Normal Iron Metabolism - Hepatitis&More:

Normal Iron Metabolism - Hepatitis&More:

Eradication of HCV induced by DAAs is associated with a 71% reduction in HCC risk George N. Ioannou, Pamela Green, Kristin Berry George N. Ioannou, BMBCh, MS, FAASLD Director Hepatology Veterans Affairs Puget Sound Health Care System Associate Professor of Medicine University of Washington SEATTLE Background Most HCV-infected patients will undergo antiviral treatment with DAAs most will achieve SVR The impact of DAAs on HCC has become controversial Aims Determine whether: 1.DAA-induced SVR is associated with a reduced risk of developing (de novo) HCC. 2.The reduction in HCC risk caused by DAA-induced SVR is different than the reduction cause by IFNinduced SVR 3.Treatment with DAAs as compared to treatment with IFN is associated with HCC Study Setting

National Veterans Affairs (VA) Healthcare System 167 medical centers around the country Largest integrated healthcare system in the USA Largest number of HCV-infected patients: n=174,000 (in 2013) <60,000 in 2017 Largest number of patient with cirrhosis (n=60,553) and HCC (n=7670) in VA care in a single year. Study Design Study Design: Retrospective Cohort Study Follow-up started: 180 days after the start-date of the (first) antiviral treatment Follow-up continued until: Development of HCC (Outcome, event) Censored: Death, Last f/u in the VA Follow-up extended to 6/15/2017 Study Design

Analysis: Cox Proportional Hazards regression (survival analysis) Adjustment for potential confounders Exposure: a. SVR12 vs Treatment Failure b. Treatment with DAA vs Treatment with IFN Outcome: Development of new HCC >180 days after treatment Exclusions: missing SVR12, genotype HCC prior to antiviral Rx or within 180 days <180 days of follow-up Study Population Started antiviral therapy 1999-2015 N=62,354

IFN-only N=35,871 58% DAA+IFN N=4535 7% DAA-only N=21,948 35% Followed until 6/15/2017 Range of follow-up = 2-18 yrs Mean follow-up = 6.1 years Incident HCCs = 3271 Regimens Regimen IFN ONLY 58% DAA + IFN 7.3% Interferon PEG Boceprevir+PEG Telaprevir+PEG Sofosbuvir+PEG

DAA ONLY Sofosbuvir (daclatasvir) 35% Sofosbuvir+Simeprevir Sofosbuvir/Ledipasvir Paritaprevir/Ritonavir/ Ombitasvir/Dasabuvir N % 2,629 4.2 33,242 53.3 3,090 5.0 479 0.8 952 1.5

2,786 4.5 1,993 3.2 12,763 20.5 4,406 7.1 Patients with SVR had lower HCC incidence - both patients with and without cirrhosis SVR No SVR No Cirrhosis SVR No SVR Cirrhosis SVR is associated with lower HCC risk SVR Patients

Cirrhosis No Cirrhosis HCC HCC per 100 patientyears Crude Hazard Ratio Adjusted* Hazard Ratio No 4463 851 3.25 1 1

Yes 6005 326 1.97 0.57 (0.490.65) 0.50 (0.43-0.59) No 23,231 1778 0.87 1 1 Yes 28,655 316

0.24 0.29 (0.260.33) 0.32 (0.28-0.37) Adjusted for 21 confounders: decompensated cirrhosis, age, sex, race/ethnicity, body mass index , HCV genotype, HCV viral load, HIV co-infection, HBV co-infection, type 2 diabetes mellitus, alcohol use disorders, substance use disorder, platelet count, serum bilirubin, serum creatinine, serum albumin, serum AST/ALT ratio, blood INR and blood hemoglobin levels. A. IFN only SVR No SVR SVR Patients with SVR had lower HCC incidence irrespective of regimen: - both patients with and without cirrhosis No SVR C. DAA only B. DAA+IFN SVR

No SVR No Cirrhosis SVR No SVR Cirrhosis DAA-induced SVR and reduction in HCC incidence No Cirrhosis, SVR No Cirrhosis, No SVR, Cirrhosis, SVR No Cirrhosis, No SVR SVR is associated with lower HCC risk: All regimens SVR Patients HCC HCC per Crude Adjusted* Risk 100 Hazard Hazard Reduction patient- Ratio Ratio % years IFN-only DAA+IFN

DAA-only No 23,883 2348 1.07 1 1 Yes 11,988 303 0.28 0.25 0.32 No 1772 116

1.73 1 1 Yes 2763 59 0.6 0.34 0.48 No 2039 165 5.2 1 1 Yes

19,909 280 0.92 0.18 0.29 Adjusted for 22 confounders: cirrhosis, decompensated cirrhosis, age, sex, race/ethnicity, body mass index , HCV genotype, HCV viral load, HIV co-infection, HBV co-infection, type 2 diabetes mellitus, alcohol use disorders, substance use disorder, platelet count, serum bilirubin, serum creatinine, serum albumin, serum AST/ALT ratio, blood INR and blood hemoglobin levels. 68% 52% 71% Antiviral Regimen is not associated with HCC: DAA versus IFN Cirrhosis NO Cirrhosis

Regimen HCC per 100 Patient-yrs Crude Adjusted Hazard Hazard Ratio Ratio IFN only 3.0 1 1 DAA+IFN 2.6 0.86 0.95 DAA only 3.6 1.23

0.97 IFN only 0.64 1 1 DAA+IFN 0.59 1.11 0.90 DAA only 0.57 1.33 0.98 Analysis limited to 2009-2015 Secondary analysis limited to 2 yrs of follow-up Limitations 1. We studied only incidence not recurrence of HCC 2. We did not include a no treatment control group.

Instead, we used the IFN group as the control group for the DAA group 3. The association between SVR and reduced HCC risk may not be causative. Conclusions DAA-induced SVR is associated with a 71% reduction in HCC risk Eradication of HCV is associated with similar reduction in HCC risk irrespective of regimen Eradication of HCV is associated with a similar reduction in HCC in cirrhotic and non-cirrhotic patients Receipt of DAAs is not associated with increased HCC risk compared to receipt of IFN

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