hcc in cirrosi: mauro borzio
TRANSCRIPT
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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
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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
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J Hepatol 2016
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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
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Risk of HCC in HCV patients with an SVR
D’ambrosio, Liv Intern 2016
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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
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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%
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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
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DAAs Allow Increased Access to HCV Therapy The German Registry DHC-R, 2014-15
Welzel T ISVHLD Berlin 2015
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HCC e DAAs
Is the warning justified?
Two clinical scenarios
De novo HCC
HCC recurrence
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De novo HCCDe novo HCC
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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
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Studies supporting the negative role of DAAs on de
novo HCC occurrence
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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.
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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
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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
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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
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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
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Data on HCC occurrence:N studies: IFN 17, DAAs 9N patients: IFN 5521, DAAs 6002
Waziry R et al.J Hepatol 2017 in press
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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
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HCC recurrenceHCC recurrence
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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.
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IFN-based antiviral therapy in HCV patients with completely cured HCC: a meta-nalysis
Manthravady et al Intern J Oncol 2016
OS
RFS
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Cabibbo G et al. Liv Internat 2017
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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%
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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
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Petta S et al on behalf of ITA.LI.CA study group 2017
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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
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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
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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
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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
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Waziry R et al.J Hepatol 2017 in press
Data on HCC occurrence:N studies: IFN 17, DAAs 9N patients: IFN 5521, DAAs 6002
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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
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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
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GrazieGrazie