만성C형간염 치료
심재준
경희대학교병원 소화기내과
Kyung Hee Univ. School of Medicine
Department of Internal Medicine
Jae-Jun Shim MD, PhD
2016.3.3. 경희의료원 내과
Questions
왜 C형간염이 중요한가?
국내 C형 간염의 감염 상태(역학)는 어떠한가?
C형간염바이러스(HCV)의 특징은 무엇인가?
현재 C형간염의 치료는 어떻게?
향후 C형간염 치료의 전망은?
현재 국내에서 사용 가능한 치료 약제는?
왜 C형간염이 중요한가?
유병률
의료기관 내 감염: 사회적 이슈 (다나의원, 원주한양정형외과의원, 전수감시체제 전환 등)
만성 간질환의 주요한 원인
최신 치료제 등장
A Nationwide Seroepidemiology of HepatitisC Virus Infection in South Korea
Using an estimated 2009 population of Korea, theage, sex and area-adjusted anti-HCV positive ratewas 0.78%.
Kim DY, et al. Liver Int 2013
HCV infection, 10% of liver-related mortality (cirrhosis or livercancers), in a single health care center about 1,800 deaths/year in Korea
JJ Shim, KASL 2014
Adapted from Chen SL, Morgan TR. Int J Med Sci. 2006;3:47-52.
*20%-30% of individuals are symptomatic.
AcuteInfection*
Chronic
Infection
50%-80%
Clearance ofHCV RNA
20%-50%
Extrahepatic Manifestations
Cirrhosis
20%-25% over 20 years
Hepatocellular Carcinoma (HCC)
1%-4% per year
Decompensated
Cirrhosis (DCC)
5-yr survival rate 50%
Natural History of HCV Infection
oOder age
oLonger duration of infection
oHigher inflamm. grade and fibrosis stage
oAlcohol, HBV, HIV
oObesity (NASH)
oIron overload
C형간염바이러스(HCV)의 특징은 무엇인가?
RNA virus
Life cycle, replication mechanism이 잘 밝혀졌다
완치가 가능
Hepatitis C virus
□RNA virus
□Half-life: a few hours
□Production and clearance of an estimated 1012 virions per day in a given individual.
Nature Reviews Microbiology 2007
Lifecycle of hepatitis C virus (HCV)
Takaji Wakita
Dr. Volker Lohmann
Science 1999
Nature Med 2005
G1b HCV RNA
Huh7 HCC cell lines
HCV RNA replication system in a cell line
G2a HCV RNA
Huh7 HCC cell lines
HCV viral replication and excretion of viral particles
대박
대박
11
11
22
22
44
44
55
55
33
33
Asunaprevir
Sofosbuvir
Ledipasvir
Rosen HR. N Engl J Med 2011;364:2429
현재 C형간염의 치료는 어떻게?
Standard treatmentPeg-interferon (Peg-IFN) + Ribavirin (RBV)
Peg-IFN-α2b
(Peg-intron®,MSD)
Peg-IFN-α2a(Pegasys®,Roche)
Inhibit viral replication
Upregulate IFN stimulated genes
Immunomodulatory effects
Dose: weight-based [15 mg/kg #2 or 1,000 mg(<75 kg), 1200 mg (≥ 75 kg)] PO
G1, 4, 5, 6
G2,3: obese (BMI>25), insulin resistance,metabolic syndrome, severe fibrosis (LC)
800 mg #2 PO (fixed dose)
G2 or G3
1.5 μg/kg every 1 week (Wt based)
180 μg/kg every 1 week (fixed dose)
13/35
Direct-acting Antiviral Agents (DAAs)
NS3 serine protease inhibitors
Boceprevir, telaprevir (FDA 2011)
Simeprevir (FDA 2013)
Paritaprevir (ABT450)/r (FDA 2014)
Asunaprevir (not FDA, only approved
in Japan)
NS5A inhibitors
Daclatasvir (2015)
Ledipasvir (2014)
Ombitasvir (2014)
Velpatasvir (in 2016)
NS5B polymerase inhibitors
Nucleoside/nucleotide analogue
Sofosbuvir (FDA 2013)
Non-nucleoside analogue
Dasabuvir (ABT-333) (FDA 2014)
Rosen HR. N Engl J Med 2011;364:2429
~previr
~asvir
~buvir
Development of Tx strategyin the era of DAAs (Directly Acting Antiviral agents)
1
1
PegIFN + RBV + DAA
2
2
3
3
IFN-free (DAAs ± RBV)
One pill (FDC)
Peg-IFN + RBV + PI (Boceprevir or telaprevir)
SPRINT-21
Naïve
G1
BOC, boceprevir (protease inhibitor, PI); TVR, telaprevir; PEG, peginterferon; RBV, ribavirin; All, bothnaïve and previously treated patients; RGT: response guided therapy
ADVANCE2
Naïve
G1
ILLUMINATE3
Naïve
G1
1.N Engl J Med 2011;364:1195-206.
2.N Engl J Med 2011;364:2405-16.
3.N Engl J Med 2011;365:1014-24
SVR of control grp
44
40
Simeprevir + PEG-IFN + RBV
CONCERTO-11
Naïve, Japan
G1b
SMV, simeprevir (NS3/4A inhibitor); PEG, peginterferon; RBV, ribavirin; RGT, response-guided therapy
QUEST-12
Naïve
G1
PROMISE3
Relapse
G1
1.Hayashi N. et al. J Hepatol 2014 Epub
2.Lancet 2014;384:403-13
3.Gastroenterology 2014;146:1669-1679
4.Lancet 2014; 384: 414–26.
QUEST-24
Relapse
G1
SVR of control grp
50
* No additional benefit in G1a, Q80K mutation(SVR 52-75% vs 50-53%)
62
50
Development of Tx strategyin the era of DAAs (Directly Acting Antiviral agents)
1
1
PegIFN + RBV + DAA
2
2
3
3
IFN-free (DAAs ± RBV)
One pill (FDC)
DAAs 특징
NS3/4A PI
NS5A Inhibitor
NS5B NI
NS5B NNI
Potency
+++
+++
++
++
Coverage
Narrow (G1)
G1~6
G1~6
Narrow
Genetic barrier
Low
Low
High
Low
Drugs
Boceprevir
Telaprevir
Simeprevir
Paritaprevir
Asunaprevir
Grazoprevir
Daclatasvir
Ledipasvir
Ombitasvir
Velpatasvir
Elbasvir
Sofosbuvir
Beclabuvir
Dasabuvir
PI, protease inhibitor; NI, nucleos(t)ide analogue inhibitor; NNI, non-nucleoside analogue inhibitor
Paritaprevir(ABT-450)/r/Ombitasvir + Dasabuvir± RBV
SAPPHIRE-I1
Naïve, LC(-)
G1
ABT, ABT-450 (NS3/4A inhibitor, paritaprevir); LC, liver cirrhosis; SOF, sofosbuvir (NS5B inhibitor); PEG,peginterferon; RBV, ribavirin; R, ritonavir; OBT, ombitasvir (NS5A inhibitor); DBV, dasabuvir (NS5Binhibitor)
SAPPHIRE-II2
Prior treated
G1
PEARL-III3
Naïve, LC(-)
G1b
1.N Engl J Med 2014;370:1594-603.
2.N Engl J Med 2014;370:1604-14.
3.N Engl J Med 2014;370:1983-92.
4.N Engl J Med 2014;370:1973-82.
PEARL-IV3
Naïve, LC(-)
G1a
TURQUOISE-II4
LC(+)
G1
$83,320
Sofosbuvir + (PEG + RBV)
NEUTRINO1
Naïve
G1, G4, G5, G6
SOF, sofosbuvir (NS5B inhibitor); PEG, peginterferon; RBV, ribavirin wt based (1000 mg <75kg, 1200mg > 75kg); All, both naïve and previously treated patients
FISSION1
Naïve
G2
POSITRON2
PEG ineligible
G2
VALENCE3
All
G3
1.N Engl J Med 2013;368:1878-87.
2.N Engl J Med 2013;368:1867-77.
3.N Engl J Med 2014;370:1993-2001.
$84,000
\3,800,000
Sofosbuvir + Ledipasvir
ION-11
Naïve
G1
SOF, sofosbuvir (NS5B inhibitor); LDV, ledipasvir (NS5A inhibitor)
ION-21
Previously Tx
G1
ION-32
No cirrhosis
G1
1.N Engl J Med 2014;370:1889-98.
2.N Engl J Med 2014;370:1483-93.
3.N Engl J Med 2014;370:1879-88.
4.N Engl J Med 2015;373:705-13
ION-44
HIV coinfected
G1, G4
$94,000
\4,600,000
Simeprevir + Sofosbuvir
COSMOS1
Naïve or NR
G1
SMV, simeprevir (NS3/4A inhibitor); SOF, sofosbuvir (NS5B inhibitor); RBV, ribavirin; NR, previouslynot responded
COSMOS1
Naïve, fibrosis(+)
G1
1.Lancet 2014; 384: 1756–65
2.AASLD 2014 Abstract #46
TRIO-N2
Naïve
G1
Real life Exp1
Any
G1
Daclatasvir + asunaprevir ± beclabuvir
HALLMARK DUAL1
Naïve Non-response Ineligible
G1b*
DCV, daclatasvir (NS5A inhibitor); ASV, asunaprevir (NS3/4A inhibitor); BEC, beclabuvir (NS5B inhibitor);RBV, ribavirin
1.Lancet 2014;384:1597-1605
2.JAMA. 2015;313:1736-1744
* SVR in NS5A-Y93H (8%), L31M,V (5%) = 38%, 41%, respectively
UNITY-22
Naïve Tx-experienced
G1a or G1b
Fixed-dose combination twice daily(DCV-TRIO)
Daclatasvir + sofosbuvir
DCV, daclatasvir (NS5A inhibitor); SOF, sofosbuvir (NS5B inhibitor); RBV, ribavirin
1. N Engl J Med 2014;370:211-21. 2. N Engl J Med 2015;373:714-25 3. HEPATOLOGY 2015;61:1127-1135
AI4440401
Naïve
G1
AI4440401
Naïve
G2, G3
* Adding RBV or 24 weeks of therapy didnot improve SVR rate.
ALLY-22
HIV-1 and Naïve or
previously treated
G1,G2,G3,G4
ALLY-33
Naïve or
previously treated
G3, LC(-)**
** G3 with LC (+): very low SVR12 (63%)
Grazoprevir + Elbasvir
GZVR, grazoprevir (NS3/4A protease inhibitor); EBVR, elbasvir (NS5A inhibitor)
1.Ann Intern Med. 2015;163:1-13
2.Lancet 2015; 386: 1537–45
C-EDGE1
Naïve
G1,G4,G6
Fixed-dose combination once daily
C-SURFER2
CKD (stage 4-5)
G1
C형간염 경구 칵테일 요법의 현재
인터페론 없이 90% 이상의 높은 완치율(SVR)을 보임.
두통, 피로감 외에 약물 부작용 거의 없음.
치료 전후 필요한 검사
유전자형(G1a vs. G1b vs. G2 vs. G3 vs. others) 검사가 필수.
RAV (돌연변이종 바이러스) 검사가 사전에 필요(ASV+DCV 요법).
정기적인 간기능 검사 필요(ASV+DCV 요법).
간경변 여부도 확인 필요.
향후 C형간염 치료의 전망은?
Development of Tx strategyin the era of DAAs (Directly Acting Antiviral agents)
1
1
PegIFN + RBV + DAA
2
2
3
3
IFN-free (DAAs ± RBV)
One pill (FDC)
Test and CureNo genotyping, No imaging nor biopsy
1b, 2a
1b, 2a
1b,3a,2a,2b,2c
1b,3a,2a,2b,2c
1a, 1b,2a,2b,3a
1a, 1b,2a,2b,3a
3a, 1b
3a, 1b
1b, 6
1b, 6
HEPATOLOGY 2015;61:77-87
Global prevalence of each HCV genotypes
Sofosbuvir + Velpatasvir
ASTRAL-11
Any
G1,2,4,5,6
SOF, sofosbuvir (NS5B inhibitor); VEL, velpatasvir (NS5A inhibitor)
ASTRAL-22
Any
G2
ASTRAL-32
Any
G3
1.N Engl J Med. 2015;373:2599-607
2.N Engl J Med. 2015;373:2608-17
3.N Engl J Med. 2015;373:2618-28
ASTRAL-43
Decompensated LC
G1,2,3,4,6
** No RBV: SVR 83%, esp. in G3 with LC (+): 50%
Development of Tx strategyin the era of DAAs (Directly Acting Antiviral agents)
1
1
PegIFN + RBV + DAA
2
2
3
3
IFN-free (DAAs ± RBV)
One pill (FDC)
현재 국내에서 사용 가능한 치료 약제는?
Distribution of genotypes in Korea
Genotype
(N = 421)
Genotype
(n = 491)
Others
During 2007 ~ 2011, HCV infection (n=930)
Current status of Rep. of Korea
Seong et al. J Med Virol 2013;85:1724
•G1b 86% (n = 422)
•G2a/c 63.2% (n = 266)
Daclatasvir
NS5A
G1b
Daclatasvir
NS5A
G1b
DAAs approved in Korea (2015~)
Asunaprevir
NS3A PI
G1b
Asunaprevir
NS3A PI
G1b
Sofosbuvir
NS5B
G1,2,3,4
Sofosbuvir
NS5B
G1,2,3,4
Ledipasvir
NS5A
G1
Ledipasvir
NS5A
G1
Sofosbuvir
NS5B
G1,2,3,4
Sofosbuvir
NS5B
G1,2,3,4
Harvoni®
Sovaldi®
Daklinza®
Sunvepra®
a HCV RNA < LLOQ (25 IU/mL) TD or TND; responder/treated; b Patients with baseline sequence data and excluding non-virologic failures.
•13% (16/125) and 0% (0/125) of patients had key NS5A and NS3 RAVs at baseline, respectively
•Higher SVR rates seen in patients without key baseline NS5A RAVs Y93 or L31 (92%)
Korean and Taiwanese patients combined (N = 138)
< 65
≥ 65
Male
Female
<800K
≥800K
Age
Gender
HCV RNA
87
82
Absent
Present
Cirrhosis
77
89
40
49
83
100
34
38
53
61
64
77
25
26
92
112
96
With
Without
Key NS5A RAV1,b(Y93H or L31F/I/M/V)
38
92
6
16
99
108
SVR12, %a
Asunaprevir (ASV) + daclatasvir (DCV) for 24 weeks
Virologic Response by Baseline Factors – RAV(Resistance-Associated Variants)
Kao JH, et al. APASL 2015. Oral 1424.
Safety Profile by EthnicityRisk of acute hepatic injury
Parameter
KoreanN = 65
TaiwaneseN = 71
Total GlobalN = 645
Deaths
0
0
0
SAEsa
5 (7.7)
6 (8.5)
39 (6.0)
AEs leading to discontinuationb
0 (0)
2 (2.8)
10 (1.6)
Common AEs (≥10% overall)
Headache
Fatigue
Diarrhea
Nausea
7 (10.8)
6 (9.2)
5 (7.7)
2 (3.1)
12 (16.9)
16 (22.5)
20 (28.2)
1 (1.4)
159 (24.7)
140 (21.7)
103 (16.0)
75 (11.6)
Grade 3/4 laboratory abnormalities
Lymphocytes (< 0.5 × 10⁹ cells/L)
Platelet count (< 50 × 10⁹ cells/L)
ALT (≥ 5xULN)
AST (≥ 5xULN)
Total bilirubin (≥ 2.5xULN)
Lipase (≥ 3.1xULN)
3 (4.6)
2 (3.1)
0
0
0
0
1 (1.4)
1 (1.4)
2 (2.8)
2 (2.8)
0
1 (1.4)
8 (1.2)
11 (1.7)
15 (2.3)
12 (1.9)
3 (0.5)
18 (2.8)
aAll SAEs were reported in 1 patient each with the exception of hepatocellular carcinoma which occurred in 2 patients;
bDiscontinuation due to adverse events occurred in 2 patients, both Taiwanese (ALT increase and constipation/bronchiectasis; AEs resolvedfollowing discontinuation and both patients achieved SVR12).
Kao JH, et al. APASL 2015. Oral 1424.
Sofosbuvir + RBV in Asian G2
Overall1
Any
G2
SOF, sofosbuvir (NS5B inhibitor); RBV, ribavirin, wt based
Naïve1
Any
G2
Tx-Exp1
Any
G2
1.EASL 2015 April 22-26 Vienna Austria
Asian Patients with Genotype 2 HCV Infection Receiving 12 Weeks of Sofosbuvir Plus Ribavirin: Results From an International, Multicenter Phase 3 Study
유전자2형의 치료G2: SOF+RBV, 12w
초치료, 간경변 여부 상관 없이
과거 치료 실패 여부 상관 없이
12주
Sofosbuvir
1T (400 mg) qd
With or without food
Ribavirin
<75kg=1000 mg #2
≥75kg=1200 mg #2
With food
98%
유전자1b형의 치료G1b: ASV+DCV for 24w; SOF/LDV for 12w
Asunaprevir
NS3A PI
G1b
Asunaprevir
NS3A PI
G1b
Daklinza®
Sunvepra®
Harvoni®
Daclatasvir
NS5A
G1b
Sofosbuvir / Ledipasvir
NS5B/NS5A inhibitor
G1,2,3,4/G1
ASV 1 Cap (100 mg) every 12 hr
DSV 1T (60 mg) qd
With or without food
Resistant-Associated Variant assay
RAV (Y93, L31)
Acute hepatic injury (ASV)
LFT F/U every 2w
CIx: decompensated LC
24주
90%
SOF/LDV 1T (400/90mg) qd
With or without food
Naïve with or without cirrhosis (LC) = 12w
Naïve, HCV<6,000,000 IU/mL, no LC = 8w
Tx experienced without LC = 12w
Tx experienced with LC = 24w
12주
96%
In the future
•One pill one day
–Irrespective of genotype (no need of genotyping)
–Shorter treatment course (2~3 months)
–Fewer adverse events (no need of specialists)
Jayasekera CR N Engl J Med 2014 Apr
만성C형간염의 치료
Application of Gene ExpressionData Analysis in Liver Diseases
Jae-Jun Shim, MD, PhD
Kyung Hee University Hospital
Department of Internal Medicine
2016.3.3.
Cancer is a genetic disease
□ Oncogenes
•RAS, WNT, MYC, ERK
•BCR-ABL
•DNAJB1-PRKACA: fibrolamella HCC
•IDH1: hydroxyglutarate DNA hypermethylation
□Tumor suppressor genes
•P53, Rb, APC, BRCA1,-2, PTEN
Gene expression analysis
Southern blotting
Quantitative RT-PCR method
Microarray
RNA Seq (NGS)
Microarray
Fudan data (HCC, n = 228)
수 십 ~ 수 백 개의 샘플
2 ~ 3만개의 Gene expressions
Pattern recognition
Clustering analysis
Expression data clustering visualization (Heat map)
Unsupervised analysis
•91 HCC tumors (NCI)
HEPATOLOGY 2004;40:667– 676
HCC survival gene set (n=406)
Nature Med 2006
Gene signatures in HCC
Signature
(uniq genes)
Category
Methods
Ref
NCI-P
(406)
Prediction of general prognosis (OS or PFS)
Unsupervised clustering of NCI-HCC cohort
Original cohort, selected genes associated with survival
Lee, et al.
2004, Hepatology
HS
(907)
Stem cell signature
Comparing Rat hepatoblasts, Transgenic mouse HCCs, and
Human HCCs
Lee, et al.
2006, Nature Med
SNU-R
(628)
Cancer recurrence
Original cohort, selected genes associated with early recurrence(<1year)
Woo, et al.
2008, Clin CancerRes
BC
Beta-catennin activation
SOH
(610)
Silence of Hippo path.
Transgenic mouse models (Mst1/2-/- and Sav1-/-)
Sohn, Shim et al.
2015, Clin CancerRes
HIR
(233)
Hepatic injury and regeneration signature
Serial biopsy before and after hepatectomy, LT
Kim, Sohn et al.
2014, Plos Med
IR
Immune response
VA_fib
Fibrosis
Liver biopsy in patients with chronic hepatitis C
CC-like
Cholangiocarcinoma-like
TCGA data
Inactivation of Hippo pathway issignificantly associated withpoor prognosis in hepatocellularcarcinoma
Bo Hwa Sohn1,2+, Shim Jae-Jun1,2, Sang-Bae Kim1,2+, Kyu Yun Jang3, Soo Mi Kim4, Ji HoonKim5,, Hwang Jun Eul1,2, Hee-Jin Jang1,2, Hyun-Sung Lee1,2, Sang-Cheol Kim6, Woojin Jeong7,Sung Soo Kim8, Eun Sung Park9, Jeonghoon Heo10, Yoon Jun Kim11, Dae-Ghon Kim12, Sun-Hee Leem13, Ahmed Kaseb14, In-Sun Chu15, Randy L. Johnson16, Yun-Yong Park17*, and Ju-Seog Lee1,2,8*
1Department of Systems Biology, 2Kleberg Center for Molecular Markers, 14Department of Gastrointestinal MedicalOncology, and 16Department of Biochemistry and Molecular Biology, Division of Cancer Medicine, The University ofTexas MD Anderson Cancer Center, Houston, Texas, USA.
3Department of Pathology, 4Department of Physiology, and 12Division of Gastroenterology and Hepatology,Department of Internal Medicine, Chonbuk National University Medical School and Hospital, Jeonju, Korea.
5Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University College ofMedicine, Seoul, Korea.
6Samsung Genome Institute, Samsung Medical Center, Gangnam-Gu, Seoul, Korea.
7Department of Life Sciences, Division of Life and Pharmaceutical Sciences, Center for Cell Signaling and DrugDiscovery Research, Ewha Womans University, Seoul, Korea.
8Department of Biochemistry and Molecular Biology, Medical Research Center and Biomedical Science Institute,School of Medicine, Kyung Hee University, Seoul, Korea.
9Institute for Medical Convergence, Yonsei University College of Medicine, Seoul, South Korea.
10Departments of Molecular Biology and Immunology, Kosin University College of Medicine, Busan, Korea.
11Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul,Korea.
13Department of Biological Science, Dong-A University, Busan, Korea.
15Korean Bioinformation Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea.
17ASAN Institute for Life Sciences, ASAN Medical Center, Department of Medicine, University of Ulsan College ofMedicine, Seoul , Korea
The Hippo pathway is a tumor suppressor in the liver, as demonstratedby the development of hepatocellular carcinoma (HCC) after the pathwayis inactivated in the livers of mice. However, the clinical significance ofHippo pathway inactivation in HCC is currently unknown. In current study,we aim to assess the clinical significance of inactivation of Hippo pathwayin HCC.
Background & Aims
The Hippo Pathway
Genes & Dev. 2010. 24: 862-874
We analyzed gene expression data from Mst1/2-/- and Sav1-/- miceand identified a 610-gene expression signature that reflected Hippopathway inactivation in the liver (silence of Hippo [SOH] signature).By integrating gene expression data from mouse models withthose from human HCC tissues, we developed a prediction modelthat could identify HCC patients with an inactivated Hippo pathwayand used it to test its significance in four independent cohorts ofHCC patients (n = 546), via univariate and multi-variate Coxanalyses. ( Fig. 1)
Methods
Figure 1. Gene expression patterns that weresignificantly associated with the silence of Hippopathway in the mouse liver.
(A)Venn diagram of genes selected using a two-sample t-test with amultivariate permutation test (10,000 random permutations). The bluecircle (gene list X) represents genes that were differentially expressedbetween normal livers from wild-type (WT) mice and non-tumor tissuesfrom mutant (Sav1-/- and Mst1/2-/-) mice (ST). The red circle (gene list Y)represents genes that were differentially expressed between all non-tumor liver tissues and all hepatocellular carcinoma tissues from mutant(Sav1-/- and Mst1/2-/-) mice. A stringent cut-off (P < 0.001 and 2-folddifference) was used to retain only the genes whose expression wassignificantly different between the two groups of tissues examined. The737 probes (610 unique genes) in the X not Y category displayed uniqueexpression patterns that are significantly associated with the silence ofHippo pathway.
(B)Expression patterns of selected genes in the Venn diagram. Coloredbars at the top of the heat map represent the tissues indicated.
Table 1. Baseline clinical and pathologicalfeatures of HCC patients
Variable
NCI
cohort
Koreancohort
FULCI
cohort
MSH
cohort
Number of Patients
113
100
242
91
male
81 (72%)
83 (83%)
211 (87%)
27 (30%)
female
32 (28%)
17 (17%)
31 (13%)
54 (59%)
NA
10 (11%)+
Age
Median
56
55
50
68
range
26-85
25-70
21-77
42-80
AFP* (>300 ng/ml)
+
51 (45%)
32 (32%)
110 (45%)
15 (17%)
-
53 (47%)
68 (68%)
128 (53%)
54 (59%)
NA
9 (8%)
0
4 (2%)
22 (24%)
HBV#
+ (%)
54 (48%)
58 (58%)
218 (90%)
- (%)
59 (52 %)
17 (17 %)
6 (2.5%)
NA
25 (25%)
18 (7.5%)
91 (100%)
AJCC Stage
I
35 (35%)
96 (40%)
II
17 (17%)
78 (32%)
III
48 (48%)
51 (21%)
IV
0 (0%)
0 (0%)
NA
113 (100%)
17 (7%)
91 (100%)
*Alpha-fetoprotein.
#Hepatitis B virus
+Patient Sex information is not available for patient who received livertransplantation
NA, not applicable
Variable
NCI
cohort
Koreancohort
FULCI
cohort
MSH
cohort
BCLC Stage
0
0 (0%)
20 (8%)
A
53 (53%)
152 (63%)
B
37 (37%)
24 (10%)
C
6 (6%)
29 (12%)
D
4 (4%)
0 (0%)
NA
113 (100%)
17 (7%)
91 (100%)
Death
71
43
96
Median Follow-up
(Month)
23.5
48.5
51.6
Figure 2. Significant association between the silenceof Hippo (SOH) signature and prognosis in patientswith hepatocellular carcinoma.
(A)Schematic overview of the strategyused to predict the probability thatSOH was present in human HCC onthe basis of gene expressionsignatures. KO, knockout; WT, wildtype; BCCP, Bayesian compoundcovariate predictor.
(B)Receiver operating characteristiccurve analysis of SOH probabilityover 3-year recurrence of HCC inthe National Cancer Institute cohort.
(C) (D) Kaplan-Meier plots ofrecurrence-free survival and overallsurvival of SOH and AH subtypepatients in the National CancerInstitute cohort. P values wereobtained from the log-rank test. The+ symbols in the panel indicatecensored data.
Figure 3. Validation of robustness of silence ofHippo signature in independent cohorts.
(A, B) Kaplan-Meier plots of recurrence-free survivaland overall survival of patients with the silence ofHippo and active Hippo subtypes in the Koreancohort.
(C, D) Kaplan-Meier plots of recurrence-free survivaland overall survival of the two subtypes of patients inthe Fundan University Liver Cancer Institute cohort. Pvalues were obtained from the log-rank test. The +symbols in the panel indicate censored data.
Table 2. Univariate and Multivariate Cox RegressionAnalyses of Recurrence Free Survival.
Univariate
Multivariate
Hazard Ratio (95% CI)
P-value
Hazard Ratio (95% CI)
P-value
Patient Sex
(M or F)
1.4 (0.89 – 2.18)
0.14
1.22 (0.78 – 1.93)
0.37
Age
(>60 years)
0.88 (0.62 - 1.25)
0.49
0.88 (0.61 – 1.29)
0.52
AFP
(>300 ng/ml)
1.25 (0.94 – 1.67)
0.12
1.01 (0.75 – 1.38)
0.9
Cirrhosis
(Yes or No)
1.08 (0.72 – 1.64)
0.68
1.1 (0.71 – 1.68)
0.67
Tumor size
(>5 cm)
1.34 (1.0 – 1.79)
0.04
1.11 (0.81 – 1.54)
0.5
BCLC stage
(0,A,B,C,D)
1.37 (1.16 – 1.7)
1.3 x 10-4
1.28 (1.08 – 1.53)
0.003
SOH signature
(SOH or AH)
1.83 (1.31 –2.5)
3.2 x 10-4
1.6 (1.12– 2.28)
0.008
CI, confidence interval
AFP, alpha-fetoprotein
BCLC, Barcelona Clinic Liver Cancer stage
SOH, silence of Hippo pathway
AH, active Hippo pathway
Inactivation of the Hippo pathway in HCC issignificantly associated with poor prognosis.
Conclusion
