1. 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

2. Background
Most HCV-infected patients will undergo antiviral treatment with DAAs  most will achieve SVR
The impact of DAAs on HCC has become controversial

3. 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

4. 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.

5. 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

6. 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

7. Started antiviral therapy
Study Population
Started antiviral therapy
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

8. 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

9. 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

10. 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
( )
0.50
( )
No Cirrhosis
23,231
1778
0.87
28,655
316
0.24
0.29
( )
0.32
( )
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.

11. 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

12. DAA-induced SVR and reduction in HCC incidence
No Cirrhosis, SVR
No Cirrhosis, No SVR,
Cirrhosis, SVR
No Cirrhosis, No SVR

13. 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.

14. 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
Secondary analysis limited to 2 yrs of follow-up

15. 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.

16. 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