINF

and RBV• SVR = 46%

S Maruyama et al.J Hepatol. 2013; 58:11-15.


HCV TREATMENTACS AND ISCHEMIC CVA

ACS Ishemic CVA0

2

4

6

8

No HCVNo TxTreatment

% of Patients

YC Hsu et al. Hepatology 2014; 59: 1293–302.


CHRONIC HCVMETABOLIC SYNDROME

Metabolic SyndromeHypertension2TDMDyslipidemiaNAFLObesity HCV

• Metabolic syndrome is common in all societies throughout the developed world

• By chance alone 33% of patients with HCV will have metabolic syndrome

• HCV can be cured• Progressive liver injury may still

occur from NASH• Since liver biopsy is now rarely

performed for HCV• NASH may be missed


CHRONIC HCVMETABOLIC SYNDROME

ML Shiffman, NT Gunn.Liver Int 2017; 37 (suppl 1):13-18.

CHRONIC HCV

METABOLICSYNDROME

IR

T2DM

NASH

Cirrhosis

HCC

ESRD ACS

NAFL CKD CAD CVD

STROKE


HCV AND METABOLISMSUMMARY

HCV affects not only the liverIt alters metabolismWhich is also a killer

The core protein of the virusAppears to be driving this busWhich causes resistance to insulin And leads to diabetes mellitusIn not only the obeseBut some skinny of us



The team of diabetes and HCV

Can lead to MI through vascular injury

Increase stroke mortality

Failure of the kidney

And this impacts the public health of our city



So in this year of Brexit and TrumpThere is no reason to be down in the dumpThe Fantastic 4 have come to townHarvoni, Epclusa, Zepetier and the new guy from AbbvieWill put an end to all but a few with the CAnd this should reduce metabolic injury

Documents

IMPACT OF HCV THERAPY ON METABOLISM AND PUBLIC HEALTH …€¦ · IMPACT OF HCV THERAPY ON METABOLISM AND PUBLIC HEALTH Mitchell L Shiffman, MD ... • Demonstrate that these metabolic