Corso formativoAIGO1° Ed.

03 Ottobre 2017

Il trattamento dell’epatite cronica da HCV con DAAs e HCC:

luci ed ombre

Mauro BorzioU.O.C. Gastroenterologia ed

Endoscopia DigestivaASST Melegnano-Martesana

HCC in cirrosi:HCC in cirrosi:i trattamentii trattamentilocoregionalilocoregionali

By 2050 highly effective therapies(expected SVR 90%) could prevent:

The ideal scenario: widespread implementation of screening, DAA treatmentof all infected and unlimited treatment capacity.

HCV infection could become a rare disease in the next 20 years. The USA Model

2014 DAAs introduction(expected SVR 90%) could prevent:

24,200 cases of decompensatedcirrhosis

78,800 cases of HCC

126,500 liver-related deaths

9,900 liver transplantations

Kabiri M et al, Ann Intern Med. 2014;161:170-80

J Hepatol 2016

Eradication of HCV and the Development of HCC A Meta-analysis of Observational Studies

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

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

Risk of HCC in HCV patients with an SVR

D’ambrosio, Liv Intern 2016

Risk of HCC in SVR patients(Chinese multicentre cohort)

1271 HCV treated cases from 2002 to 2009 (IFN/PegIFN ± RBVSVR: 871 (39% F3/F4), 37 cases of HCC in SVR during a median FU of 41.3 months

Cumulative incidence of HCC0.8% at 1 year1.2% at 2 years3% at 3 years

Chang et al J Antimicrob Ther 2012; 67:2765

A novel predictive risk score of HCC in SVR patients(Chinese multicentre cohort)

Factor PointsAge > 60 5Plt < 160 109 4AFP > 20 ng/ml 4Fibrosis F3-F4 6

Score risk< 10 low10-15 intermediate> 15 high

Chang et al J Antimicrob Ther 2012; 67:27651111

0.2%

22.1%

66.7%

Variable ReportedAnnualIncidence(%) *

Number of Individuals (%)

Estimated Annual HCC Cases

Estimated Annual Incidence (%)

IFN-based

(N=578)

IFN-free(N=413)

IFN-based

(N=578)

IFN-free(N=413)

IFN-based

(N=578)

IFN-free(N=413)

Age

< 45 0.077 160 (27.7) 1 (1.7) 0.12 0.0

Incidence of HCC After SVR in the Era of IFN-free Therapy for HCV

< 45 0.077 160 (27.7) 1 (1.7) 0.12 0.0

45 - 54 0.213 168 (29.0) 16 (3.9) 0.36 0.03 0.35 0.85

55 - 64 0.529 201 (34.8) 59 (14.3) 1.06 0.31 (2.01/578) (3.50/413)

65+ 0.953 49 (8.5) 331 (80.1) 0.47 3.15

Cirrhosis

No 0.159 522 (90.3) 257 (62.2) 0.83 0.41 0.28 0.62

Yes 1.393 56 (9.7) 156 (37.8) 0.78 2.17 (1.61/578) (2.58/413)

Toyoda et al, Hepatology 2016*According to El-Serag

DAAs Allow Increased Access to HCV Therapy The German Registry DHC-R, 2014-15

Welzel T ISVHLD Berlin 2015

HCC e DAAs

Is the warning justified?

Two clinical scenarios

De novo HCC

HCC recurrence

De novo HCCDe novo HCC

Risk of de novo HCC in HCV patients treated

with DAAs

Premises

• No RCT (unethical)

• Most studies are retrospective

• Historical controls misleading (huge difference between IFN-basedand IFN-free DAAs-based treatment cohorts)

• Most available studies carried out on too small cohorts

• Inadequate follow-up

Studies supporting the negative role of DAAs on de

novo HCC occurrence

Studies not supporting the negative role of DAAs on

de novo HCC occurrence

Romano A, Hepatology 2016;64(S1):10°; Nahon P, Gastroenterology. 2017;152:142‐156.

2,877 patients with cirrhosis

who started DAAs

between March 2015 and July 2016

273 (9.5%) patients excluded

• 185 with previous HCC

• 55 with previous OLT

• 33 on waiting list for OLT 138 (4.8%) patients not evaluated

21 death (4 liver related and

Flow-chart of the RESIST – HCV cohortRESIST: Rete Sicilia Selezione Terapia

• 33 on waiting list for OLT • 21 death (4 liver related and

17 liver unrelated)

• 19 stopped therapy for AEs

• 30 drop-outs

• 68 no SVR data available

2,466 (85.7%) patients

evaluated for HCC occurrenceCalvaruso V: EASL 2017

Median follow-up since starting DAAs: 14 months (range 2-22)

Cumulative incidence of HCC by Kaplan-Meier analysis

Cu

mu

lati

ve

Ra

te o

f H

CC

(%

)No SVR

Overall

SVR

Calvaruso V: EASL 2017

Overall HCC occurrence

Time Events, N. (%) Cumulative Rate

(Kaplan – Meier estimates x 100)

6 months 24 (1.0) 1.0%

12 months 59 (2.4) 2.7%

18 months 73 (2.9) 4.4%

24 months 78 (3.1) 7.4%

Cu

mu

lati

ve

Ra

te o

f H

CC

(%

)

SVR

No SVR- CP B

p < 0.0001

Cumulative incidence of HCC

according to Child-Pugh class and SVR statuso

ccu

rre

nce

(%)

Calvaruso V: EASL 2017

No SVR- CP A

SVR- CP A

SVR- CP B

Ra

te o

f H

CC

occ

urr

en

ce

VA PROSPECTIVE COHORTN. 22.500Cirrhosis 8766 (39%)SVR 19.518 (87%)

Risk factors incidence (%/y)

Gastroenterology 2017;153:996–1005

Incidence 0.9 %/y

Incidence 3.4 %/yRisk factors incidence (%/y)

Male 0.92Female 0.28

Cirrhosis yes 1.82no 0.34

Alcohol abuse yes 1.01no 0.72

Data on HCC occurrence:N studies: IFN 17, DAAs 9N patients: IFN 5521, DAAs 6002

Waziry R et al.J Hepatol 2017 in press

PegIFN+RBV n: 244 Cirrhosis: 29%DCV/ASV n: 154 Cirrhosis: 54%

Nagaoki Y, PLoS ONE 12(8): e0182710.

Propensity score analysis

HCC occurrence (%)1y 3 y 5Y

PegIFN +RBV (66) 1.5 10 12 NSDCV/ASV (66) 1.5 10 19

HCC recurrenceHCC recurrence

Risk of HCC recurrence after a curative

treatment in HCV patients treated with DAAs

Premises

• No RCT (unethical)

• Most studies are retrospective

• Most available studies carried out on too small cohorts• Most available studies carried out on too small cohorts

• Inadequate follow-up

• Several confounding biases:

• the design of study (retrospective or prospective)

• inclusion criteria

• baseline patients and tumour characteristics

• type of curative HCC treatment (resection , percutaneous ablation, TACE)

• assessment of CRR,

• HCC recurrence definition (early or late and local or distant),

• time frames between tumour cure and DAA therapy and between last assessment of tumour response and DAA therapy

• history of prior successfully treated HCC recurrences before DAA therapy.

IFN-based antiviral therapy in HCV patients with completely cured HCC: a meta-nalysis

Manthravady et al Intern J Oncol 2016

OS

RFS

Cabibbo G et al. Liv Internat 2017

Cabibbo et al, on behalf ITA.LICA. Group. Liv Int 2017

Pooled Actuarial Recurrence Rate- at 6 months (mo): 7.4%- at 24 mo: 47%

Pooled Survival Recurrence Rate- at 3 years (yrs): 80%- at 5 yrs: 59%

Studies supporting the negative role of DAAs on HCC recurrence

Reig M, J Hepatol 2016; Conti F, J Hepatol 2016; Yang JD J Hepatol 2016

Petta S et al on behalf of ITA.LI.CA study group 2017

5 European Centres47 patients evaluable82.6 % BCLC A81 % Child AResection 35%, ablation 54 %, TACE 33%

Disease-free survival curve with HCC treatment as the starting point showing disease-free rates of 96%, 81% and58% at 6, 12 and 24 months, respectively.

Disease-free survival curve with the start of DAA therapy as the starting point showing disease-free rates of 77% and 58% at 6 and 12 months, respectively

Kolli P et al. J Hepatol 2017; 66:876-878

22 Partecipating centres143 HCCs with CRRBCLC 0 24%, BCLC A 76%Child A 86%, B 14%Resection 36%, Ablation 46%, TACE 18%

Cabibbo G et al. On behalf of Rete Sicilia Selezione Terapia – HCV (RESIST-HCV) 2017 in press

A, tumour size <2.5 cm and no prior HCC recurrences; B, tumour size <2.5 cm and prior HCC recurrences; C, tumour size >2.5 cm and no prior HCC recurrences; D,tumour size >2.5 cm and prior HCC recurrences

Cabibbo G et al. On behalf of Rete Sicilia Selezione Terapia – HCV (RESIST-HCV) 2017 in press

ANRS CO22 HEPATHER cohortInclusion period: August 2012-September 2014ANRS CO12 Cirvir cohortInclusion: 2006-2012ANRS CO23 CUPILT cohortInclusion period: October 2013-December 2015

Pol S. J Hepatol; 2016; 65:734–740

Waziry R et al.J Hepatol 2017 in press

Data on HCC occurrence:N studies: IFN 17, DAAs 9N patients: IFN 5521, DAAs 6002

Recurrence pattern of HCC with CRR following DAAs treatment

Author N rec Naive HCC Recurrent HCC

Milano in Milano out Milano in Milano outMilano in Milano out Milano in Milano out

Reig 2016 16/58 16 - 12 4

Pol 2016 7/314 6 1 3 4

Cabibbo 2017 29/143 29 - 18 11

Reig M. J Hepatol 2016; Pol S. J Hepatol; 2016; Cabibbo G. Alim Pharm Ther 2017

CONCLUSIONI

• Non esistono al momento evidenze certe a supporto di un ruolo negativo della terapia con DAAs sulla carcinogenesi epatica

• Per quanto riguarda il rischio di comparsa di HCC de novo

• Non sembra dissimile da quanto osservato con terapia con IFN

• La SVR riduce il rischio

• Predittori di aumentato rischio: mancata SVR, età, cirrosi avanzata• Predittori di aumentato rischio: mancata SVR, età, cirrosi avanzata

• Per quanto riguarda il rischio di recidiva di HCC con precedente CCR

• Dati contrastanti dovuti ad eccessiva eterogeneità degli studi

• La maggior parte degli studi (cohorti prospettiche) negano un aumentato rischio

• predittori di aumentato rischio: stadio del tumore iniziale, precedenti recidive, età, fibrosi avanzata

• Frequente riscontro di recidive ad alta aggressività

GrazieGrazie