hospital universitario de valme, sevilla, spain · 12/12/2014 1 in partnership with hospital...

12/12/2014

1

in partnership

with

Hospital Universitario de Valme, Sevilla, Spain

Dr Nicolás Merchante

Five Nations Conference on

HIV and Hepatitis

Hepatocellular carcinoma

Nicolás Merchante

Hospital Universitario de Valme. Sevilla, Spain.

Grupo Español para el Estudio de las Hepatitis Víricas (GEHEP)

Five Nations Conference on HIV and Hepatitis

London, UK. 8th December 2014

12/12/2014

2

Disclosures

None to declare

Outline

• Epidemiology, pathogenesis and clinical presentation.

• Surveillance.

• Staging, treatment and prevention.

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3

HCC in HIV:

The price of hepatitis viral coinfection and cirrhosis

• Risk factor: Chronic liver disease.

– Chronic hepatitis viral infection: HCV, HBV.

– Alcohol use.

– Role of NASH?

• HCC disease burden in HIV/HCV-coinfected patients with cirrhosis:

– 2nd most frequent type of liver decompensation.

– Leading cause of liver-related death.

HCV genotype and risk for HCC

1Raimondi S. J Hepatol 2009.

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4

Kanwal F.

Hepatology 2014.

HCV genotype and risk for HCC

G3 (vs G1) independently associated with HCC:

AHR 1.80 (95% CI 1.61-2.03)

[Multivariate model adjusted by age, sex, race, year

of diagnosis, HIV, diabetes, BMI and SVR]

• Retrospective. 2000-2009. Median follow-up: 5.4 years.

• n=110.480 HCV-infected patients with detectable RNA.

SNPs and risk for HCC in cirrhosis

Cirrhosis

Hepatocellular carcinoma

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Biological pathway Gene SNP Etiology Ethinicity

Oxidative stress/

iron metabolism

GSTM1

GSTT1

SOD2 A16V

MPO G-463A

CAT T-262C

HFE C282Y

Deletion

Deletion

rs4880

rs2333227

rs1001179

rs1800562

HBV/HCV

HBV/HCV

Alcohol

Alcohol/HCV

HCV

Alcohol

Mixed

Mixed

Caucasian

Caucasian

Caucasian

Caucasian

Detoxifying systemsUGT1A7 R131K

N129K

CYP1A2 G-3860A

rs17868323

rs1692021

rs2069514

VHC

VHB/VHC

VHB/VHC

Asian

Asian

Asian

InflammationTNF G-308A

TNFα

G-238A

TNFα

G-863A

IL1β C-511T

IL1β C-31T

IL10 A-592C

TGF β 1

RANTES G-403A

NFKβIA G881A

rs1800629

rs361525

rs1800630

rs16944

rs143627

rs1800872

rs13447341

rs2107538

rs3138053

HBV/HCV

HBV/HCV

HBV/HCV

Alcohol/HCV

Alcohol/HCV

HBV/HCV

HBV

Alcohol

HBV

Mixed

Mixed

Mixed

Asian

Asian

Mixed

Asian

Caucasian

Asian

DNA synthesis and

repair mechanisms

MTHFR C-677T

MTHFR A1298C

TYMS 3’UTR1949del6

XPC L-939G

XRCC3 C-18067T

rs1801133

rs1801131

rs16430

rs2228001

rs861539

Alcohol/HBV/HCV

Alcohol/HBV/HCV

Alcohol/HBV/HCV

HBV/HCV

HBV/HCV

Mixed

Mixed

Mixed

Asian

Asian

Cell cycle regulationMDM2 G-309T

P53 R72P

rs2279744

rs1042522

HBV

HCV

HBV/HCV

HBV

Asian

Asian

Mixed

Asian

Hormone metabolismESR1 T29C

ESR1 (TA)n repeat

ESR1 Pvull CG

rs2077647

rs3138774

rs2234693

HBV

HBV

HBV

Asian

Asian

Asian

Growth factorsEGF A61G S4444903 HCV

Alcohol/HBV/HCV

Caucasian

Afro-american

Micro-RNAsIL

αTTCA Indel

miR-146ª GC

rs3783553

rs2910164

Alcohol/HBV/HCV

HBV/HCV

Asian

Immune responseCD24 C170T rs8734 HBV Asian

SNPs and risk of hepatocellular carcinoma in cirrhosis

Nahon P. J Hepatol 2012.

SNPs and risk for HCC in cirrhosis

Study Gene SNP Etiology of

liver disease

Ethnicity

Kumar 2011

Miki 2011

Zhang 2010

Clifford 2010

Kab 2005

Valenti 2011

Trépo 2011

Fabris 2011

MICA region

DEPDC5

UBE4B-KIF1B-PGD region

TPTE2 region

DDX18 region

GFRA1

CRHR2

SCYB14

PNPLA3

IL-28B C/T

rs2596542

rs1012068

rs17401966

rs2880301

rs2551677

hCV1250702

rs2267716

rs2237062

rs738409

rs12979860

HCV

HCV

HBV

HBV/HCV

HBV/HCV

HCV

HCV

HCV

HCV

Alcohol

HCV

Asian

Asian

Asian

Asian

Asian

Asian

Asian

Asian

Caucasian

Caucasian

Caucasian

GWAS studies: SNPs associated with the risk of HCC

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• Methodological limitations of previous studies:

• Selection of inadequate control populations.

• Inclusion of heterogeneous cohorts of HCC (etiology, cirrhosis).

• Most studies conducted in Asian populations or HBV-related HCC.

• GWAS studies:

– Conflicting results and poorly replicated.

– Relevant factors as the presence of cirrhosis not controlled.

• Reported associations of SNPs may be linked to inflammation or

fibrosis progression and not specifically with HCC development.

• No available data in HIV-infected patients.

SNPs and risk for HCC in cirrhosisSummary

HCC in HIV-infected patients:

a predictable consequence of age

and the effect of ART on survival

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HCC in HIV-infected patients:

an emerging problem.

• France: HCC-related mortality has increased from 16% of liver-related

deaths in 2000 to 42% in 20101,2.

• US:

• The prevalence of HCC in the Veteran Affairs healthcare system has

increased from 0.07% to 1.6% between 1996-20093.

• Increasing incidence of HCC in HIV population, with an excess risk 4

times higher than general population4.

• Spain: The incidence of HCC has increased from 0.2 to 2.8 cases per

1000 person-years from 2000 to 20095.

1Salmon-Ceron D. J Hepatol 2009. 2 Cacoub P. 47th EASL Conference 2012. 3 Ioannou GN. Hepatology 2013. 4Sahasrabuddhe VV. Cancer 2012. 5Merchante. Clin Infect Dis 2013.

• N= 82 HCC cases in HIV patients from 1999 to 2010 in 18 hospitals in Spain.

• The incidence of HCC increased by a factor of 14 from 2000 to 2009

in HIV/HCV-coinfected patients.

Merchante N.

Clin Infect Dis 2013;56:143-50.

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Frequency of HCC in HIV-infected patients

in Spain: have we reached the plateau?.N=189 HCC cases in HIV-infected patients from 28 centers in Spain

2 1 14 5

8 9

13

20

24

36

22 2321

0

5

10

15

20

25

30

35

40

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012

Merchante N. Unpublished data.

Number of HCC cases diagnosed by calendar year

Epidemiology of HCC in HIV-infected patients

in Spain: data from the GEHEP cohort.N=189 HCC cases in HIV-infected patients from 28 centers in Spain

Characteristics Value

Age, median (Q1-Q3) 47 (45-51)

Male sex, n (%) 164 (87)

Etiology, n (%)

HCV

HBV

HBV/HCV

Alcohol

149 (79)

20 (11)

18 (9)

2 (1)

HCV genotype, n (%)1

1

2

3

4

61 (49)

1 (1)

45 (36)

17 (14)

Merchante N.18th SEIMC Conference. Valencia, Spain. April 2014.

1Available in 124 out of 167

HCV-infected patients.

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• Still controversial:

• Some investigations have suggested that HIV shortens the time

from HCV infection to the development of HCC1-3.

• Other retrospective studies have not demonstrated that HIV

increases the risk of HCC4-5.

• Prospective studies assessing the incidence of HCC in individuals

with HCV-related cirrhosis with or without HIV are needed.

1Garcia-Samaniego J Am J Gastr 2001. 2Davila JA. Gastroenterology 2004. 3 Puoti M. AIDS 2004. 4 Kramer JR. Am J Gastr 2005. 5 Garcia-Garcia JA. AIDS Res Hum Retroviruses 2006.

HCC in HIV/HCV coinfected patients:

a higher incidence

than in HCV-monoinfected population?

Risk of HCC in HIV/HCV coinfected patients with cirrhosis:The effect of early diagnosis of cirrhosis by transient elastography

Merchante N.

Unpublished data.

• N=392 HIV/HCV-coinfected patients with compensated liver cirrhosis (LS ≥ 14 kPa).

• Median (Q1-Q3) follow-up: 42 (25-57) months.

• 12 (3%) HCC cases during follow-up.

1 2 2 3 48

0

20

40

60

80

100

1 year 2 years 3 years 4 years 5 years 6 years

%

Probability of developing HCC during follow-up

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Merchante N.

Hepatology 2012.

• N=239 HIV/HCV-coinfected patients with compensated liver cirrhosis (LS ≥ 14 kPa).

• Median (Q1-Q3) follow-up: 20.7 (9.5-34.5) months.

• Liver decompensations (LD): 31 (13%; 95% CI: 9%-17%).

Probability of LD and/or HCC at 1-year:

• LS < 40 kPa: 3%.

• LS ≥ 40 kPa: 20%.

Accuracy to predict a LD and/orHCC of LS < 40 kPa:

NPV: 92%; PPV 30%

Gelu-Simeon M.

AIDS 2014;28:1379-91.

Mechanisms involved in hepatocarcinogenesis

in HIV/HBV or HCV-coinfected patients

Metabolic syndrome

Immunodeficiency Dysbiosis

HIV proteins

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CDE Diet CDE Diet + MVCControl DietControl Diet

Plos One 2013;8 (1):e53992.

No. Cases

HIV+ HIV-

% HCC

Therapy

(curative)

HCC stage

in HIV

(vs non HIV)

2-year survival %

(HIV vs non-HIV)

Independent

association of

HIV with

poor survival

Puoti1 41 384 40% More

advanced

11% vs 41%

2-year survival in

HIV cases that

received therapy

for HCC: 41%

YES

Bräu2 63 226 48% (29%) Similar 16% vs 18% NO

Berreta3 104 484 85% (45%) Less

advanced

67% vs 72%

Similar survival

in HIV vs non HIV

treated pts.

YES

Lim4 23 450 87% (43%) Less

advanced

3-year survival

44% vs 48%

NO

HCC in HIV: worse clinical outcome?Case-control studies comparing survival of HCC in HIV vs non-HIV

1Puoti M. AIDS 2004.2Bräu N. J Hepatol 2007. 3Berreta M. Oncologist 2011. 4Lim C. J Acquir Immune Defic Syndr 2012.

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Outline


• Surveillance.


Surveillance

• Surveillance seems to improve survival in uncontrolled studies:

– Lead time and length time bias.

• One randomised controlled trial of surveillance in China1.

– 18816 HBV patients. Twice-yearly US plus AFP vs no surveillance.

– Despite suboptimum adherence to surveillance (< 60%); better survival in

screened patients (66% vs 31% at 1 year, 53% vs 7% at 3 years, 46% vs 0% at

5 years).

• A validation trial in developed regions is not feasible2:

– US is part of routine assessment of patients with CLD.

– Perceived benefit from surveillance would impair recruitment of patients.

1Zhang BH. J Cancer Res Clin Oncol 2004. 2Poustchi H. Hepatology 2011.

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Kansagara D. Ann Intern Med 2014; 161: 261-9.

Cochrane Database of Systematic Reviews 2012.

Surveillance: Systematic Reviews.

EVIDENCE BASED MEDICINE CONVERSATION

Surveillance:

Should be wait for strength evidence? .

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Surveillance

• Ultrasonography is the preferred imaging method for surveillance:

– Well tolerated and widely available.

– 60-80% sensitivity and > 90% specificity.

– Screening every 6 months is recommended.

– 3-monthly US increases detection of small nodules but has no effect on

survival1 and twice yearly screening has better results than annual2.

• AFP should not be used as a surveillance test.

– Very low sensitivity and low specificity.

– Combined use of AFP and US does not increase detection rates and raises

false-positive suspicions and cost.

– 56% of HCC cases diagnosed in HIV patients had normal AFP at diagnosis3.

1Trinchet. Hepatology 2011; 54: 1987-97. 2Santi V. J Hepatol 2010; 53: 291-7. 3Merchante N. Clin Infect Dis 2013; 56: 143-50.

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SurveillanceCurrent recommendations for surveillance of HCC

in HIV-infected patients in Spain

• Surveillance is recommended in HIV infected patients with:

– Liver cirrhosis, regardless of etiology (A1).

– HBV chronic infection and an additional risk factor for HCC (A3):

• Asian men > 40 years and asian women > 50 years.

• African.

• Family history of HCC.

• Surveillance will consist in the performance of an US every 6 months (A2).

Practical guideline for non-AIDS neoplasms and HIV infection. Panel of experts from GESIDA. January 2014 Update.

Surveillance impacts on survival

in HIV-infected patients with HCC. GEHEP Cohort.

Patients

Screening 92 66 46 37 32 25 24 19 13

No screening 85 24 15 10 9 5 4 4 2

Screening

No screening

Merchante N.18th SEIMC Conference.

Valencia, Spain. April 2014.

• 189 HIV patients with HCC from 28 hospitals in Spain.

• No screening was an independent predictor of mortality:

AHR 2.2 (95% CI 1.4-3.4).

[Multivariate model adjusted by age, sex, CD4, HIV RNA, AFP,

Child-Pugh stage and BCLC stage].

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Outline


• Surveillance.


Barcelona-Clinic Liver Cancer (BCLC)

staging and treatment strategy

Forner A. Lancet 2012.

Stage

0 (Very early)

A (early)

B (intermediate)

C (advanced)

D (end stage)

ECOG PerformanceStatus

0 0 0 1-2 3-4

Liver Function

Child-PughA

Child-PughA-B

Child-PughA-B

Child-PughA-B

Child-PughC

Tumor stage Single < 2 cm

Single or 3 nodules <

3cm

Large multinodular

Vascularinvasion or

extrahepaticspread

Any

Recommended therapy

Curative therapies (ablation, resection, LT)

TACE Sorafenib Supportive care

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LT in HIV-infected patients

Stock PG. Hepatology 2014.

71-81%

HCV

control

group

Setting and period Patients Main findings

Vibert E.

Hepatology

2011.

Single center

France

2003-2008

N= 16 HIV+ / 58 HIV-

Only LT due to HCC

3-year survival:

74% vs 85% (p=0.08).

Higher dropout rate in HIV

Di Benedetto F.

Oncologist

2013.

3 centers

Italy

2004-2009

N= 30 HIV + / 125 HIV –

Only LT due to HCC

3-year survival:

65% vs 70% (p= NS)

Platt HL.

AASLD

2014

38 Centers

Canada, USA, Brazil,

Argentina, Germany,

Spain, UK, Australia

1992-2014

N=29 HIV+

Only LT due to HCC

5-year survival:

85%.

LT for HCC in HIV-infected patients

LT for HCC in HIV/HCV-coinfected patients has similar survival rates

than in HCV-monoinfected patients.

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Sorafenib in HIV-infected patients

Berreta M. Anticancer Drugs 2013.

• Efficacy:

• Response: PR 3 (11%); SD 12 (44%); PD 12 (44%)1. Median TTP2: 5 months.

• Median survival after sorafenib initiation: 12.8 months (5.6 for BCLC C-D).

• Safety:

• Adverse effects:

• Diarrhea 44% (grade 3-4: 15%); Hand-and-foot skin reaction 26% (grade 3-4:

15%); Hypertension 15% (grade 3-4: 11%).

• One patient prematurely stopped sorafenib due to hypophosphatemia.

1PR: Partial response; SD: Stable disease; PD: Progressive disease; 2TTP: Time to progression.

n= 27 HIV+ with unresectable HCC treated with sorafenib (2007-2010).

BCLC stage at diagnosis: A 7%, B 67%, C 19%, D 7%.

Merchante N. EASL 2011. Abstract 1341.

BCLC

Stage A

n=53

BCLC

Stage B

n=34

BCLC

Stage C

n=63

BCLC

Stage D

n=28

BCLC Recommended HCC Therapy (Rx) Curative Rx TACE Sorafenib No Rx

(Palliative)

Patient Received Recommended or

More Effective HCC Rx, total, n (%)

More Effective Rx

Recommended Rx

32 (60%)

--

32 (60%)

21 (62%)

8 (24%)

13 (38%)

28 (44%)

23 (36%)

5 (8%)

Patient Received Less Effective

or no HCC Rx, total, n (%)

Less Effective Rx

No Rx

21 (40%)

13 (25%)

8 (15%)

13 (38%)

2 (6%)

11 (32%)

35 (55%)

--

35 (55%)

HIV-infected patients frequently received no therapy or

less effective HCC therapy as indicated by BCLC stage

Liver Cancer in HIV Study GroupLiver Cancer in HIV Study Group

12/12/2014

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Merchante N.

Clin Infect Dis 2013;56:143-50.

Potential curative therapies improve survival in HIV-infected patients

The real clinical picture of HCC in HIV-infected

patients in Spain: data from the GEHEP cohort.N=189 HCC cases in HIV-infected patients from 28 centers in Spain

Characteristics at diagnosis, treatment and prognosis Value

HCC diagnosis made by screening, n (%) 97 (51)

Multilocular, n (%) 91 (48)

Vascular invasion, n (%) 48 (25)

Extrahepatic metastases, n (%) 23 (12)

BCLC stage, n (%)

A

B

C

D

56 (32)

28 (16)

68 (39)

22 (13)

Treatment, n (%)

Curative

Non curative

No therapy

49 (26)

63 (33)

77 (41)

Merchante N.

18th SEIMC Conference. 2014.

Overall mortality: 68%.

Median (Q1-Q3) survival time: 6 (2-20) months.

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BCLC A.

Median survival 52 mo.

BCLC B


BCLC C


BCLC D


Merchante N.

18th SEIMC Conference. 2014.

BCLC stage predicts survival of HIV-infected

patients with HCC. GEHEP Cohort.

189 HIV patients with HCC from 28 hospitals in Spain.

Overall median (Q1-Q3) survival time: 6 (2-20) months.

HIV RNA and clinical outcome of HCC in HIVHIV viral load independently predicts survival

in HIV-infected patients with HCC

Citti C. AASLD 2014.

• N=347 HIV patients with HCC

• HIV RNA was an independent

predictor of mortality in a

multivariate model adjusted by

BCLC, screening, alcohol, Child-

Pugh score, platelet count and CD4.


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Predicting Survival of HIV-Infected patients

with Liver Cancer: the SHILCA score.

Merchante N. CROI 2014

Merchante N. EASL 2014

Chen TY, Merchante N. AASLD 2014

SHILCA score=

Log10 HIV RNA * 0.221

+ Age (10yr) * 0.441

+ Size largest lesion (cm) * 0.086

+ 0.774 (if extrahepatic metastases)

– Albumin (g/dL) * 0.424

+ log10 AFP (ng/mL) * 0.243

+ Performance Status (per unit) * 0.439

Derivation cohort: 256 HIV patients

from Canada, USA, Brazil, Argentina,

UK and Germany.

Validation cohort: 174 HIV patients

from Spain and New York City.


Waiting is not an option !

Prevention

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SVR is associated with a lower risk of ESLD, HCC

or death in HIV/HCV-coinfected patients

Limketkai BN.

JAMA 2012.

Cumulative survival free of ESLD, HCC or death

according to response to HCV treatment from baseline

…but waiting for F4 to achieve SVR

is too late to prevent HCC

• 166 HIV/HCV-coinfected patients with compensated cirrhosis who started peg-IFN + RBV.

• 43 (25%) achieved SVR. Median follow-up: 55 months

• SVR was associated with a lower risk of liver decompensation and overall mortality.

Mira JA. Clin Infect Dis 2013.

Liver decompensation Death from any cause

SVR

No SVR

p=0.002 p=0.02

SVR

No SVR

Density of incidence of HCC:

• SVR: 0.5 cases per 100 person-years (95% CI 0.1-2.9)

• Non SVR: 0.8 cases per 100 person-years (95% CI 0.2-2.2)

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Merchante N.

AIDS 2014;28:41-7.

HIV/HCV-coinfected patients who achieved SVR

are still at risk of developing HCC

• n=167 HCC cases in HIV/HCV-coinfected patients in 26 hospitals in Spain.

• 13 (7.8%) cases were diagnosed in patients with previous SVR.

– Median (Q1-Q3) elapsed time from SVR to HCC diagnosis: 28 (20-39) months.

– Aggressive clinical course:

• US without nodules in the previous 6 months in 6 cases.

• Advanced stage (BCLC B-D) at diagnosis in most cases

• Median (Q1-Q3) survival: 3 (1-39) months.

• Genotype 3 more common than in non-SVR cases (83% vs 32%; p=0.001).

Surveillance of HCC with US should be maintained in HIV/HCV-coinfected

patients with cirrhosis who achieve SVR with anti-HCV therapy.

Concluding remarks

• The incidence of HCC has increased in the last decade in HIV-

infected patients, mainly driven by HCV-related cirrhosis.

• The clinical management of ESLD and HCC still needs to improve:

– Poor adherence to HCC surveillance with periodic US in cirrhotics.

– Late diagnosis of HCC in a high proportion of patients.

– Low rates of potential curative therapies and dramatically low survival.

• The erradication of HCV with antiviral therapy is the best approach

to prevent HCC, but:

– Starting therapy with F3/F4 fibrosis is too late to fully prevent HCC.

– HCC surveillance should be maintained in patients with cirrhosis in spite of

the consecution of SVR.

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• GEHEP COHORT (SPAIN):– HEPAVIR: Francisco Téllez (Hospital de La Línea, Cádiz), Antonio Rivero Juárez, Antonio Rivero

Román, Ángela Camacho (Hospital Reina Sofía, Córdoba), María José Ríos Villegas (HospitalVirgen Macarena, Sevilla), Alberto Romero (Hospital de Puerto Real, Cádiz), Marcial Delgado(Hospital Carlos Haya, Málaga), Manuel Márquez Solero (Hospital Virgen de la Victoria,Málaga), Mohamed Omar (Complejo Hospitalario de Jaén), Miguel Angel López Ruz (HospitalVirgen de las Nieves, Granada), Dolores Merino (Complejo Hospitalario de Huelva).

– SEICV: Esperanza Merino (Hospital General Universitario de Alicante), Francisco Jover(Hospital Clínico Universitario de San Juan de Alicante), Maria José Galindo (Hospital Clínicode Valencia), José López Aldeguer (Hospital Universitario y Politécnico La Fe, Valencia),Enrique Ortega (Hospital General de Valencia), Carlos Mínguez (Hospital General deCastellón), Sergio Padilla (Hospital General de Elche), Concepción Amador (Hospital MarinaBaixa, Villajoyosa), Joan Gregori (Hospital de Orihuela),

– SEINORTE: Francisco Rodríguez-Arrondo (Hospital Universitario de Donostia), Josefa Muñoz(Hospital de Basurto), Koldo Aguirrebengoa (Hospital de Cruces, Bilbao), Eduardo Martínez(Hospital de Galdakao), Joseba Portu (Hospital de Txagorritxu, Vitoria), Luis Metola (Hospitalde San Pedro, Logroño), Rafael Silvariño (Hospital de San Eloy, Baracaldo).

– Cristina Tural, Boris Revollo (Hospital German Trias i Pujol, Badalona), Maria RemediosAlemán Valls, María Jehovana Hernández, Juan Luis Gómez Sirvent (Hospital Universitario deCanarias, Santa Cruz de Tenerife).

• Liver Cancer in HIV Study Group. Chairman: Norbert Bräu. VA Medical Center Bronx, NY, USA.

Acknowledgments

Grupo de Investigación de la

Unidad Clínica de Enfermedades Infecciosas

Hospital Universitario de Valme, Sevilla, ESPAÑA.

• Group Coordinator: Juan A. Pineda.

• Clinic: Juan Macías, Nicolás Merchante, José A. Mira, Celia Cifuentes.

• Pharmacy: Karin Neukam, Eva Recio, Patricia Monje.

• Laboratory: Luis M. Real, María Mancebo, Rocío Núñez, Elisabet Pérez

Navarro, Manuel Parra.

Acknowledgments

12/12/2014

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