IMPACT OF HCV THERAPY ON METABOLISM AND PUBLIC HEALTH

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1 IMPACT OF HCV THERAPY ON METABOLISM AND PUBLIC HEALTH Mitchell L Shiffman, MD Director Health System Richmond and Newport News, VA Medical Group Good Help to Those in Need

2 DISCLOSURES CONFLICTS OF INTEREST Company Abbvie American Regent Bayer Beckman-Colter Bristol Myers-Squibb Conatus CymaBay Galectin Genfit Gilead Intercept Immuron Merck NGMBio Novartis Roles Advisor meetings, Grant support, Speaker Speaker Speaker Grant support Advisor meetings, grant support, Speaker Grant support Grant support Grant support Grant support Advisor meetings, Grant support, Speaker Grant support, Advisor meetings, Speaker, Grant support Grant support, Advisor meetings, Speaker, Grant support Grant support

3 A GLOBAL HEALTH PROBLEM LIVER Chronic HCV is a significant health burden USA 4 M EU 14 M Worldwide 185 M CIRRHOSIS LIVER CANCER

4 EXTRAHEPATIC TARGETS Hepatitis C Virus LIVER EXTRAHEPATIC TARGETS IMMUNE RESPONSE METABOLISM Cryoglobulinemia

5 EFFECTS ON METABOLISM HEPATITIS C VIRUS INSULIN RESISTANCE TYPE 2 DM Chronic Kidney Disease Coronary Artery Disease Cerebral Vascular Disease Estimated 47 M persons have T2DM from HCV T2DM is 4x more common in patients with HCV HCV proceeds appearance of 2TDM by 1-2 years HCV induced 2TDM is a significant public health problem

6 HEPATITIS C VIRUS GENETIC SEQUENCE Structural Proteins C E1 E2 P7 NS3 NS4 A NS4 B NS5 A NS5 B HCV Core Protein Suppress immune Response Alters glucose metabolism Non-Structural Proteins Primary role: Replication Translation

7 INSULIN RESISTANCE 8 5 IR (%) Log HCV RNA (IU/ml x 1 ) HCV General IR No IR Population S Harrison. Hepatology 26; 43:1168. S Harrison et al. Clin Gastroenterol Hepatol 28; 6:

8 AND IR IMPACT OF OBESITY Plasma Insulin (pmol/l) HCV Ye s <3 >3 BMI HOMA-IR HCV Ye s <3 >3 BMI S Mehta et al. Hepatology 23; 38:5-56.

9 ASSESSING INSULIN RESISTANCE 2 EGP Basal Contro l Insulin Clamp 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 29; 5:

10 DEVELOPMENT OF DM 2 HCV (+) Risk of DM (%) Ye s REVEAL Study Cohort 93 HCV (+) 16,928 HCV (-) Monitored prospectively for development of DM YEARS YJ Lin et al. Liver Intl. 216; 37:

11 OTHER 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

12 CORONARY ARTERY DISEASE Free of CAD (%) HCV (+) Ye s YEARS US VA hospital system 82, 83 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. 29; 49:

13 HCV CORE PROTEIN CAROTID ARTERY PLAQUE 1 1 CA Plaque (%) CA Plaque (%) Yes No Log HCV Core Protein (pg/ml) HCV Core Protein Y Ishizaka et al. Circ J 23; 67:26-4.

14 CAROTID VASCULAR INJURY 16 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 PWV (cm/s) HCV P<.1 No HCV H Tomiyama et al. Atherosclerosis. 23; 166:41-43.

15 CEREBROVASCULAR DISEASE Death from Stroke (%) HCV (+) Ye s YEARS 1,37 patients with HCV 22,358 negative for HCV Ages 3-65 years All anti-hcv positive confirmed by HCV RNA Enrollment HCV associated with 2.6 fold increased risk for stroke MH Lee et al. Stroke. 21; 41:

16 ALBUMINUREA 5 % of Patients >6 AGE RANGE (Years) HCV (-) JI Tsui et al. JASN 26; 17:

17 IMPACT OF DM ON ESRD Incidence (%) HCV (+) YEARS Patients: 19,574 5% with HCV Diabetes for 3.9 years Hypertension: 39% CAD: 11% Hyperlipidemia: 16% Factors associated with development of ESRD Hypertension Chronic HCV JC Hwang et al Medicine 216; 95:e2431.

18 IMPACT 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

19 IMPACT OF HCV TREATMENT HOMA AND IR Mean HOMA 2 1,8 1,6 1,4 1,2 1,8,6,4,2 Baseline SV R EOF De Novo IR (%) SVR NR A Aghemo et al Hepatology 212; 56:

20 IMPACT OF HCV TREATMENT DEVELOPMENT OF DM 4 AGE>5 Yrs 8 Cirrhosis New T2DM (%) NR SVR New T2DM (%) SVR NR YEARS YEARS Y Arase et al. Hepatology. 29; 49:

21 IMPACT OF HCV TREATMENT EXTRAHEPATIC DISEASE SVR % OF PATIENTS Lymphoma DM ESRD Y Kawamura et al. Am J Med 27; 12: Y Arase et al. Hepatology 29; 49: YC Hsu et al. Hepatology 214; 59: Treatment No Treatment IN PTS WITH DM

22 HCV TREATMENT IMPACT ON CARDIAC DISEASE Cardiac Severity Score Baseline S Maruyama et al. J Hepatol. 213; 58: SV R EOF 21 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%

23 HCV TREATMENT ACS AND ISCHEMIC CVA 8 % of 6Patients 4 2 No HCV No Tx Treatment ACS Ishemic CVA YC Hsu et al. Hepatology 214; 59:

24 METABOLIC SYNDROME Metabolic Syndrome Hypertension 2TDM Dyslipidemia NAFL Obesity 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

25 METABOLIC SYNDROME CHRONIC HCV IR METABOLIC SYNDROME T2DM NAFL CKD CAD CVD NASH ESRD ACS STROKE Cirrhosis HCC ML Shiffman, NT Gunn. Liver Int 217; 37 (suppl 1):13-18.

26 HCV AND METABOLISM SUMMARY HCV affects not only the liver It alters metabolism Which is also a killer The core protein of the virus Appears to be driving this bus Which causes resistance to insulin And leads to diabetes mellitus In not only the obese But some skinny of us

27 HCV AND METABOLISM SUMMARY 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

28 HCV AND METABOLISM SUMMARY So in this year of Brexit and Trump There is no reason to be down in the dump The Fantastic 4 have come to town Harvoni, Epclusa, Zepetier and the new guy from Abbvie Will put an end to all but a few with the C And this should reduce metabolic injury