NON-HEPATIC COMPLICATIONS OF HCV. Kenneth E. Sherman, MD, PhD Gould Professor of Medicine University of Cincinnati College of Medicine

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1 NON-HEPATIC COMPLICATIONS OF HCV Kenneth E. Sherman, MD, PhD Gould Professor of Medicine University of Cincinnati College of Medicine

2 DISCLOSURES RESEARCH GRANTS/CONTRACTS (to Institution) AbbVie Gilead Merck MedImmune Innovio Advisory Board Merck (paid to institution) MedImmune DSMB Janssen MedPace SynteractHCR

3 AUDIENCE QUESTION A 49 yo man seeks life insurance He receives the following labs and shares them with his physician Cholesterol 242 HDL 34 LDL 146 Hgb 13.4 (>13.5) Plt 127K ( K) ALT 43 (15-45) AST 36 (14-45) -TSH 6.8 (.7-5.5)

4 Audience Response 1. Looks normal- Don t worry about it 2. Needs a statin 3. Might have cirrhosis- HCV testing needed 4. Mildly anemic- Eat more red meat

5 CHASM: C- Hepatitis Associated Systemic Manifestations

6 Lipoprotein (LDL/VLDL) Extracellular space Receptor binding LDLR GAG SR-BI Cell membrane Cytosol CD81 CLDN1 Clathrin-coated pit Endosome H+ Capsid release Acidified endosome H+

7 HCV MODULATES LIPID METABOLISM Fierro NA et al. W J GASTRO, 2014

8 Structural and non structural HCV proteins RNA 5 UTR region Domains I-VI 9.6 kb 3 UTR region 5B-SL3 Poly U tail p7 IRES-mediated translation Polyprotein C E1 E2 NS2 NS3 A NS4 B A NS5 B p7 Polyprotein processing C E1 E2 NS2 NS3 A NS4B NS5A A NS5B B * * * * * * * * Core Envelope glycoproteins Protease Serine protease Helicase Serine protease cofactor Membr. web? RNA-dependant RNA polymerase

9 HCV DIVERSITY HCV replicates at high levels (>10 trillion virions/day) 99% in Liver 1% Extrahepatic Lack of error correction leads to drift Drift is observed in two forms Quasispecies Genotypes

11 OCULAR MANIFESTATIONS Sicca Syndrome Mooren s Corneal Ulcers

12 SICCA SYNDROME

13 Mooren s Corneal Ulcer

15 HCV Replication in Human Thyroid Cells Blackard et al, THYROID 2013

16 Ferri C et al. W J GASTRO 2015 Putative Mechanisms Thyroiditis/Type 2 DM

18 DIABETES & HCV Strongly linked in epidemiologic studies Proposed Mechanisms Direct infection and injury to islet cells Up Modulation of Peroxisome Proliferator-activated receptor gamma (PGC-1 α ) which induces gluconeogenesis HCV Core induced increase in IRS-1 (Insulin Receptor Substrate) leading to insulin resistance Epidemiologic phenomenon linked to association of Type II DM to IL28b TT Shlomai A et al. J HEPATOL 2012; Kawaguchi T et al AM J PATHOL 2004 Stattermayer AF et al H HEPATOL 2012

20 HCV & CARDIOVASCULAR DISEASES Adinolfi LE et al. W J GASTRO 2014

22 CRYOGLOBULINEMA & VASCULITIS Ferri C et al. W J GASTRO 2015

23 OTHER CUTANEOUS MANIFESTATIONS Porphyria Cutanea Tarda Lichen Planus

24 PCT

25 Oral Lichen Planus

27 MPGN

28 HCV & RENAL CELL CA Renal Cell Carcinoma Increasing over 3 Decades Prospective Study of HCV Association Developed Consecutive Renal Cell and Colon Ca patients enrolled N= 140 RCCa N= 100 Colon Ca Chronic Kidney disease more common in those with RCCa Renal Cell P< Colon Ca Gonzalez HC et al, DIG DIS SCI, 2015

30 HCV BRAIN RECEPTORS Fletcher et al, GASTROENTEROLOGY, 2012

31 HCV & ASTROCYTES Astrocytes have all receptors needed for HCV attachment but failed to support HCV entry HCV induces IL-18 which is directly neurotoxic This interaction may be sufficient to cause CNS dysfunction in astrocytes and motor neurons Liu Z et al, J NEUROVIROL, 2014

NEUROIMAGING & NEUROCOGNITIVE FUNCTION N= 76 HCV and 20 Controls All received Neurocognitive Assessment 29 HCV and all controls underwent brain MRI HCV

32 NEUROIMAGING & NEUROCOGNITIVE FUNCTION N= 76 HCV and 20 Controls All received Neurocognitive Assessment 29 HCV and all controls underwent brain MRI HCV alters features of frontostriatal structures associated with fatigue and cognitive performance Thames AD et al, Neurology, Neuroimmunology & Neuroinflammation, 2015

34 Three Pathways for HCV-induced Lymphomagenesis. Fabrizio Marcucci, and Alfonso Mele Blood 2011;117: by American Society of Hematology

35 Percent SVR Associated With Reduced Long-Term Risk of All-Cause Mortality in an International, Multicenter Study 30 All-Cause Mortality Non-SVR P< SVR Time (years) International, multicenter, long-term follow-up study from 5 large tertiary care hospitals in Europe and Canada. Patients with chronic HCV infection started an interferon-based treatment regimen between 1990 and 2003 (n=530). van der Meer AJ, et al. JAMA. 2012;308:

37 CONCLUSION HCV is frequently encountered and often unrecognized as an etiology of systemic disease processes HCV can be CURED and this may lead to Decreased All Cause Mortality Regression of some but not all manifestations seen in CHASM

38 There are, in truth no specialties in medicine, since to fully Know many of the most important diseases a man must be familiar with their manifestations in many organs. William Osler

HCV MEDICATIONS & Kenneth E. Sherman, MD, PhD Gould Professor of Medicine Director, Division of Digestive Diseases University of Cincinnati

HCV MEDICATIONS & Kenneth E. Sherman, MD, PhD Gould Professor of Medicine Director, Division of Digestive Diseases University of Cincinnati HCV MEDICATIONS & THERAPEUTIC TRIALS Kenneth E. Sherman, MD, PhD Gould Professor of Medicine Director, Division of Digestive Diseases University of Cincinnati DISCLOSURES Active or Within 12 Months Research