Chronic infections Metabolic syndrom HBV: 350-400 Millions...

Cirrhosis

Hepatocellular carcinoma: HCC

HBV HCV

12°

1.5-5%/year

25% /5 year

Chronic infections

HBV: 350-400 Millions

HCV: 170-200 Millions

25-30 years

10-30%

Metabolic syndrom

(Overweight,diabetes)

Non Alcoholic

Steato Hepatitis

(NASH)

Chemical

carcinogens

Iron overload

Inflammation

Fibrosis

Intestinal Microbiota

HIV

Hepatocellular Carcinoma

Epidemiology data: China

2

1 Globocan 2008 (IARC) - 05/04/2011

Number of new liver cancers in

2020 1

All ages – both sexes

China

HCC prevalence is particularly high in China

and it has constantly increased over the recent years.

HCC is the 2nd

-3rd

cause of cancer death in China.

General population

70 Millions HBV

6 Millions HCV

Cirrhotic liver HCC

90% HCCs develop on cirrhotic livers

(60% in Africa)

H C C HBV HCV

CHRONIC INFLAMMATION

FIBROSIS

(IMMUNE RESPONSE

CYTOKINES)

Cirrhosis

HCV:

HCV core, E2, NS3

NS5A

Low chromosomal instability

HBV

HBx, PreS/S

HBSP

HBV DNA integration

Chromosomal instability: P53, Axin 1

LOH: 1p, 4q, 6q, 9p, 13q, 16p, 16q

Selection of HCV and HBV genome quasi-species in tumor cells

Exome sequencing in HCC

Sequencing the whole coding

region of the genome (20,000

genes)

Mean of 40 damaging somatic mutations / tumor Range: 5 to 121 /tumor

Guichard et al, Nature Genetics, 2012

Tumor Non-tumor

Each tumor result from a unique combination of mutations

IRF2 7%

P53 42%

CDKN2A

CTNNB1 42%

AXIN 1 APC

NFE2L2 10%

HBV HCC Non-HBV HCC

Major Signaling Pathways

P53 &

Cell cycle WNT/β-Catenin Oxydative

Stress

Amadeo et al, Gut 2014

Patient management

Therapeutic options

7

1 Bruix Lancet Oncology 2009; Hepatology 2010; Ferlay

Int J Cancer 2010

2 Artinyan A. Cancer 2010;116:1367-77

Intervention Curative

therapy HCC staging

Liver

transplantation Early (10%)

Resection Early (25-40%)

TACE*

RFA*

PEI*

Intermediate

Sorafenib Advanced

Palliative

therapy Advanced

HCC survival by intervention HCC current therapeutic options

Cu

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lati

ve s

urv

ival

0,2

0,4

0,6

0,8

1,0

*Trans-arterial chemoembolization

Radiofrequency ablation

Percutaneous ethanol injections

MicroRNAs as serum biomarkers: separation of serum samples from HBV, HCV and control

groups by 13 miRNAs.

Li L et al. Cancer Res 2010;70:9798-9807

© 2010 by American Association for Cancer Research

Training

set

Validation

set

Control HCV HBV

Direct and indirect effects of HBV chronic

infection

Integration of HBV DNA

Into host chromosomes :

Insertional mutagenesis

of cellular genes

Genetic

instability

Prolonged expression of viral genes

HBx, COOH-terminally deleted HBx

PreS1/PreS2/S: LHBs

Modulation of liver cell proliferation and

viability

Host immune

response

Inflammation

oxydative

stress

HBV DNA integration sites

• Frequent insertion in cellular genes: 73/93 HCC tested

• Recurrent integration sites:

- hTERT

- Calcium signalling related genes

- Mixed lineage leukemia genes: MLL2 and MLL4

- 60s ribosomal protein-like encoding genes

• Evidence for alterations in the target cellular gene

expression

Brechot Seminars in Cancer Biology 2001;

Paterlini-Brechot Oncogene 2003,

Saigo Human Mutation 2008; Murakami Gut 2005;

Tamori Clin Cancer Res 2005

TERT promoter mutations in HCC

305 hepatocellular carcinomas

179 HCC with somatic mutation of the TERT promoter (59%)

TERT promoter mutation is the most frequent somatic genetic alteration in HCC

TERT-encoding gene is a frequent insertion site for HBV DNA

Nault et al. Nature Communications,

2013

Brechot Seminars in Cancer Biology 2001;

Paterlini-Brechot Oncogene 2003,

Saigo Human Mutation 2008; Murakami Gut 2005;

Tamori Clin Cancer Res 2005

Male HBV HCV

Alcohol NASH

25 % 65 %

Preneoplastic lesions

Regenerative Dysplastic

HCC

CTNNB1 ARID1A ARID2

RPS6KA3 TP53

AXIN1 Others

Somatic mutations….

Risk factors

Cirrhotic macronodules

Malignant tumor

TERT promoter

mutations

TERT promoter mutation is the most frequent somatic genetic alteration in HCC

Cirrhosis

0 %

Telomere shortening Absence of telomerase activity

Telomerase reactivation

Nault et al. Nature Communications, 2013

HBV Genetic Variability : Impact on chronic

hepatitis severity and liver carcinogenesis?

HBV Genotypes

A: Africa

B: Asia

C: Asia

D: Mediteranean area

E: Middle Africa

F: South America

HBV genome mutations

PreS

EnhII

Basal Core promoter

(BCP)

PreCore

X

- Genotype C

- Mutations in core promoter

and PreS/S sequences

Associated

with severity: cirrhosis, HCC

Pronostic biomarkers?

Chien-Jen

Jama 2006;

295: 65-73

RELATIONSHIP BETWEEN HBV DNA LEVEL AND HCC

High level

HBV viremia

is a risk factor

For HCC

Available HBV Therapies

• Pegylated IFN-a

• Nucleoside/nucleotide analogues

• Lamivudine

• Adefovir

• Telbivudine

• Entecavir

• Tenofovir

• Tenofovir/emtricitabine

Cumulative Incidence of HBV

Resistance

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

24%

38%

49%

67% 70%

0%

3%

11%

18%

29%

0.5% 1.2%

1.2% 1.2%

4%

17%

0%

LAM ADV ETV LdT TDF

0.2% 0%

Year 1

Year 2

Year 3

Year 4

Year 5

0% 0% 0% 0% 0%

(EASL CPGs: Management of chronic hepatitis B; J Hepatol 2012;57:167-85)

3 Years Results of Entecavir

Therapy (HBeAg+ and -)

(Zoutendijk et al., Lancet 2011;54:443-51)

Cumulated

probability to

achieve virological

response

(HBV DNA <80 IU/mL)

Long-Term Histology Results on

Entecavir (HBeAg+ and -)

(Chang et al., Hepatology 2010;52:886-93)

Knodell necroinflammatory score Ishak fibrosis score

*Median follow-up: 6 years (range: 3-7 years)

HCC Incidence on ETV Therapy vs

Historical LAM and Control

(Hosaka et al., Hepatology 2013;58:98-107)

Non-cirrhotics Cirrhotics

HBV cure ?

5 Years Results of Tenofovir

Therapy (HBeAg+ and -)

HBeAg+ (n=266) HBeAg- (n=375)

Normalized ALT 73% 85%

HBV DNA <69 IU/mL (ITT) 65% 83%

HBV DNA <69 IU/mL (on Rx) 97% 99%

HBeAg loss 49% -

HBe seroconversion 40% -

HBsAg loss 10% -

HBs seroconversion 8% -

(Marcellin et al., Lancet 2013;381:468-75)

HCC Incidence in Genotype D HBV

Patients on >18 Mths NUCs

• HCC incidence: • Non-cirrhotics: 0.36 per 100 person/years

• Cirrhotics: 4.80 per 100 person/years

• Independant predictors of HCC • Cirrhosis (13-fold increased risk)

• Age >60 years (5-fold increased risk)

• Lack of virological response/resistance (NS)

(Pellicelli , et al., AASLD 2012)

HBV and liver cancer:

HBV Persistence HBsAg negative, HBV DNA positive

infections

- Risk factor for HCC developpment?

- Technological issues: sensitivity, specificity

etc..

- Real impact on liver disease severity?

HepadnaViruses as a risk factor for

HCC in seronegative individuals

Frequent liver tumors in woodchucks with resolved

WHV infection :

• 100% of chronic WHV carrier woodchucks develop

HCC

• No HCC was seen in normal, uninfected woodchucks

• 17% of WHsAg negative, serologically recovered

woodchucks develop HCC

From B. C. Tennant, Woodchuck hepadnaviruses, in Viral Hepatitis,1998

Chronic WHV carriers

N = 50

Resolved WHV infections

N = 21

Normal control animals

N = 56

HBV DNA +

vs

HBV DNA –

8.25 fold increased

Risk of HCC

Ikeda J Viral Hepatitis 2009; 16: 437

Risk of HCC in HBsAg negative, HBV DNA positive

patients Prospective studies

HBV treatments: Yes

HBV cure ?No

Therapeutic vaccines?

Drugs targeting HBV cccDNA ?

Hepatitis C virus infection: a systemic disease with the possibility to cure

• Why to treat? - Hepatic manifestations

- Extra-hepatic manifestations

- Cryoglobulinemic vasculitis

or lymphoma

But also general manifestations

related to

- “Lymphocytic activation”

associated with chronic infection

23 820 adults, Taiwan

1095 anti-HCV positive; 69.4% with detectable HCV RNA

0 2 4 6 8 10 12 14 16 18 20

12

10

8

6

4

2

0

Persisting detectable HCV RNA is a

risk factor for liver-related mortality

The REVEAL HCV Cohort Study Follow-up (years)

Cu

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ort

alit

y (%

)

Liver cancer

p<0.001 for comparison among three groups p<0.001 for HCV RNA detectable vs undetectable

10.4%

1.6%

0.3%

Lee M-H et al, J Infect Dis 2012;206:469–477

HCV seropositive, HCV RNA detectable

HCV seropositive, HCV RNA undetectable

HCV seronegative

20

18

16

14

12

10

8

6

4

2

0 0 2 4 6 8 10 12 14 16 18 20

Follow-up (years)

Cu

mu

lati

ve m

ort

alit

y (%

)

Hepatic diseases

12.8%

1.6% 0.7%


Chronic HCV increases morbi-

mortality from non-hepatic

diseases

20

18

16

14

12

10

8

6

4

2

0 0 2 4 6 8 10 12 14 16 18 20

Follow-up (years)

Cu

mu

lati

ve m

ort

alit

y (%

)

Extrahepatic diseases



HCV seronegative

19.8%

12.2%

11.0%

p<0.001 for comparison among three groups p=0.002 for HCV RNA detectable vs undetectable

Significant association between HCV and:

- diabetes (OR = 1.8)

- cardio-vascular morbidity (OR=2.37)

- cerebro-vascular mortality (OR= 2.7)

- renal disease (HR for ESRD

< 59 y= 7.8 vs. 3.2)

- extra-hepatic (breast: OR=2) cancers

White D et al. J Hepatol 2008;49:831–844

Su F-H et al. BMC Cancer 2011;11:495

Su F-H et al. Am J Kidney Dis 2012;60:553−560

Kakinami L et al. Int J Clin Pract 2013;67:6–13

Lee M-H et al. Stroke 2010;41:2894–2900


Sustained virologic response (SVR)

is the objective of therapy

• SVR= virologic cure

• Most of HCV-related manifestations are

mainly reversible

Cirrhosis reversal

Glomeluronephritis

reversal Diabetes improvement

Lymphoma

remission

HCV cure decreases mortality from both

hepatic and non-hepatic diseases

20

18

16

14

12

10

8

6

4

2

0

20

18

16

14

12

10

8

6

4

2

0 0 2 4 6 8 10 12 14 16 18 20 0 2 4 6 8 10 12 14 16 18 20

Follow-up (years) Follow-up (years)

Cu

mu

lati

ve m

ort

alit

y (%

)

Cu

mu

lati

ve m

ort

alit

y (%

)

Hepatic diseases Extrahepatic diseases



HCV seronegative

12.8%

1.6% 0.7%

19.8%

12.2%

11.0%






The REVEAL HCV Cohort Study

HCV cure decreases mortality from

both hepatic and non-hepatic diseases

20

18

16

14

12

10

8

6

4

2

0

20

18

16

14

12

10

8

6

4

2

0 0 2 4 6 8 10 12 14 16 18 20 0 2 4 6 8 10 12 14 16 18 20

Follow-up (years) Follow-up (years)

Cu

mu

lati

ve m

ort

alit

y (%

)

Cu

mu

lati

ve m

ort

alit

y (%

)

Hepatic diseases Extrahepatic diseases



HCV seronegative

12.8%

1.6% 0.7%

19.8%

12.2%

11.0%






The REVEAL HCV Cohort Study

Such a benefit (SVR-related reversal of hepatic and

extra-hepatic disease) has to be offered in theory to

any HCV-infected patient

Sulkowski MS and al. JAMA 2002

HR 1.03 (0.86-1.23) HR 1.05 (0.85-1.30) HR 1.28 (0.98-1.68)

No modification related to HCV

HIV/HCV Co-infection

No HAART HAART

Meta-analysis of 26 studies

Deng L, et al. World J Gastroenterol2009;15:996–1003 HAART: highly active antiretroviral therapy

100 10 1 0.1 0.01 10 1 0.1 0.01 100

Allory, 2000

Bierhoff, 1997

Di Martino, 2001

Eyster, 1993

Grabczewska, 2005

Lesens, 1999

Makris, 1996

Pol, 1998a

Pol, 1998b

Romeo, 2000

Serfaty, 2001

Soto, 1997

Telfer, 1994

Fixed effects

Random effects

Benhamou, 1999

Brau, 2006

Gaslightwala&Bini, 2006

Gonzalez, 2006

Macias, 2005

Marine-Barjoan, 2004

Martinez-Sierra, 2003

Mohsen, 2003

Monto, 2005

Rodriguez-Torrez, 2006

Sarmento-Castro, 2007

Valle Tovo, 2007

Verma, 2006

Fixed effects

Random effects

Risk ratio (95% CI) Risk ratio (95% CI)

HCV mono-infection

HIV/HCV co-infection

HCV mono-infection

HIV/HCV co-infection

HIV/HCV Co-infection: harmfull

impact of HIV

ARV liver toxicity

Soriano V et al. AIDS 2008

ddI d4T

AZT

3TC FTC

ABV TDF

EFV

NVP

SQV

ATV LPV

APV DRV

TPV

RTV

T20

NRTI NNRTI PI Newer ARVs

RAL

MRV

ETV

High risk Low risk

From: HIV, Age, and the Severity of Hepatitis C Virus–Related Liver Disease: A Cohort Study

Ann Intern Med. 2013;():. doi:10.7326/0003-4819-158-9-201305070-00604

Liver fibrosis and age among persons coinfected with HIV and HCV and those with only HCV.

For each age, predicted liver fibrosis scores were calculated using a regression equation that included the race, sex, alcohol use, body mass index, hepatitis B virus surface antigen level status, and HCV RNA level values for a representative participant (black overweight male who has no regular alcohol use, is hepatitis B virus surface antigen–negative, and has high HCV viral load) for persons coinfected with HIV and HCV (dashed line) and for persons with only HCV (solid line). For example, a 40-year-old HIV and HCV coinfected person with these characteristics was calculated to have a predicted FibroScan score of 9.04 kPa. For this same degree of fibrosis, the predicted age in a similar person but with only HCV was 49.2 years. Over the entire age range, the average difference in estimated age between persons coinfected with HIV and HCV and those with only HCV was 9.2 years (90% coverage limit, 5.2 to 14.3 years). HCV = hepatitis C virus.

Figure Legend:

HIV/HCV Co-infection: harmfull

impact of HIV

Mortality of 69.913 french PLWHIV (2008-2012)

Adjusted on age, gender, alcohol, decompensated cirrhosis, AIDS

Mallet V et al. CROI 2014

HCV infection is a severe disease

in PLWHIV

HIV

HBV/HIV

HCV/HIV

Hepatitis C therapy in 2014

HCV Cure

Four pivotal Peg-IFN/RBV studies in HIV/HCV co-infected patients Characteristic APRICOT1 ACTG 50712 RIBAVIC3 Barcelona4

Number enrolled 868 133 412 95

Peg-IFN 2a 2a 2b 2b

RBV 800 mg 600 mg up to 1 g 800 mg 800 mg up to 1.2 g

HIV and CD4 status

>200 cells/mm3 or 100–200

cells/mm3 if HIV-RNA <5000 copies/mL

>100 cells/mm3 + HIV-RNA <10,000

copies/mL or >300 cells/mm3,

tx naïve + not starting ART during trial

>200 cells/mm3

>250 cells/mm3 and HIV-RNA <10,000

copies/mL

ALT “elevated” NA NA >1.5x ULN

Genotype 1, % 60–61 77–78 48 49

Bridging fibrosis or cirrhosis, %

15–16 9–11 (cirrhosis) 39 30

Genotype 1 Peg-IFN/RBV SVR rate, n/N (%)

51/176 (29) 7/51 (14) 21/123 (17)* 22/59 (38)*

1.Torriani FJ, et al. N Engl J Med 2004;351:438–50; 2. Chung RT, et al. N Engl J Med 2004;351:451–9; 3. Carrat F, et al. JAMA 2004;292:2839–484

4. LagunoM, et al. AIDS 2004;18:F27–36

*Genotype 1 or 4 ART: ARV therapy; Peg-IFN: peginterferon; RBV: ribavirin SVR: sustained virologic response; tx: treatment; ULN: upper limit of normal

E1 C E2 p7 NS2 NS3 NS4A NS4B NS5A NS5B

Viral targets Host targets

Understanding of HCV life cycle

revealed several potential

innovative drug targets

*

*On clinical hold, Idenix press release; **On clinical hold, Novartis press release

NS3 NS5A NS5B Cyclophilin A The NS3/4A serine protease is

essential for post-translational

processing of HCV

polyproteins1

Multifunctional membrane-associated phosphoprotein essential component of the HCV-RNA replication complex2,3

NS5B is an HCV-specific, RNA-

dependent RNA polymerase1

Host protein involved in HCV

replication through interaction

with NS5A and the HCV

polymerase4

Boceprevir

Telaprevir

ABT-450/r, ACH-1625

Asunaprevir, Simeprevir, BI-

201335

Danoprevir/r, GS-9451

MK-5172

Daclatasvir

GS-5885

ABT-267

PPI-668

Nucleos(t)ide analogue

Sofosbuvir, Mericitabine,

IDX-184*

Non-nucleoside analogue

BI-207127, ABT-333

ABT-072, BMS-791325

Tegobuvir, Setrobuvir

VX-222, Filibuvir

Alisporivir**

SCY-635

Adapted from 1. Pawlotsky JM, et al. Gastroenterology 2007;132:1979–98; 2. Tellinghuisen TL, et al. Nature 2005;435:374–9; 3. Gish R & Meanwell NA. Clin Liver Dis. 2011;15:627–39; 4. Coelmont L, et al. PLoS One 2010;5:e13678.

« 2011 » DAAs

2011-2014

Combination PEG-IFN – RBV Treatments with IFN

Treatment of chronic hepatitis C

SVR in GT1 45% 60-75%

EASL guidelines 2011

2011 DAAs

2011-2013

Combination PEG-IFN – RBV Treatments with IFN

Treatment of chronic hepatitis C

SVR in GT1 45% 75% 75-95%

Sofosbuvir 1Q14 Simeprevir 2Q14 Daclatasvir 3Q14

New DAAs

Combination PEG-IFN – RBV

- Better efficacy (pan-genotypic)

- Better tolerability - Reduction of duration - Easier dosing schedule - Reduced pill burden

Summary of sofosbuvir/ledipasvir + RBV studies

1 Mangia A et al., EASL 2014, Abs. O164;;2Afdhal N et al., EASL2014, Abs. O109; 3 Kowdley KV et al. Etats-Unis, EASL 2014, Abs. O56 actualisé

ION-1 1

12 vs 24 w. G1 naïves

ION-2 2

12 vs 24 w. Pretreated G1

ION-3 3

8 vs 12 w. G1 naïve non cirrhotics

98 %

99 %

99 %

97 %

99 %

99 %

94 %

96 %

94 %

93 %

SVR 12

SOF + LDV

SOF + LDV + RBV

SOF + LDV

SOF + LDV + RBV

SOF + LDV

SOF + LDV + RBV

SOF + LDV

SOF + LDV + RBV

SOF + LDV

SOF + LDV + RBV

SOF + LDV

0 8 12 24 w.

95 %

EASL 2014

An almost universal virologic cure

Options in 2014

• IFN-based regimens

• Sofosbuvir + Peg-IFNa + ribavirin (all genotypes)

• Simeprevir + Peg-IFNa + ribavirin (genotypes 1, 4)

• Daclatasvir + Peg-IFNa + ribavirin (genotypes 1, 3,

4-6)

• IFN-free regimens

• Sofosbuvir + ribavirin (genotypes 2, 3)

• Sofosbuvir + simeprevir (genotypes 1, 4)

• Sofosbuvir + daclatasvir (genotypes 1, 3, 4-6)

Osinusi A, et al. JAMA. 2013;310(8):804-811.

Sulkowski MS, et al. AASLD 2013. #212.

Zeuzem S, et al. AASLD 2013#1085.

Lawitz E, et al. N Engl J Med. 2013 May 16;368(20):1878-87.

GT 1 SOF + RBV

24 weeks

GT 2 SOF + RBV

12 weeks

GT 3 SOF + RBV

12 weeks

SOF + RBV: Comparison HCV mono- vs. HCV/HIV co-infected

GT 3 SOF + RBV

24 weeks

SVR

12

(%

)

68 76

0

20

40

60

80

100

SPARE PHOTON-1

SVR

12

(%

)

93 88

0

20

40

60

80

100

VALENCE PHOTON-1 SV

R1

2 (

%) 56

67

0

20

40

60

80

100

FISSION PHOTON-1

SVR

12

(%

)

85

0

20

40

60

80

100

VALENCE


Osinusi A, et al. JAMA. 2013;310(8):804-811.

Sulkowski MS, et al. AASLD 2013. #212.

Zeuzem S, et al. AASLD 2013#1085.

Lawitz E, et al. N Engl J Med. 2013 May 16;368(20):1878-87.

GT 1 SOF + RBV

24 weeks

GT 2 SOF + RBV

12 weeks

GT 3 SOF + RBV

12 weeks

SOF + RBV: Comparison HCV mono- vs HCV/HIV coinfected

GT 3 SOF + RBV

24 weeks

SVR

12

(%

)

68 76

0

20

40

60

80

100

SPARE PHOTON-1

SVR

12

(%

)

93 88

0

20

40

60

80

100

VALENCE PHOTON-1 SV

R1

2 (

%) 56

67

0

20

40

60

80

100

FISSION PHOTON-1

SVR

12

(%

)

85

0

20

40

60

80

100

VALENCE

The concept of difficult-to-treat population

has been removed by the antiviral potency of DAAs


Hepatitis C therapy in 2014

Question: Universal access to affordable

price to save lives ??

HCC

HBV HCV

Alcohol

Metabolic disorders

Obesity,diabetes: 3-5 fold increased HCC risk

Non Alcoholic Steato Hepatitis(NASH)

Chemical

Carcinogens

(Aflatoxin)

Iron overload

(Hemochromatosis)

Steatosis Steatohepatitis

Stable… Fibrosis /cirrhosis

INFECTIOUS AGENTS

Viruses

Bacteria

Fungi

Parasites?

NUTRITION-METABOLISM

Host infected cells

Bacterial metabolism

The interplay between infection

metabolism and nutrition

HCV and liver lipid metabolism:

HCV particles assembly around lipid structures

HCV chronic infection induces liver steatosis;

a risk factor for fibrosis

Chronic active

hepatitis

Cirrhosis

HCC

HBV

HCV

Intestinal

microbiota

Metabolic

Disorders

Non

Alcoholic

Steato

Hepatitis

(NASH)

The gut microbiota

.. 10 times more bacteria in our gut (1014

)

than eucaryotic cells in our body (1013

)!

. 10-100 times more genes in intestinal

bacteria vs human genome !

. 1.5 kg; 40% of fecal weight

Only 30% of the gut bacteria can be cultured

(with standard protocols…)

F Sommer and F Bäckhed Nature Reviews Microbiology 2013

Inflammation

Animal transfer: NAFLD is « transplantable »:

Fecal transplantation

Modification of intestinal microbiota in patients

with NASH

Chronic active

hepatitis

Cirrhosis

HCC

HBV

HCV

Intestinal

microbiota

Metabolic

Disorders

Non

Alcoholic

Steato

Hepatitis

(NASH)

TLR4-/-

TLR4 WT

LPS/ TLR4 signalisation pathway and gut microbiota

play a role in hepatic carcinogenesis

Dapito DH et al., Cancer Cell, 2012

ATB

Experimental protocol of HCC induction:

DEN + CCl4 in mice:

- Knock dowm for TLR4 gene

- WT treated with LPS

- WT treated with antibiotics

LPS

Mecanism of HCC progression.

Inflammation mediated by LPS-TLR4-NF-kB pathways

actives mitogenic factors expression

Darnaud M et al., J Hepatol. 2013

Yoshimoto et al. Nature 2013

Microbiome-based strategies for cancer prevention and

treatment

Schwabe RF et al., Nature Reviews Cancer. 2013

Cirrhosis

Hepatocellular carcinoma: HCC

HBV HCV

12°

1.5-5%/year

25% /5 year

Chronic infections

HBV: 350-400 Millions

HCV: 170-200 Millions

25-30 years

10-30%

Metabolic syndrom

(Overweight,diabetes)

Non Alcoholic

Steato Hepatitis

(NASH)

Chemical

carcinogens

Iron overload

Inflammation

Fibrosis

Intestinal Microbiota

HIV

HCC

Novel therapies

Targeted chemotherapy

Oncolytic viruses

Therapeutic vaccines

Biomarkers:

-early diagnosis

- prognosis, theranostics

Chronic

hepatitis

Cirrhosis

HBV

HCV

Na-Iodine symporter (NIS) and Iodide 131 for gene therapy-

mediated HCC

Faivre :Cancer Research 2004; Liu:Gastroenterology 2007 Hervé: Human Gene Therapy

2008

Antivirals

Therapeutic

vaccines?

Vaccination

HBV: yes

HCV: no

Chronic infections Metabolic syndrom HBV: 350-400 Millions...

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