Resolved: HCC is increased by DAA therapy !

Douglas T. Dieterich, M.D

Director, Institute for Liver Medicine

Professor of Medicine Division of Liver Diseases,

Icahn School of Medicine at Mount Sinai

?

“Decompensating Event” Stage

3 Bleeding

Stage 4 First non

bleeding decompensation

Stage 5 Second

decompensation

Death or OLT SEPSIS

Renal Failure

Compensated Cirrhosis Decompensated Cirrhosis

Stage 1

Stage 2

No Varices No Ascites

Varices No Ascites

HVPG: 5-12 mm Hg HVPG > 12 mm Hg

Modified from Arvaniti V. et al., Gastroenterology 2010; 139:1246-1256

Hepatocellular carcinoma

HVPG: < 5 mm Hg

F0 Fibrosis

F3 Fibrosis

Non-cirrhotic

Risk of HCC throughout the course of chronic HCV disease

Does HCV clearance affect the risk of developing HCC?

Eradication of HCV and risk of HCC: a meta-analysis of IFN-based studies

Morgan et al, Ann Int Med 2013;158:329-337

Forest Plot Of Adjusted Hazard Effects In Persons At All Stages Of Fibrosis

Mortality due to HCC or decompensation in cirrhotics with SVR: 440 HCV patients in Italy

Di Marco V, Gastroenterology 2016

DAAs treatment and HCC

Does DAA treatment increase:

Relapse rate of HCC ? De novo risk of HCC?

HCC “aggressive” presentations ?

Vocabulary of Hepatocellular Carcinoma (HCC)

RECURRENCE: Reappearance of HCC in a subject

(with or without liver disease) with a previous HCC

judged to be cured by any technique (TACE,

Y90,RFA, resection)

OCCURRENCE: De novo appearance of HCC in a

subject (with or without liver disease) with no

history or previous evidence of an HCC

DAA HCV Clearance may Inhibit HCC specific T cell immunity

Host immune modulations by DAA • Quick resolution of anti-HCV immune response

(memory T cell de-differentiation, restoration of CD4, CD8 T cells, deactivation of NK cells)

(Spaan, JID 2016, Serti, Gastro 2015, Burchill, JVH 2015, Martin, J Hep 2014, Perello, CGH 2016)

• Simultaneously diminished immune response to other viruses

Anti-HCV immunity

Anti-tumor immunity

HCV

Anti-HCV immunity

Anti-tumor immunity

Accelerated growth of already existing tumor clones?

Cancer risk persists Chronic liver disease

HCV

Healthy liver

Epigenome changes

Modifications of histones are induced

HCV

Alteration of

gene expression

Liver disease

Upregulation of cancer

driver expression

HCC

Hepatocyte genome and histones

DAAs and cancer risk: Viral cure does not

eliminate HCV-induced epigenetic changes

Cartoon modified from Zeisel et al., J. Hepatol. 2013

Persistent changes after cure

HCV infection

Cure

Modifications of histones persist

27.5% 72.4%

Unexpectedly high rate of early tumor recurrence in patients with HCV-related HCC undergoing IFN-free therapy

Reig M. J Hepatol. 2016

Unexpectedly high rate of early tumor recurrence in patients with HCV-related HCC undergoing IFN-free therapy

Overall median follow-up time after DAA was 5.7 months

(0.4-14.6).

3 pts died and 16 developed radiologic tumor recurrence.

Median time between HCC treatment and start of DAA was 11.2 months

Median time from DAA start to recurrence was 3.5 months

HCC recurrence rate was equal to 27.6%, significantly higher than in the STORM study

Reig M. J Hepatol. 2016

41.9%

Reig M. J Hepatol. 2016

Unexpectedly high rate of early tumor recurrence in patients with HCV-related HCC undergoing IFN-free therapy

BCLC-Pre-DAA

The evolution of each patient is described in 3 time periods Whole cohort (n=77)

months

Grey boxes= ‘time window between last complete response assessment and DAA initiation’

Blue boxes = ’time between HCC treatment and last assessment of complete response by imaging’.

‘HCC evolution

after starting DAA’

Yellow boxes= ‘time window between DAA initiation and last assessment with complete response’

Red boxes = ‘time between the date of the start dose of DAA and the date of 1st radiologic tumor recurrence’

Black boxes = ‘time between the date of the 1st radiologic tumor recurrence and the date of the 2nd radiologic tumor recurrence or progression

24/77patients

(31.2 %)

HCC recurrence

Reig M. EASL 2017

Summary of the HCC patients with SVR treated with DAA

16.7% BSC

37.5 % Ablation

Resection LT

45.8 % TACE

Sorafenib Regorafenib

RE Clinical Trials

Whole cohort (n=77)

Median follow-up -months 12.4

(IQR: 8.4-18-7)

HCC progression n= 24 (31.2%)

Death n=5 (6.5%)

HCC recurrence (n=24)

Median time between start DAA and 1st HCC recurrence -months 3.5

(IQR: 2-7.6)

2nd recurrence or progression n=10

Median time between 1st- 2nd HCC recurrence/progression -months 6

(IQR:3.2-8.2)

Recurrence/progression within the 6 month of 1st HCC recurrence 6/20 (30%)

Death n=5 (20.8%)

BCLC: Barcelona Clinic Liver Cancer; DAA: direct antiviral agents; BSC: Best support care; TACE: Transarterial Chemoembolization; TARE: Radioembolization

Reig M. EASL 2017

HCC recurrence following SVR

RR non adjusted RR adjusted IC 95 % P value

Average follow-up 0,86 0,79 0,55-1,15 0,19

Average Age 1,11 1,11 0,96-1,27 0,14

Treatment 1,36 0,62 0,11-3,45 0,56

Hagihara, 2011

0,05

HCC recurrence rate/100 personne-years

Authors, year ES (IC 95 %) Weight, %

50

Kanogawa, 2015

Kunimoto, 2016

Jeong, 2007

Saito, 2014

Sanefuji, 2009

Minami, 2016

Global (I-squared = 0,0 %, p = 0,638)

9,15 (4,58-18,30)

6,49 (3,49-12,05)

7,87 (4,82-12,84)

13,26 (7,14-24,65)

12,88 (6,14-27,01)

13,33 (4,30-41,34)

8,10 (4,05-16,19)

9,21 (7,18-11,81)

12,90

16,13

25,81

16,13

11,29

4,84

12,90

IFN AAD

Conti, 2016

Authors, year

Pol CO22, 2016

Pol CO12, 2016

Pol CO23, 2016

Reig, 2016

Rinaldi, 2016

Minami, 2016

Torres, 2016

Zavaglia, 2016

Lei-Zeng, 2016

Global (I-squared = 89,1 %, p = 0,000)

0,05

HCC recurrence rate /100 personne-years

50 100

45,82 (28,49-73,71)

8,11 (5,43-12,10)

4,40 (0,62-31,20)

2,82 (1,35-5,92)

54,24 (33,23-88,53)

26,67 (3,76-189,31)

20,98 (9,43-46,70)

0,07 (0,00-2,28e+07)

1,42 (0,20-10,07)

0,08 (0,00-2,60e+07)

12,14 (5,00-29,46)

14,96

15,15

8,86

14,10

14,92

8,86

13,87

0,20

8,86

0,20

ES (IC 95 %) Weight, %

HCC Risk after DAAs treatments : meta-analysis

Meta regression of HCC recurrence

Waziry R et al. EASL 2017, Abs. PS-160

Increased Risk No Risks

HCC incidence decreases with longer folllow-up No data on HCC severity

HCC recurrence by average follow-up

0 1 2 3 4 5 6 7 8

IFN

DAA

0

10

20

30

40

50

60

Average follow-up (years)

HC

C r

ecu

rren

ce

(pe

r 1

00

pe

rso

n-y

ear

s)

Impact of follow-up on the risk of recurrence of HCC after antiviral treatments: a meta-analysis

Waziry R et al. EASL 2017, Abs. PS-160

Selection Bias : Sicker patients get DAA’s

Vocabulary of Hepatocellular Carcinoma (HCC)

RECURRENCE: Reappearance of HCC in a subject

(with or without liver disease) with a previous HCC

judged to be radically cured by any technique

(TACE, RFTA, resection)

OCCURRENCE: De novo appearance of HCC in a

subject (with or without liver disease) with no

history or previous evidence of a liver tumor

HCC occurrence following SVR

Meta regression of HCC occurrence

Waziry R et al. EASL 2017, Abs. PS-160

Ogawa, 2013 D’ambrosio, 2011 Bruno, 2009 Mallet, 2006 Cardoso, 2010 Yu, 2006 Hung, 2006 Morgan, 2010 Aleman, 2013 Chenquer, 2010 Moon, 2015 Fernandez-Rodriguez, 2010 Janjua, 2016 Rutter, 2015 Velosa, 2011 Nahon, 2017 Marco, 2016 Global (I-squared = 45,7 %, p = 0,21)

0,01 30

HCC occurrence rate /100 personne-years

3,67 (1,75-7,70) 0,71 (0,23-2,20) 1,74 (0,83-3,64) 0,78 (0,25-2,43) 1,66 (0,75-3,70) 2,04 (1,06-3,93) 2,22 (0,92-5,34) 0,20 (0,05-0,80) 1,03 (0,46-2,29) 0,98 (0,14-6,98) 1,12 (0,16-7,94) 0,99 (0,41-2,37) 0,74 (0,33-1,64) 0,95 (0,48-1,91) 0,36 (0,05-2,56) 0,88 (0,61-1,28) 0,85 (0,41-1,78) 1,14 (0,86-1,52)

7,34 4,41 7,34 4,41 6,78 8,25 6,12 3,27 6,78 1,84 1,84 6,12 6,78 7,83 1,84

11,70 7,34

Authors, year ES (IC 95 %) weight, % IFN

Cardoso, 2016

Conti, 2016

Rinaldi, 2016

Kozbal, 2016

Lei-Zeng, 2016

Romano, 2016

Affronti, 2016

Muir, 2016

Carrat, 2016

Global (I-squared = 78,3 %, p = 0,000)

0,01

HCC occurrence rate/100 personne-years

30

DAA

7,41 (2,78-19,74)

4,51 (2,35-8,67)

10,29 (4,91-21,59)

1,80 (0,97-3,35)

0,04 (0,00-1,30e+07

1,78 (1,22-2,59)

3,33 (1,25)

0,12 (0,02-0,85)

3,30 (2,67-4,08)

3,09 (1,92-4,96)

10,33

13,68

12,74

14,05

0,06

16,55

10,33

4,44

17,83

Unadjusted RR Adjusted RR IC 95 % p

Average follow-up 0,88 0,77 0,62-0,97 0,03

Average age 1,11 1,06 0,99-1,14 0,08

Treatment 2,77 0,75 0,22-2,52 0,62

ES (IC 95 %) weight, %

HCC Risk after DAAs treatments : meta-analysis

HCC incidence decreases with longer folllow-up No data on HCC severity

0 2 4 6 8 10 12 14 16

IFN

DAA

0

2

4

6

8

10

12

14

Average follow-up (years)

HC

C o

ccu

rre

nce

rat

e

(pe

r 1

00

pe

rso

n-y

ear

s)

HCC occurrence by average follow-up

Waziry R et al. EASL 2017, Abs. PS-160

Impact of follow-up on the risk of occurrence of HCC after antiviral treatments: a meta-analysis

Hepatocellular carcinoma after SVR with IFN-free regimens in HIV/HCV-coinfection

Nicolás Merchante1, Boris Revollo2, Francisco Rodríguez-Arrondo3, Esperanza Merino4, María J. Galindo5, Marta Montero6, Antonio Rivero-Juárez7,

Marcial Delgado-Fernández8, María J. Ríos-Villegas9, Juan A. Pineda1.

1H Valme, Sevilla; 2H German Trias i Pujol, Badalona; 3H Donostia, San Sebastián; 4HGU Alicante, Alicante; 5H Clínico Valencia; Valencia; 6H La Fe, Valencia; 7H Reina Sofía, Córdoba;

8H Regional Universitario, Málaga; 9H V. Macarena, Sevilla.

GEHEP-002 Study Group

Results (III): Characteristics of HCC cases after SVR by period of diagnosis (n=40)

Before 2014 (n=27)

2014-2016 (n=13)

Months from SVR1 24 (10-63) 16 (3-36)

Genotype 3, no (%) 16 (59) 4 (31)

Child-Pugh A, no (%) 14 (52) 9 (69)

Previous HCC screening, no (%) 11 (41) 10 (77)

Multicentric HCC, no (%) 14 (52) 6 (46)

Milan criteria, no (%) 10 (37) 7 (54)

Portal thrombosis, no (%) 9 (33) 4 (31)

Extra-hepatic metastases, no (%) 5 (19) 1 (8)

BCLC stage, no (%) 0-A B C D

10 (37)

1 (4) 13 (48) 3 (11)

7 (54) 2 (15) 4 (31) 0 (0)

1Median (Q1-Q3)

Conclusions

• The proportion of HCC cases diagnosed in HIV/HCV-coinfected

patients with previous SVR has significantly increased parallel to the

arrival of DAA IFN-free strategies.

• This finding may be, at least partially, explained by the fact that

DAA’s have allowed treating patients at advanced stages of liver

disease in which the protective effect of SVR on the risk of HCC

could be less marked.

• Although the potential role of DAA for HCC emergence should be

clarified, our study has not found evidence for an increased

incidence of HCC with DAA use.

1. SVR to DAA regimens reduces, but not abolishes, the risk of

developing HCC at all stages of cirrhosis

2. The residual risk of HCC after SVR is proportional to patient’s

age, stage of liver disease and co-morbidities at the time of Rx

3. The pattern of growth of HCC after HCV eradication may differ

from that of viremic patients, and deserves investigation

4. Viral eradication may improve the prognosis of HCC patients

due to prevention of decompensation

DAAs, HCV clearance and HCC: the take-home message

Unresolved Question

• Do you wait till HCC is NED before HCV Rx or

• Do you Rx HCV as soon as HCC is diagnosed ?