Eradication of HCV induced by DAAs George N. Ioannou, BMBCh, MS, FAASLD Director Hepatology Veterans Affairs Puget Sound Health Care System Associate Professor of Medicine University of Washington SEATTLE Eradication of HCV induced by DAAs is associated with a 71% reduction in HCC risk George N. Ioannou, Pamela Green, Kristin Berry

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: DAA-induced SVR is associated with a reduced risk of developing (de novo) HCC. The reduction in HCC risk caused by DAA-induced SVR is different than the reduction cause by IFN-induced SVR 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

Started antiviral therapy 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 N % Interferon 2,629 4.2 PEG 33,242 53.3   Regimen N % IFN ONLY 58% Interferon 2,629 4.2 PEG 33,242 53.3 DAA + IFN 7.3% Boceprevir+PEG 3,090 5.0 Telaprevir+PEG 479 0.8 Sofosbuvir+PEG 952 1.5 DAA ONLY 35% Sofosbuvir (±daclatasvir) 2,786 4.5 Sofosbuvir+Simeprevir 1,993 3.2 Sofosbuvir/Ledipasvir 12,763 20.5 Paritaprevir/Ritonavir/ Ombitasvir/Dasabuvir 4,406 7.1

Patients with SVR had lower HCC incidence Patients with SVR had lower HCC incidence - both patients with and without cirrhosis SVR No Cirrhosis No SVR SVR Cirrhosis No SVR

SVR is associated with lower HCC risk Patients HCC HCC per 100 patient- years Crude Hazard Ratio Adjusted* Cirrhosis No 4463 851 3.25 1 Yes 6005 326 1.97 0.57 (0.49-0.65) 0.50 (0.43-0.59) No Cirrhosis 23,231 1778 0.87 28,655 316 0.24 0.29 (0.26-0.33) 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.

had lower HCC incidence irrespective of regimen: A. IFN only Patients with SVR had lower HCC incidence irrespective of regimen: - both patients with and without cirrhosis SVR No SVR SVR No SVR C. DAA only B. DAA+IFN SVR No Cirrhosis No SVR SVR Cirrhosis No SVR

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 Patients HCC HCC per 100 patient- years Crude Hazard Ratio Adjusted* Risk Reduction % IFN-only No 23,883 2348 1.07 1 Yes 11,988 303 0.28 0.25 0.32 68% DAA+IFN 1772 116 1.73 2763 59 0.6 0.34 0.48 52% DAA-only 2039 165 5.2 19,909 280 0.92 0.18 0.29 71% 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.

Antiviral Regimen is not associated with HCC: DAA versus IFN HCC per 100 Patient-yrs Crude Hazard Ratio Adjusted Cirrhosis IFN only 3.0 1 DAA+IFN 2.6 0.86 0.95 DAA only 3.6 1.23 0.97 NO 0.64 0.59 1.11 0.90 0.57 1.33 0.98 Analysis limited to 2009-2015 Secondary analysis limited to 2 yrs of follow-up

Limitations We studied only incidence not recurrence of HCC 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