HCV and IR

HCV and IR

HCV and comorbidities after SVR ILC 22 April 2017 Francesco Negro University Hospital of Geneva, Switzerland Disclaimer I am advising Merck, AbbVie, Gilead I have received unrestricted educational grants from Gilead and AbbVie Excess extrahepatic mortality associated with HCV The REVEAL HCV Cohort Study

19,636 HBsAg-seronegative adults, aged 30-65 yrs 1,095 anti-HCV+ [5.6%] 2,394 deaths after an average FU of 16.2 years Causes of death All causes All liver-related HCC Multivariate-adjusted HR (95% CI) in anti-HCV+ 1.89 (1.66 2.15) 12.48 (9.34 16.66) 21.63 (14.83 31.54) All extrahepatic diseases

1.35 (1.15 1.57) All cancers, except HCC 1.32 (1.00 1.74)* Diabetes 1.49 (0.91 2.42) Cardiovascular diseases 1.50 (1.10 2.03) Renal diseases

2.77 (1.49 5.15) *Oesophagus, prostate, thyroid gland LEE et al, J Infect Dis 2012;206:469-77 Pooled prevalence and odds ratios for some HCV-associated extrahepatic manifestations A meta-analysis (n=102 studies) of prevalence, QOL and economic burden CRD, chronic renal disease; lymphoma studies included 207,284 HCV-infected persons YOUNOSSI et al, Gastroenterology 2016;150:1599-1608 The health burden of HCV-associated extrahepatic manifestations A meta-analysis (n=102 studies) of prevalence, QOL and economic burden

Total direct costs (2014 USD): 1,506 million (range 922 2,208 million USD): 443.4 million USD: type 2 diabetes 430.7 million USD: depression 197.5 million USD: cardiovascular diseases 120.3 million USD: mixed cryoglobulinemia YOUNOSSI et al, Gastroenterology 2016;150:1599-1608 No analysis of indirect costs (significant!) Difficult to dissect bona fide, HCV-related manifestations from comorbidities Morbidity and mortality beyond the liver

in HCV-infected persons Renal Metabolic (insulin resistance / diabetes) Cardiovascular HCV infection increases the risk of developing chronic kidney disease A Systematic Review and Meta-Analysis Prevalence of CKD is not increased Eight cross-sectional studies (n = 788,027: 79,450 anti-HCV+ and 708,577 anti-HCV-) Adjusted OR 1.16 (95% CI 0.98-1.33, P = NS) Prevalence of proteinuria is increased Six studies (n = 107,356: 7413 anti-HCV+ and 99,943 anti-HCV-) Adjusted OR 1.508 (95% CI 1.19-1.89, P = 0.0001)

Incidence of CKD is increased Nine longitudinal studies (n = 1,947,034: 223,150 anti-HCV+ and 1,723,884 anti-HCV-) Adjusted HR 1.43 (95% CI 1.23-1.63, P = 0.0001) FABRIZI et al, Dig Dis Sci 2015;60:3801-13 The Kidney Disease: Improving Global Outcomes (KDIGO) recommendations HCV-infected patients should be tested at least annually for proteinuria, hematuria and eGFR to detect possible HCVassociated kidney disease Patients with CKD should be tested for HCV Kidney Disease: Improving Global Outcomes (KDIGO), Kidney Int 2008;73(suppl 109):S1-S99 Ageing Atherosclerosis Diabetes

Hypertension Urinary tract obstruction Drugs HCV is a non-traditional risk factor for CKD (image credit: http://www.internetbillboards.net) Pathogenesis of HCV-related CKD Glomerular damage1 Type I membrano-proliferative glomerulonephritis (MPGN) associated with type II mixed cryoglobulinemia (MC) (~60%) 2 MPGN without MC Membranous GN Focal segmental glomerulosclerosis Fibrillary glomerulopathy

Nephrosis, nephritic syndrome, isolated low eGFR / proteinuria / hematuria 1 FABRIZI et al, Am J Kidney Dis 2013;61:623-37; 2ROCCATELLO et al, Am J Kidney Dis 2007;49:69-82 Mixed cryoglobulinemia (MC) and HCV: prevalence and features Up to 91% of MC patients have HCV infection SAADOUN et al, Arch Intern Med 2006 Up to 70% of HCV patients have MC (types II or III) LUNEL et al, Gastroenterology 1994 CHARLES & DUSTIN, Kidney Int 2009 Only a minority (4.9%) have symptoms (vasculitis) YOUNOSSI et al, Gastroenterology 2016

After adjusting for age, gender and estimated duration of infection, cirrhosis is the most important factor associated with MC (OR = 4.87, 95% CI = 3.32-7.15) KAYALI et al, Hepatology 2002 Leading causes of death: cardiovascular complications (in case of renal involvement), B cell lymphoma ROCCATELLO et al, Am J Kidney Dis 2007; FERRI et al, Br J Haematol 1994 Morbidity and mortality beyond the liver in HCV-infected persons Renal Metabolic (insulin resistance / diabetes) Cardiovascular Prevalence of type 2 diabetes in HCV+ vs. uninfected (The Third NHANES Survey, 1988-1994; n=9841)

VHC+ VHC- Adjusted OR for diabetes (> 40 yrs) 3.77 (95% CI: 1.81-7.87) (independent of BMI, age, sex, race, family history of diabetes) MEHTA et al, Ann Intern Med 2000;133:592-599 Chronic HCV infection and risk for diabetes: a community-based prospective study (REVEAL Cohort: n=16,928 anti-HCV- vs. 930 anti-HCV+; 180,244 PY; median FU 11.0 yrs) Adjusted HR = 1.53 (1.291.83) Adjusted for ALT = HR 1.40 (1.171.67) LIN et al, Liver Int 2016 July 16 [Epub ahead of print]

Insulin resistance/T2D in HCV: impact on liver disease Accelerated fibrosis progression Case-control study on 121 chronic hepatitis C patients with F0-F1, matched to uninfected controls by sex, BMI, waist-to-hip ratio By MV, the HOMA-IR score (but not steatosis) was independently associated with fibrosis stage (P<0.001) and progression rate (P=0.03) HUI et al, Gastroenterology 2003;125:1695-704 Increased risk of HCC in advanced fibrosis

541 chronic hepatitis C patients (Ishak 4-6, 85 with diabetes), median FU 4.0 years Diabetes: independent predictor of HCC in patients with Ishak 6 (HR 3.28, 95% CI 1.35-7.97, P=.009) VELDT et al, Hepatology 2008;47:1856-62 Increased risk of cirrhosis complications Single center retrospective study (n=348) By MV, increased risk of bacterial complications (HR 2.098, 95% CI 1.227 3.589, P=0.007) ELKRIEF et al, Hepatology 2014;60:823-31 End-stage renal disease as a cause of mortality in patients with HCV and diabetes Taiwan National Health Insurance Research Database: 1411 HCV treated vs. 1411 HCV untreated vs. 5644 uninfected, matched by propensity scores

(demographic factors, comorbidities, diabetes therapy) Cumulative incidence of ESRD (HR 0.16, 95% CI 0.07 0.33)* *Multivariate comorbidity-adjusted HR in treated vs. untreated cohort HSU et al, Hepatology 2014;59:1293-302 HCV is associated with increased CV mortality especially in subgroups with diabetes A meta-analysis of observational studies PETTA et al, Gastroenterology 2016;150:145-55 Morbidity and mortality beyond the liver in HCV-infected persons

Renal Metabolic (insulin resistance / diabetes) Cardiovascular Increased overall and cardiovascular mortality in blood donors according to anti-HCV status Survival probability 1.00 0.75 10,259 HCV+ vs 10,259 HCVblood donors (mean FU 7.7 years) 0.50

0.25 Overall mortality HCV negative HCV positive 0.00 0 20 40 Cardiovascular mortality HCV negative HCV positive

60 80 100 Age (years) Cardiovascular mortality 2.21, 95% CI 1.41 3.46) Overall(HR Mortality GUILTINAN et al, Am J Epidemiol 2008;167:743750 Classical CVD risk factors may be absent in HCV Uninfected (n=585)

Past HCV (n=67) Chronic HCV (n=113) BMI (kg/m2) 27.5 (5.91) 28.9 (5.49) 27.4 (5.75) WHR

0.88 (0.08) 0.90 (0.07) 0.91 (0.09) SBP (mm Hg) 124.2 (20.4) 128.0 (26.8) 125.2 (22.9) DBP (mm Hg) 80.4 (11.4)

82.1 (13.6) 81.2 (12.1) Fasting glucose (mg/dl) 85.6 (25.4) 91.3 (32.5) 92.7 (42.4) Total cholesterol (mg/dl) 181.2 (40.6)

189.2 (38.4) 160.4 (33.1) LDL cholesterol (mg/dl) 109.9 (36.8) 114.5 (36.3) 93.4 (30.9) HDL cholesterol (mg/dl) 47.2 (11.1) 46.7 (10.5)

46.7 (12.1) Triglycerides (mg/dl) 121.0 (66.2) 140.3 (65.0) 101.9 (45.1) MARZOUK et al, Gut 2007;56:1105-10 HCV increases CV mortality: a meta-analysis *

*Mortality increased only among patients under OST coinfected with HIV PETTA et al, Gastroenterology 2016;150:145-55 The risk of developing carotid plaques in HCV+ depends on the prevalence of smoking PETTA et al, Gastroenterology 2016;150:145-55 The risk of cerebrovascular events in HCV+ depends on the prevalence of diabetes and hypertension PETTA et al, Gastroenterology 2016;150:145-55 Carotid atherosclerosis and chronic hepatitis C A prospective study of risk associations Prevalence of carotid plaques according to age and fibrosis, HCV-1

p=0.51 Carotid plaques (% of patients) p=0.008 55 yrs; F02 n=67 55 yrs; F34 n=21 > 55 yrs; F02 n=43 > 55 yrs; F34

n=43 PETTA et al, Hepatology 2012;55:13171323 Does HCV clearance improve extrahepatic morbidity and mortality? Mortality from extrahepatic diseases in anti-HCV+, HCV RNAis comparable to uninfected controls LEE et al, J Infect Dis 2012;206:469-77 DAA for HCV-associated MC-related vasculitis The VASCUVALDIC Study

24 patients with HCV-cryoglobulinemia vasculitis (80% type II, 58% F3 or F4) Purpura and peripheral neuropathy (67%), arthralgia (58%), GN (21%), skin ulcers (12%) SOF 400 mg QD + RBV (2001400 mg/d), 24 weeks (7 received immunosuppressants) SVR 74% Purpura, skin ulcers and arthralgia disappeared in all cases Kidney involvement improved in 4/5 SAADOUN et al, Ann Rheum Dis 2016;75:1777-82 DAA for HCV-associated MC 44 patients with MC (29 type II MC, 4 renal involvement, 2 B-cell lymphoma) SOF + SIM/DAC/LDV + ribavirin SVR 100% Clinical response of vasculitis in all

Four patients with renal involvement: Normalization of eGFR in the patient with MPGN Resolution of nephrosis in 1 Improved eGFR and disappearance of proteinuria in 2 GRAGNANI et al, Hepatology 2016;64:1473-82 Impact of successful antiviral therapy on HCV-related, cryoglobulinemia-associated syndrome GRAGNANI et al, Hepatology 2015;61:1145-53 2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides JENNETTE, Clin Exp Nephrol 2013;17:603606 HCV-related cryoglobulinemia

Vasculitis affecting vasa nervorum (epineural arterioles) Irreversible ischemic nerve damage (axonal degeneration and loss, demyelination) After antiviral treatment, HOMA-IR decreases only among SVR (n=50, treated with pegIFNa + RBV) ROMERO-GOMEZ et al, Gastroenterology 2005;128:636-41 SVR reduces the incidence of insulin resistance during FU

431 HCV+ patients (Milan Safety Tolerability Cohort), 12% insulin resistant (HOMA-IR>2) After 24 months of FU, de novo insulin resistance occurred less frequently in SVR than in nonSVR (7% vs. 17%, p=.007) AGHEMO et al, Hepatology 2012;56:1681-7 Suppression of serum HCV RNA by IFN-free regimens correlates with improved insulin sensitivity n = 30, HCV-1, treated with danoprevir n = 5, HCV-3a without MS, treated with SOF/LDV + RBV MOUCARI et al, Gut 2010;59:16941698 GASTALDI et al (ongoing clinical trial) SVR is associated with a two-thirds reduction of the risk of developing diabetes

2,842 Japanese non-diabetic patients with chronic hepatitis C IFN-a ribavirin 143 patients developed diabetes after a 6.4 years: 26/1175 SVR (2.2%) vs 117/1667 non-SVR (7%) Factor associated with T2D development Advanced fibrosis HR (95% CI) p 3.30 (2.06 5.28) .001 Lack of SVR

2.73 (1.77 4.20) .001 Pre-diabetes 2.19 (1.43 3.37) .001 Age 50 years 2.10 (1.38 3.18) .001 ARASE et al, Hepatology 2009;49:739-744

Cumulative incidence of type 2 diabetes in chronic hepatitis C: SVR vs non-SVR years Age >50 years years Cirrhosis years Pre-diabetes Curing HCV reduces the risk of developing diabetes by ~2/3

ARASE et al, Hepatology 2009;49:739-744 Antiviral therapy reduces the renal and cardiovascular complications in 9572 chronic hepatitis C patients with diabetes Taiwan National Health Insurance Research Database: 1411 HCV treated vs. 1411 HCV untreated vs. 5644 uninfected, matched by propensity scores (demographic factors, comorbidities, diabetes therapy) Cumulative incidence of ESRD Cumulative incidence of acute coronary events Cumulative incidence of ischemic stroke (HR 0.16, 95% CI 0.07 0.33)* (HR 0.64, 95% CI 0.39 1.06)*

(HR 0.53, 95% CI 0.30 0.93)* *Multivariate comorbidity-adjusted HR in treated vs. untreated cohort HSU et al, Hepatology 2014;59:1293-302 Risk of HCC in HCV-related advanced fibrosis after SVR Multicenter study on 630 patients with SVR after treatment with (peg)IFN-based therapies Median FU 5.7 y (IQR 2.98.0), 51 incident HCC cases Predictor of HCC Following SVR* HR (95% CI) P Age at SVR, yrs (vs. younger than 55 yrs)

<45 45-60 >60 1.00 (reference) 8.54 (1.13 64.64) 8.91 (1.12 70.79) NA .038 .039 Diabetes 2.36 (1.02 5.42) .044

1.04 (1.00 1.09) 0.56 (0.32 1.01) 0.048 0.084 Platelet count AST/ALT ratio VAN DER MEER et al, J Hepatol 2017;66:485-93 Predictors of HCC occurrence after SVR VA cohort study, 22,028 HCV pts treated with PegIFNa RBV between 1999 and 2009 HCC incidence (x 1000 PY): 3.27 SVR vs 13.2 non SVR (HR: 0.358) Predictor of HCC Following SVR*

HR (95% CI) P Cirrhosis Age at SVR, yrs (vs. younger than 55 yrs) 55-64 65 or older 4.45 (2.53-7.82) < .0001 2.40 (1.53-3.77) 4.69 (2.04-10.78)

.0002 .0003 Diabetes 2.07 (1.35-3.20) .0010 0.56 (0.32-1.01) .0522 1.91 (1.14-3.18) .0131

HCV genotype (vs. genotype 1) HCV-2 HCV-3 *Cox proportional hazards model adjusted for competing risk of death EL-SERAG et al, Hepatology 2016;64:130-7 Diabetes before antiviral therapy (together with age and low platelet count) predicts HCC occurrence after SVR also in patients with F0-F2* (n=1112, FU 55.9 months; 93 incident HCC at a yearly rate of 1.79%; Kaohsiung MUH, Taiwan) DM no DM *DM or lack thereof did not affect HCC rate in non-SVR or F3-F4 HUANG et al, Medicine 2016;95:27(e4157)

Most F0-F2 patients who developed HCC despite SVR had glucose metabolism alterations before therapy (and despite improved glucose homeostasis after SVR) IGT/subDM = risk increased 3-fold DM = risk increased 10-fold 6/54 if DM (11.1%) 10/268 if IGT/subDM (3.7%) 3/267 if normoglycemic (1.1%) HUANG et al, Medicine 2016;95:27(e4157) Effect of antiviral treatment on cardiovascular outcomes Taiwan National Health Insurance Research Database (NHIRD) (n=12,384 treated with pegIFN/RBV vs. 24,768 untreated controls, matched by propensity scores and length of FU)

Cumulative incidence of acute coronary events Cumulative incidence of ischemic stroke 1.76 (95% CI 1.44-2.08) 2.96 (95% CI 2.46-3.45) 2.21 (95% CI 1.7-2.71) P=0.027 1.31 (95% CI 0.85-1.77) P=0.001 HSU et al, Gut 2015;64:495-503

Effect of antiviral treatment on renal outcomes Taiwan National Health Insurance Research Database (NHIRD) (n=12,384 treated with pegIFN/RBV vs. 24,768 untreated controls, matched by propensity scores and length of FU) Cumulative incidence of ESRD 1.32 (95% CI 1.01-1.64) P<0.001 0.15 (95% CI 0.04-0.26) HSU et al, Gut 2015;64:495-503 Effect of viral clearance on HCV-associated extrahepatic morbidity and mortality HCV is associated with significant extrahepatic morbidity and mortality Clearance of HCV is associated with improved extrahepatic morbidity and mortality (renal, metabolic, cardiovascular)

There is some evidence that viral clearance should be achieved early during the natural history of infection Chronic hepatitis C patients should be screened for signs of extrahepatic involvement (eGFR, glucose metabolism alterations, carotid plaques) even at early stages of liver disease, and treated

Recently Viewed Presentations

  • Making a start

    Making a start

    Hand Tools Keywords Bradawl Callipers Kerf Pincers Ratchet Rebate Spokeshave Definitions Bradawl ; (noun) - an awl for making small holes for brads or small screws Calipers ; (noun) - an instrument for measuring the distance between two points (...
  • Regulatory Affairs Nick Littlebury nlittlebury@diamondpharmaservices.com Wednesday 10th October

    Regulatory Affairs Nick Littlebury [email protected] Wednesday 10th October

    Diamond BioPharm Limited, UK. Regulatory affairs is an interesting, challenging and rewarding career. The salary, benefits and career prospects are very good once you have got your foot in the door. Research the career thoroughly and get applying!
  • Teaching and Experiencing Christian Prayer Christian Prayer Drawing

    Teaching and Experiencing Christian Prayer Christian Prayer Drawing

    Christian prayer tradition rich and diverse. Challenges in teaching and expression of Christian prayer. Review your current practice. ... USING CHRISTIAN PRAYER FORMS. Daily Prayer of the Church. Antiphonal Prayers. Blessings. Intercessions. Prayer Planning Table pp. 29-30. ACTIVITY THREE ...
  • Tutorial for Supervisors - Home | BASIS

    Tutorial for Supervisors - Home | BASIS

    If ordering from a catalog in Razorbuy, your Receiving entry . WILL ALWAYS . be by quantity. Limitation. Only have this availability for lines that have been setup to perform quantity receiving. You may only receive 12 lines at a...
  • . Homework . Your child will continue to

    . Homework . Your child will continue to

    Art This half term we will be learning about the artist, Edward Tingatinga to support our Africa topic. We will be studying the patterns, colours and shapes he uses.
  • Chapter 13- Earth&#x27;s History - Mrs. Ellis&#x27; Science Class!

    Chapter 13- Earth's History - Mrs. Ellis' Science Class!

    The Cenozoic Era-Age of Mammals. Cenozoic Era. ... However, a wave of late Pleistocene extinctions rapidly eliminated these animals from the landscape (during the last Ice Age) In North America, the mastodon and mammoth both relatives of the elephant became...
  • The Odyssey Background Notes

    The Odyssey Background Notes

    Homer was the poet who wrote both Greek epic poems, The Iliad and The Odyssey. The . Iliad . is about a ten-year war at Troy. The Odyssey. is about Odysseus' ten-year journey back home after the war. Homer wrote...
  • Pharmacogenomics: Genetic Factors in Drug Metabolism

    Pharmacogenomics: Genetic Factors in Drug Metabolism

    Variabililty in Phase II Enzymes. N-acetyltransferase (NAT2) Cancer risk. Metabolism of isoniazide, caffeine, others. UDP-glucuronosyltransferase (UGT1A1*28) Gilbert's Syndrome. Metabolism of irinotecan. Thiopurinemethyltranferase (TPMT) Metabolism of 6-mercaptopurine and azathioprine