Management of Extrahepatic Manifestations of Hepatitis C Virus in the Era of DAA Pr Patrice CACOUB, MD Dept of Internal Medicine and Clinical Immunology CNRS UMR 7087, INSERM UMR S-959, DHU I2B Université Pierre et Marie Curie Hôpital La Pitié-Salpêtrière, Paris, FRANCE patrice.cacoub@aphp.fr
Disclosures Dr P. Cacoub has received consulting and lecturing fees from: Abbvie, Astra Zeneca, Bristol-Myers Squibb, Gilead, Glaxo Smith Kline, Janssen, Merck Sharp Dohme, Roche, Servier and Vifor Dr P. Cacoub is an inventor of a patent application owned by his academic institution and licensed to ILTOO pharma, a biotechnology company developing low dose IL-2 in autoimmune diseases, in which he holds shares. Dr P. Cacoub has received grants from: CNRS, INSERM, Université Pierre et Marie Curie and ANRS
Chronic active HCV infection almost doubles the risk of mortality from non-liver related diseases Cumulative extra hepatic mortality (%) 20 18 16 14 12 10 8 6 4 2 Non-liver related disease in patients with and without active HCV infection (n=2,199) 19.8% 12.2% 11.0% HCV+, RNA+ HCV- HCV+, RNA- 0 0 2 4 6 8 10 12 14 16 18 20 Follow-up (Years) P<0.001 for comparison among all 3 groups and P=0.002 for HCV RNA detectable vs. undetectable HCV, hepatitis C virus; RNA, ribonucleic acid Lee MH, et al. J Infect Dis 2012;206:469 77
Chronic HCV infection is more than a liver disease Depression, cognitive impairment Fatigue Stroke Sicca syndrome Lymphoma Renal complications Neuropathy Thyroid disease Myocardial perfusion defects Insulin resistance, type 2 diabetes Mixed cryoglobulinaemia vasculitis Dermatological manifestations Arthralgia HCV, hepatitis C virus. Cacoub P, et al. J Hepatol. 2016;65(1 Suppl):S82-94
Extra-hepatic manifestations of HCV Presentation outline 1. Autoimmune manifestations and malignant blood diseases 2. HCV infection: a new cardiovascular risk factor 3. Insulin resistance and type 2 diabetes mellitus 4. Fatigue, depression and cognitive impairment
Autoimmune and malignant blood diseases
Main (Auto)-Immune Conditions Associated with HCV Auto-Immune Condition l Vasculitis 5 15 % l Arthralgia-myalgia 25 35 % l Sicca syndrome 10 25 % l Auto-antibodies 10 40 % l Lymphoma RR=35 Cacoub P et al, Dig Liver Dis. 2014;46 Suppl 5:S165-73
Cryoglobulinemia vasculitis Skin Purpura Glomerulonephritis Neuropathy CNS vasculitis
About 15% of HCV-infected patients will develop a symptomatic mixed cryoglobulinemia l Italian cohort (80 centers), 1,777 HCV infected patients tested for the presence of mixed cryoglobulinemia Kondili et al, EASL 2016
HCV causes production of abnormal antibodies which are able to induce a systemic auto-immune disease Rocatello D, Nephrol Dial Transplant, 2004;19(12):3054-61
New anti-virals with increased potency improve HCVrelated cryoglobulinemia vasculitis Clinical remission in HCV-related cryoglobulinemia vasculitis correlates with virological response IFN-based regimen; 6 months IFN-free regimen; 24 weeks 47 %* 88%* Saadoun et al, 2006 1 n=32 Saadoun et al, 2015 3 n = 24 Non-complete clinical response Complete clinical response *End of treatment (EoT); 24 weeks post-treatment; IFN: interferon; PEG IFN: pegylated-interferon; PI: protease inhibitor; RBV: ribavirin; SOF: sofosbuvir 1. Saadoun D, et al. Arthritis Rheum 2006;54:3696 706; 2. Saadoun D, et al. J Hepatol 2015;62:24 30; 3. Saadoun D, et al. Ann Rheum Dis 2015; doi:10.1136/annrheumdis-2015-208339
HCV-CryoVas : Virological Response after IFN-free DAA SVR (%) 100% 83% 100% 94% 100% 80% 74% 60% 40% 20% 0% 17/23 SOF + RBV 1 24 wk 10/12 SOF + SMV ± RBV 2 12-24wk 44/44 SOF + LDV 3 12 wk 33/35 SOF-based/3D 4 12-24 wk 41/41 SOF + DCV,5 12-24 wk 1.Saadoun, Ann Rheum 2015; 2. Sise, Hepatology 2016 ;3. Gragnani, Hepatology 2016; 4. Bonacci, Clin Gastro Hepatol 2016 ; 5. Saadoun, Gastroenterology 2017
HCV-CryoVas : Clinical Impact of DAAs 100 90 80 70 60 50 40 30 20 10 0 Clinical response 12 weeks post-daa Saadoun, 2015 (n=24) Sise, 2016 (n=12) Gragnani, 2016 (n=44) Bonacci, 2017 (n=35) Saadoun, 2017 (n=41) Complete response Partia response Null response Saadoun et al. Ann Rheum Dis. 2016 Oct;75(10):1777-82; Sise et al. Hepatology 2016 Feb;63(2):408-17; Gragnani et al. Hepatology. 2016 Nov;64(5):1473-1482; Bonacci and Lens et al. Clin Gastroenterol Hepatol. 2017 Apr;15(4):575-583. Saadoun et al. Gastroenterology. 2017
HCV-Cryoglobulinemia: Therapeutic approach Antiviral therapy with IFN-free DAAs Mild to moderate disease ( purpura, arthralgia, neuropathy) Severe disease ( progressive renal failure, slkin ulcer, mononeuritis mutlplex) Life threatening (rapid progressive nephritis, CNS, digestive and pulmonary involvement) Cacoub P. Ann Rheum Dis 2014 Jan;73(1):24-30 ; Ramos-Casals, et al. Med Clin (Barc). 2015;144(9):410 417 Rituximab Rituximab, plasma exchange and/or cyclophosphamide
Major Advances in Antiviral Strategies in HCV-Cryoglobulinemia Vasculitis Complete clinical response At Week 12 At end of therapy (W24) Virological response At week 12 After end of therapy (W36) PegIFN-RBV-PI 1 SOF-RBV 2 SOF-DACLA N=30 N=24 N=41 46.6% 66.7% 73.9% 66.6% 71% 87.5% 92% 74% 90.2% 90.2% 100% 100% Clearance of cryoglobulin (W24) 22.2% 41.6% 50% Serious adverse event 46.6% 8% 0% Steroids and/or Rituximab 43% 16% 4.8% PegIFN, pegylated interferon; RBV, ribavirin; PI, first generation protease inhibitor; SOF, sofosbuvir; DACLA, daclatasvir 1. Saadoun D, et al. Arthritis Rheum 2006; 2. Saadoun D, et al. Ann Rheum Dis 2015
DAAs Revert Immune Abnormalities in HCV-CryoVas 3 * Sofosbuvir plus Daclatasvir revert Treg deficiency (A) and 1 expansion of IgM + CD21 -/low memory B cells (B), T folliculer helper 0 cells (C) and Th17 cells (D) in HCV-CryoVas A CD4 + CD25 hi Foxp3 + (%) 2 HCV-CV before DAA HCV-CV end DAA A B C CD4 + CD25 hi Foxp3 + (%) * 3 2 1 0 HCV-CV before DAA HCV-CV end DAA CD27 + IgM + CD21 -/low (%) * 40 30 20 10 0 HCV-CV before DAA HCV-CV end DAA CD4 + CXCR5 + IL21 + (%) * 4 3 2 1 0 HCV-CV before DAA HCV-CV end DAA D CD4 + IL17 + (%) * 5 4 3 2 1 0 HCV-CV before DAA HCV-CV end DAA D E 5 * 40 D4 + IL17 + (%) 4 3 2 CD4 + IFN γ + (%) 30 20 10 Comarmond C et al, Gastroenterology 2017
HCV-CryoVas: Immunological Impact of DAAs Study Cryocrit at baseline Cryocrit 12 wks post-daa Cryo negative (%) Saadoun (2016) 0.35 (0.16 0.83) g/l 0 (0 0.37) g/l 46 % Sise (2016) 1.5% (0.5-4%) 0.5% (0-2%) 44 % Gragnani (2016) 7.2 ± 15% 1.8 ± 5% 39 % Bonacci/Lens (2017) 3.2% (1.5-3.7%) 0.5% (0-1.4)% 43 % Saadoun (2017) 0.56 ± 0.18 g/l 0.21 ± 0.14 g/l 50 % Saadoun et al. Ann Rheum Dis. 2016 Oct;75(10):1777-82; Sise et al. Hepatology 2016 Feb;63(2):408-17; Gragnani et al. Hepatology. 2016 Nov;64(5):1473-1482; Bonacci and Lens et al. Clin Gastroenterol Hepatol. 2017 Apr;15(4):575-583. Saadoun et al. Gastroenterology. 2017
From HCV-Cryoglobulinemia to B-Cell Lymphoma Antigen-Sensitive B Cell Proliferation Antigen-Insensitive B Cell Proliferation HCV (E2) CD81 Cytokines BAFF B cell Treg deficit Hyperγglobulinemia IgH-bcl2? Cryoglobulinemia Vasculitis B-cell lymphoma Other oncogenic events? HCV infection increases the risk of developing a B-cell lymphoma (RR=34) B-cell lymphoma Polyclonal proliferation Oligo/Monoclonal proliferation Uncontrolled proliferation IgG Anti-E2 IgM/Rheumatoid factor
Sustained Response to IFN-based Antivirals is Associated with Improvements in HCV-related B-Cell Lymphoma 1.0 l 116 patients with B-cell lymphoma (DLBCL, 39%; MZL, 39%; other, 22%) l HCV therapy given to 70 patients l SVR in 43/70 (61%) patients è SVR correlated with haematological response in MZL (P<0.001) Overall survival probability Progression-free survival probability 0.8 0.6 0.4 0.2 No antiviral treatment P=0.029 Antiviral treatment 0.0 0 10 20 30 40 50 Months 1.0 0.8 0.6 0.4 0.2 No antiviral treatment P=0.049 Antiviral treatment 0.0 0 10 20 30 40 50 Months 60 60 DLBCL: diffuse large B-cell lymphoma; MZL: marginal zone lymphoma; Sustained Virological Response Michot JM, et al. Am J Hematol 2015;90:197 203
Direct Antiviral Agents in HCV-lymphoproliferative disorders SVR in 45/46 (97.8%) Clinical response (CR + PR) 67% Arcaini L et al, Blood 2016
Chronic HCV infection: a new cardiovascular risk factor? Stroke Heart Kidney
People with HCV have an increased risk of cardiovascular disease compared to people without HCV In a meta-analysis HCV was associated with: increased risk of death from cardiovascular disease Odds ratio vs control group, 1.65, [1.07, 2.56] increased risk of stroke Odds ratio vs control group, 1.30 [1.10, 1.55] increased risk of a carotid artery plaque, a well-known risk factor of stroke Odds ratio vs control group, 2.27 [1.76, 2.94] Petta S et al, Gastroenrology 2015;150(1):145-155.e4;
Antiviral therapy is associated with a reduced risk of stroke in people with HCV 100 IBT Stroke-free survival rate 0.95 l IFN-based therapy was associated with a 61% IBT decreased risk of stroke in HCV 0.90 patients, Log-rank after adjusting for known prognostic factors. test, p = 0.003 0.85 Non- 0.80 0 1 2 3 4 5 Time (years) IBT, interferon based therapy Hsu CS, et al. APT 2013;38:415 23
Most studies showed a significant association between ischemic heart disease and HCV infection References, year Study type Country HCV+ (n) HCV- (n) Studies showing an association Vassalle et al, 2004 Cross-over Italy 491 195 Völzke et al., 2004 Transversal Germany 21 4033 Butt et al., 2009 Cross-over USA 60 60 Tsui et al., 2009 Cohort USA 84 - Ramdeen et al., 2010 Cohort USA 78 - Studies NOT showing an association Butt et al., 2007 Cohort USA 126,926 126,926 Domont F & Cacoub P, Liver Int 2016
Improvement in myocardial perfusion defects is seen in patients with sustained virological response to antiviral therapy Myocardial SPECT images of 127 HCV infected patients without known cardiac disease at baseline treated with antiviral therapy Before therapy Before therapy Before therapy End of therapy End of therapy End of therapy 6 months after therapy 6 months after therapy 6 months after therapy Sustained virological response Relapse Non Response Before antiviral therapy (M0; A), at the completion of antiviral therapy (M6; B) and 6 months after the completion of antiviral therapy (M12; C). The arrows show the regions of myocardial perfusion defects. SPECT, Single Photon Emission Computed Tomography Maruyama S, et al. J Hepatol 2012;58:11 5
Sustained virological response to antiviral therapy is associated with improvements in myocardial perfusion defect severity score Response following 48 weeks of antiviral treatment P<0.0001 P=0.0133 Severity score 9 8 7 6 5 4 3 2 1 0 P<0.0001 P=0.133 NS NS 0 12 18 0 12 18 0 12 18 Months Months Months SVR group (n=30) Relapse group (n=9) NVR group (n=6) Dashed lines indicate normal range NS: not significant; NVR: non-virological response; SVR, Sustained Virological Response Maruyama S, et al. J Hepatol 2013;58:11 5
Reduction in cardiovascular events after HCV eradication in patients with cirrhosis 3 yrs 5 yrs 9.1 % 2.3 % 12.3 % 3.5 % Prospective Cohort, ANRS CO12 CirVir 2012-2015; 1,323 patients; F-up 51 months Nahon P et al, Gastroenterology 2015
Chronic HCV infection increases the risk of death related to renal disease 0,045 0,040 0,035 0,030 0,025 0,020 0,015 0,010 0,005 0,000 p < 0.001 Anti-HCV negative (n = 16,629) Undetectable HCV RNA (n = 330) Low HCV RNA (n = 371) High HCV RNA (n = 124) 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Follow up (years) 4.3 % 2.6 % 0.5 % 0.3 % R.E.V.E.A.L. Study, Taiwan National Health Insurance Research Database n= 23 785 subjects Lai TS et al., AASLD 2014, Kidney Int 2017
The effect of sustained virological response on the risk of HCV extrahepatic manifestations 160 875 patients, HCV RNA+, 1999-2009, 128 VA med centers Genotype 1 (54.7%), HBV 1.3%, HIV 3.2% 50 59 yrs (52.1%), male (97.1%), non-hispanic white (44.9%), overweight (BMI 25-30, 38.5%) or obese (BMI 30, 27.3%), smokers (59.2%), alcohol abusers (58.3%), APRI score 2 (24.8%). Follow-up 5.1 years (IQR, 2.9 7.2 years). HCV treatment: N = 31 143 (19%) received IFN based therapy for 24.2 weeks N = 10 575 (34%) achieved SVR. N = 31 143 (19%) no HCV treatment Mahale P et al, GUT 2017
The effect of sustained virological response on the risk of HCV extrahepatic manifestations HRs were adjusted for age categories (20 39, 40 49, 50 59, 60 69 and 70+ years), sex, race, period of service, average annual number of outpatient visits, body mass index (<25.0, 25 to <30, 30+ kg/m2), smoking and alcohol abuse. Additional adjustments for baseline diabetes mellitus and hypertension were conducted in models for glomerulonephritis, coronary heart disease and stroke. Mahale P et al, GUT 2017
HCV Increases the Risk of Chronic Kidney Disease while Effective HCV Treatment Decreases Its Incidence l Retrospective US cohort, 2008-2015 l 56,448 HCV-infected patients matched with 169,344 non-hcv patients, è N = 3666 (6.6%), interferon-based dual, è N = 3534 (6.3%), interferon-based triple, è N = 4628 (8.3%), all-oral direct acting antiviral agents (DAA) è N = 43,990 (79%), did not receive any HCV treatment. Park H et al, Hepatology, 2017
Effective HCV Treatment Decreases the Incidence of Chronic Kidney Disease Minimum effective duration Tx HR: 0.70; 95% Cl, 0.56-0.88 These associations were only significant for dual (HR, 0.60; 95% CI, 0.43-0.85) and triple therapies (HR, 0.59; 95% CI, 0.37-0.94) but not for the new all-oral therapy (HR, 1.03; 95% CI, 0.68-1.55). Park H et al, Hepatology, 2017
HCV, insulin resistance and type 2 diabetes mellitus
Increased risk of Type 2 diabetes in patients with HCV: multiple mechanisms Jacobson I et al, Clin Gastroienterol Hepatol 2010; 8(12):1017-29.
Changes in insulin sensitivity according to virological response after antiviral therapy for HCV Insulin resistance according to response to antiviral therapy for HCV Solid lines = on therapy; Dashed lines = off therapy. Changes from baseline to weeks 24, 48 and 72 were statistically significant (p<0.01) only among SVR patients. HOMA, Homeostasis model assessment; SVR, Sustained virological response.
Incidence of type 2 diabetes in patients with or without response to antiviral therapy for HCV Incidence of T2DM according to response to antiviral therapy for HCV in patients with cirrhosis Incidence of T2DM according to response to antiviral therapy for HCV in patients >50 years T2DM, type 2 diabetes mellitus; SVR, Sustained Virological Response Arase Y, et al. Hepatology 2009; ;49(3):739-44
Glycemic Control by Direct-Acting Antivirals in Type 2 Diabetes Mellitus Patients with HCV G4 Dawood, Diabetes Metab J 2017
Multivariate analysis for factors affecting glycemic control with direct-acting antivirals Diabetic patients receiving DAAs should be closely monitored for reduction of antidiabetic drugs, especially insulin and sulfonylurea, to avoid hypoglycemic events. T2DM, type 2 diabetes mellitus Dawood, Diabetes Metab J 2017
HCV, Cardiovascular and Metabolic Events: Possible Mechanisms IR, insulin-resistance; HCC, hepatocellular carcinoma 1. Negro F. J Hepatol 2014; 61:S69 S78; 2. Negro F, et al. Gastroenterology 2015; 149:1345 1360;
Fatigue, depression and cognitive impairment HCV & Health Related Quality of Life
HCV is associated with fatigue and depression, and infection of brain and nerve cells Fatigue è prevalence ranges from 50 to 67% è independently predicts poor HRQoL Depression è 28% of HCV patients depressed prior to HCV therapy. è predictive of HRQoL during antiviral therapy for HCV HCV may directly affect the central nervous system (CNS): è Infection of microglial cells within the CNS è Alterations in serotonergic and dopaminergic neurotransmission Cacoub P et al, Dig Liver Dis. 2014; 46 Suppl 5:S165-73. Negro F, et al. Gastroenterology 2015;149(6): 1345-60; Lucaciu LA, Dumitrascu DL. Ann Gastroenterol 2015; 28(4):440-7
HCV can interact with cells in the brain and nervous system Flaviviridae family other neurotropic viruses: japanese encephalitis japonaise, yellow fever, tickborne encephalitis, dengue Infection of microglial cells (+++) and astrocytes Not direct infection of neurones Interaction with cerebral endothelial cells Blood brain barrier Perivascular macrophage Passage of free virus and virally infected PBMC IL1β TNFα IFNγ Neuron Astrocyte Neuronal dysfunction Microglial activation Microglia Wilkinson J et al. J Virol 2009 83(3): 1312 1319; Negro F et al, Gastroenterology 2015; 149(6):1345-60.
Evidence for an effect of HCV on the brain and nervous system Confirmed by other studies Cho/Cr! mi/cr! NAA/Cr " Correlated to neuropsy tests Forton D et al., Lancet 2001; 358(9275):38-9.
Decrease Cerebral Glucose Utilisation in HCV Patients 15 HCV non cirrhotic vs. HCV neg. Fatigue, cognitive decline, mood alteration Methods : HCV+ vs. HCV- HCV RNA+ vs. HCV RNA- Neuropsy. tests, brain PET-FDG, brain PETdopa & 5HT, brain MRI Ø Cerebral glucose utilisation is decreased in HCV+ patients Ø Correlated with dopamine transporter availability and psychometric results Heeren M et al, J Cereb Blood Flow Metabl 2011
Quality of life is affected at all stages of chronic HCV infection (not just in severe disease) QoL significantly poorer in all HCV disease stages compared to general population No significant association between disease stage and degree of impact on QoL P<0.005 for all disease stages vs. general population (all domains) Hsu PC, et al. Liver Int 2009;29:449 58.
Brain magnetic resonance signal in basal ganglia* in HCV patients according to response to antiviral therapy After HCV clearance: improvements in verbal learning and visuo-spatial memory reduced cerebral infection and/or immune activation Baseline (T1), week 12 (T2), and for treatment candidates, 12 weeks after antiviral therapy (T3) * Myoinositol/creatinine T1 vs. T3 in SVR; p<0.05 Byrnes V, et al. J Hepatol 2012;56:549 56
Patients reported outcomes at Week 24 after antiviral therapy or placebo SF36 FACIT PLACEBO SOF/VEL CLDQ WPAI Younossi Z et al, J Hepatol 2
What is the impact of HCV eradication on extrahepatic manifestations?
Extrahepatic benefits of HCV eradication (SVR following antiviral therapy): Summary reduced all-cause mortality complete resolution of mixed cryoglobulin complications regression/remission of HCV-associated lymphoma improvement in myocardial perfusion defects reduced incidence of stroke reduced renal and cardiovascular outcomes in diabetics reduced risk of insulin resistance reduced risk of type 2 diabetes improved cognitive performance reduction in fatigue gains in quality of life Autoimmune and B cell malignancies Cardiovascular diseases Diabetes and insulin resistance Cognitive and functional Negro F et al, Gastroenterology 2015; 149(6):1345-60.
HCV and extrahepatic manifestations Conclusion The disease induced by HCV is a systemic C disease which cannot be seen anymore only as an hepatitis Healthcare consequences of these extrahepatic manifestations must be urgently considered in addition to those usually associated with chronic HCV infection
APPENDIX Back-up slides
Reductions in the magnitude of protective effect with increasing time to initiation of antiviral treatment for glomerulonephritis, NHL and stroke. Mahale P et al, GUT 2017