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Bon Secours Liver Institute of VirginiaBon Secours Medical Group Good Help to Those in Need ®
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
Bon SecoursLiver Institute of Virginia
CHRONIC HCVA GLOBAL HEALTH PROBLEM
Chronic HCV is a significant health burden
– USA 4 M– EU 14 M– Worldwide 185 M
LIVER
CIRRHOSISLIVER CANCER
Bon SecoursLiver Institute of Virginia
CHRONIC HCVEXTRAHEPATIC TARGETS
Hepatitis C Virus
EXTRAHEPATIC TARGETS
IMMUNE RESPONSE
Cryoglobulinemia
METABOLISM
LIVER
Bon SecoursLiver Institute of Virginia
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
Bon SecoursLiver Institute of Virginia
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
Bon SecoursLiver Institute of Virginia
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
)
Bon SecoursLiver Institute of Virginia
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
Bon SecoursLiver Institute of Virginia
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.
Bon SecoursLiver Institute of Virginia
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.
Bon SecoursLiver Institute of Virginia
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
Bon SecoursLiver Institute of Virginia
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.
Bon SecoursLiver Institute of Virginia
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
(%
)
Bon SecoursLiver Institute of Virginia
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
Bon SecoursLiver Institute of Virginia
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.
Bon SecoursLiver Institute of Virginia
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.
Bon SecoursLiver Institute of Virginia
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.
Bon SecoursLiver Institute of Virginia
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
Bon SecoursLiver Institute of Virginia
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.
Bon SecoursLiver Institute of Virginia
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
Bon SecoursLiver Institute of Virginia
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
Bon SecoursLiver Institute of Virginia
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.
Bon SecoursLiver Institute of Virginia
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.
Bon SecoursLiver Institute of Virginia
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
Bon SecoursLiver Institute of Virginia
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
Bon SecoursLiver Institute of Virginia
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
Bon SecoursLiver Institute of Virginia
HCV AND METABOLISMSUMMARY
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
Bon SecoursLiver Institute of Virginia
HCV AND METABOLISMSUMMARY
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