Is HCC increased with DAA therapy?

No

Nicolás Merchante

Hospital Universitario de Valme.

Sevilla, Spain.

This is how we thought the future would look like after the arrival of DAA

But life has taught us to expect the unexpected…

Development of HCC in a patient with advanced cirrhosis receiving DAA:

Something unexpected?

HCC emergence after DAA: Something unexpected? Yes…..SVR reduces the risk of HCC !!!

• SVR widely associated with a risk-reduction for HCC development.

– Cumulative HCC incidence in untreated HCV-cirrhotics is 3-5% per year.

– 75% HCC risk reduction with SVR in long-term follow-up studies of cirrhotics.

• Evidence of the impact of SVR on HCC coming from IFN-based era.

– Similar HCC risk reductions after SVR to DAA to be demonstrated…but…

• The higher the SVR rates…the fewer the HCC risk…

HCC emergence after DAA: Something unexpected? Maybe not……Risk of HCC after SVR in cirrhosis

• SVR does not completely eliminate the risk of HCC, especially if

established cirrhosis was present before treatment.

– 8% of HCC cases in HIV/HCV were diagnosed after SVR (with PEG-IFN+RBV)1

• HCC surveillance with US should be maintained after SVR if F4.

• As DAA have been widely applied first to those with advanced

liver disease…new cases of HCC are expected in spite of high SVR

rates…

1Merchante N. AIDS 2014.

0

10

20

30

40

50

60

70

80

90

100

< 2002 2002-2011 2012-Oct 2014 Oct 2014-2016

%

n=6 n=162 n=111 n=43

HCC after SVR in the GEHEP-002 cohort Proportion of HCC cases after SVR

among total HCC cases in HIV/HCV-coinfected patients

p= 0.006

1 (16,7%) 17

(10,5%) 10

(9%)

14 (32,6%)

Total HCC cases

n= 319 HCC cases in HIV/HCV-coinfected pts in Spain (1996-2016)

In 42 (13%), HCC was diagnosed after SVR

Merchante N. CROI 2017 (up-dated data).

GEHEP-002 cohort (ClinicalTrials.gov ID: NCT02785835).

HCC cases after SVR to DAA not unexpected…

• HCC cases after SVR to DAA not completely unexpected…

– DAA have come too late (advanced liver disease) to prevent HCC in many patients.

– DAA have been applied to high-risk patients for HCC emergence or recurrence who would never qualify for IFN in the past.

• Why should we think that DAA may increase HCC development?.

– Two alarming reports suggesting an increased and earlier than expected frequency of HCC recurrence/emergence after DAA1,2

1Conti F. J Hepatol 2016. 2Reig M. J Hepatol 2016

Let’s read the small print of these studies

Reig M. J Hepatol 2016.

Unexpected early tumor recurrence in HCV-related HCC undergoing IFN-free therapy

• n= 58 Patients. 4 centers in Spain. Inclusion criteria:

– HCC treated by ablation, resection or TACE (October 2014-December 2015).

– Complete response before starting DAA.

– HCV treatment with all oral DAA therapy.

– At least 1 tumor status assessment after the start of AAD.

• Recurrence rate at 6 months after DAA: 16/58 (27.6%).

– Median time from DAA start to recurrence: 3.5 (1.1-8) mo.

– Recurrence was registered before finishing DAA in 8 patients.

• Median time between HCC treatment and DAA start: 11.2 (3.6-23.2) months !!

Conti F. J Hepatol 2016.

HCC development in HCV-cirrhotics treated with DAA

• n= 344 HCV CTP A or B cirrhotic patients treated with DAA in Italy.

– US at baseline excluding HCC and 12-24 weeks after end of treatment.

• Previous HCC: n=59 (17%).

– Treated with resection, ablation or TACE.

– Median time from previous HCC treatment to the start of DAA: 376 days.

7,6 3,2

29

0

20

40

60

80

100

All patients Without previous HCC With previous HCC

Proportion of patients who developed HCC after DAA

%

Resection or

Ablation

0

DAA start

12

HCC recurrence

months

16

HCC recurrence rates in DAA studies

Real recurrence rate

Are these rates of recurrence high? Not if we make the right comparison

Probability of HCC recurrence at 1 year after resection or ablation across studies

27,6 29 27,6 27 20

0

20

40

60

80

100

Reig Conti BarcelonaAblationCohort

STORMplacebo arm

Pompili

DAA studies

%

(Resection or RFA)

Probability of HCC recurrence at 3 years after resection or ablation

43

57 64

0

20

40

60

80

100

Resection RFA PEI

% • Japan (2000-2005)

• n=12968

• HCC < 3 nodules (≤ 3 cm), CPT A or B

Hasegawa K. J Hepatol 2013.

HCC recurrence in HCV-cirrhotics treated with DAA Time interval between HCC treatment and recurrence:

does it really have something to do with DAA?

Conti F. J Hepatol 2016.

Increased risk of HCC after DAA?

Summary of studies assessing DAA and HCC risk

Increased Risk No Risk

Incidence and pattern of “de novo” HCC in HCV infected patients treated with DAA

Romano A. AASLD 2016.

• NAVIGATORE cohort (Italy). n=3075 HCV F3-F4 treated with DAA.

– 853 (28%) F3. 215 (7%) CTP B.

– Patients with previous HCC excluded.

41 patients developed HCC during follow-up.

Incidence of HCC: 1.6% person/year (95% CI: 1.2-2.2).

• Higher risk in CTP B vs CTP A vs F3.

• Lower HCC incidence than historical cohorts of untreated HCV-cirrhotics.

• 2.8% (Benvegnu L. Gut 2004). 3.9 % (Sangiovanni A. Hepatology 2006).

• SVR was associated with 80% risk-reduction of HCC.

Similar rates of de novo HCC after DAA IFN-free vs DAA IFN-based therapy

0

20

40

60

80

100

DAA + PR DAA IFN-freen=490

%

n=77

1.1% 1.7%

Retrospective multicohort study. Belgium.

n=567 HCV F3-F4 treated patients. 39 (7%) coinfected by HIV.

• n=77 PR + DAA (2008-2013). 47% F4.

• n=490 DAA IFN-free (2013-2015). 67% F4.

p = 0.5

Rob B. J Viral Hep 2017 (in press).

Pol S. J Hepatol 2016.

• ANRS CO22 HEPATHER. n=267 HCV with previously treated HCC.

– DAA group. n= 189. Median follow-up after DAA initiation: 20 mo.

– Untreated group. n=78. Median follow-up: 26 mo.

Lack of evidence of an effect of DAA on the recurrence of HCC in France

HCC recurred in 40 patients

• 24 (12%) in DAA group.

• 16 (20%) in untreated pts

IR of HCC recurrence

• DAA group: 0.73/100 PY.

• Untreated: 0.66/100 PY.

• p=0.8

Pol S. J Hepatol 2016.

Lack of evidence of an effect of DAA on the recurrence of HCC in France

• Additional analysis in 2 prospective multicenter cohorts in France:

– ANRS CO12 CIRVIR. n=79 cirrhotics with previously treated HCC.

• 13 treated with DAA; 66 not treated.

– ANRS CO23 CUPILT. n=314 with previous LT for HCC treated with DAA.

47

7,7 2,2

0

20

40

60

80

100

CIRVIR CUPILT

Proportion of patients with HCC recurrence

Not treated Treated with DAA

%

Incidence of HCC recurrence after HCV therapy

Single-center retrospective study. France (2009-2015)

n=68 HCV F4 with previous HCC.

• n=23 treated with DAA. Incidence of HCC recurrence: 1.7/100 person-months.

• n=45 no HCV therapy. Incidence of HCC recurrence: 4.2/100 person-months.

Virlogeux V. Liver Intern 2017.

Nagata J. J Hepatol 2017 (in press, published on line 13th June).

HCC development or recurrence after SVR: IFN-based vs IFN-free regimens

Frequency of HCC diagnosis after SVR

in HIV/HCV-coinfected patients with cirrhosis

6,66 15

1,62 0,87 0

20

40

60

80

100

IFN PEG-IFN + RBV DAA + PR DAA IFN free

%

HCC after SVR 1 24 4 8 No. with SVR 15 160 246 916

20 centers from the GEHEP-002 cohort reported data of the number of HIV/HCV-coinfected patients with cirrhosis who achieved SVR in each period.

n=1337 HIV/HCV cirrhotics with SVR before January 2017

Merchante N. CROI 2017 (updated data).

HCC recurrence after HCV therapy in HIV/HCV-coinfected patients

0

20

40

60

80

100

IFN-based DAA IFN-free

n=19

%

n=8

4 (21) 2 (25)

39 HIV/HCV patients with HCC received therapy against HCV after HCC diagnosis

• n=8 IFN-based. All of them after HCC curative therapies.

• n=31 DAA IFN-free.

• n=19 with previous curative therapies against HCC and ultrasound

evidence of lack of nodules prior to HCV therapy.

HCC recurrence after potentially curative treatments

among those undergoing HCV therapy

p = 1.0

Merchante N. CROI 2017 (updated data).

Incidence of “de novo” HCC in HIV/HCV infected patients treated with DAA

Hason H. J Hepatol 2017 (in press).

• Single center study (Italy). 2015-2017.

• N=118 HIV/HCV F3-F4 treated with DAA.

– Patients with previous HCC excluded.

– US without hepatic nodules at baseline.

Median follow-up after DAA start 87 (74-95) weeks.

Globally, 97% SVR.

3/118 (2.5%) patients developed HCC during follow-up.

• Incidence not higher than:

• Historical controls.

• HCV+/HIV- cohorts treated with DAA.

• All HCC cases: F4 and genotype 3.

Conclusions

• New cases of HCC after SVR to DAA are expected to emerge, as

DAA 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.

• Cumulative evidence does not support any role of DAA for an

increased risk of HCC emergence or recurrence in HCV-infected

patients with or without HIV-coinfection.

Coordinator Center - Hospital Universitario de Valme (Sevilla):

Nicolás Merchante, María Mancebo, Pilar Rincón, Fernando Saussol, María J. Álvarez Ossorio,

Lara Domínguez, María Iglesias, Luis M. Real, Juan Macías, Juan A. Pineda.

Esperanza Merino (Hospital General Universitario de Alicante), Francisco Rodríguez-Arrondo (Hospital Universitario de

Donostia, San Sebastián), Boris Revollo (Hospital Universitario Germans Trias i Pujol, Badalona), José López-Aldeguer

(Hospital Universitario y Politécnico La Fe, Valencia), Maria J. Galindo (Hospital Clínico de Valencia), Josefa Muñoz,

Sofia Ibarra (Hospital de Basurto, Bilbao), Antonio Rivero-Juárez (Hospital Universitario Reina Sofía, Córdoba),

Francisco Jover (Hospital Clínico Universitario de San Juan, Alicante), Joseba Portu (Hospital Txagorritxu, Vitoria),

Marcial Delgado-Fernández (Hospital Regional Carlos Haya, Málaga), Enrique Ortega (Hospital General de Valencia),

Maria José Ríos-Villegas (Hospital Universitario Virgen Macarena, Sevilla), Alberto Romero-Palacios (Hospital

Universitario de Puerto Real, Cádiz), Maria Asunción García-Gonzalo (Hospital de Galdakao, Vizcaya), Koldo

Aguirrebengoa (Hospital de Cruces, Bilbao), Concepción Amador (Hospital Marina Baixa, Villajoyosa, Alicante),

Francisco Téllez (Hospital de La Línea de la Concepción, Cádiz), Carlos Mínguez (Hospital General de Castellón), María

Jehovana Hernández (Hospital Universitario de Canarias, Santa Cruz de Tenerife), Guillermo Ojeda (Hospital Virgen de

la Victoria, Málaga), Amaya Jimeno-Almazán, Francisco J. Vera (Hospital Santa Lucía, Cartagena), Mohamed Omar

(Complejo Hospitalario de Jaén), Miguel Angel López Ruz (Hospital Virgen de las Nieves, Granada), Miguel Raffo

(Complejo Hospitalario de Huelva), Luis Metola (Hospital de San Pedro, Logroño), Rafael Silvariño (Hospital de San

Eloy, Baracaldo), Joan Gregori (Hospital de Orihuela).

GEHEP-002 centers and investigators

FUNDING: This study was supported by grants from the Consejería de Salud de la Junta de Andalucía [PI-0014/2014], the Servicio Andaluz de Salud [grant number SAS/111239] and the Fondo de Investigaciones Sanitarias ISCIII [grant number PI13/01621 and PI16/01443]. JAP is the recipient of an intensification grant from the Instituto de Salud Carlos III [grant number Programa-I3SNS]. Besides, this work has been partially funded by the RD12/0017/0012 project as part of the Plan Nacional R + D + I and cofinanced by ISCIII- Subdirección General de Evaluación y el Fondo Europeo de Desarrollo Regional (FEDER).