Jidong Jia, MD, PhD

Beijing Friendship Hospital，

Capital Medical University

2016-3-14

New Tools for Assessing Disease Sererity,

progression and regression in HBV and HCV

Disclosure

• Consultation for

– Abbvie

– BMS

– Gilead

– Roche

Liver fibrosis is a common pathway to advanced liver disease

Pellicoro A,et al. Nat Rev Immunol 2014;14:181-94

Evaluation of liver fibrosis

Baranova A, et al. BMC Gastroenterology. 2011

Liver Histopathology

• Semi-quantitative scoring

systems:

Metavir

Ishak

Knodell

• Quantitative

morphometry :

Collagen proportionate area

(CPA)

Fibro-C-index

qFibrosis

Invasive method

Liver biopsy

- Semi-quantitative (histological)

scoring systems

- Quantitative computer-

assisted morphometric studies:

o Collagen proportionate

area (CPA)

o Fibro-C-index

o qFibrosis

Invasive method

Liver biopsy

- Semi-quantitative (histological)

scoring systems

- Quantitative computer-

assisted morphometric studies:

o Collagen proportionate

area (CPA)

o Fibro-C-index

o qFibrosis

• Limitations

Invasive

Expensive

Sampling error

Inter- and intra-observer

variation

Noninvasive Assessment for Liver Fibrosis

• Currently available tests

Biological (serum biomarker algorithms)

Physical (imaging assessment of tissue stiffness)

Physiological (breath test)

• Emerging novel tests

– Functional genomic, microparticle, protein-profiling and

bioimaging tools

– Assessment of dynamic nature of fibrogenesis

– Key to evaluation of efficacy of antifibrotic compounds

Semin Liver Dis 2015;35:166–183

Serum Biomarkers for Liver Fibrosis

Direct serum markers

• Glycoproteins/proteoglycan:

laminin, hyaluronate….

• collagens: Procollagen III, type

IV collagen….

• collagenases and their

inhibitors: MMP, TIMP-1…

• Reflect ECM turnover ( matrix

synthesis or degradation )

• Not routinely available

• Not specific to liver

Indirect serum markers

• Platelet count, PT, AST/ALT ratio

• FibroTest: α2-MG, ApoA1,

haptoglobin, γGT, and bilirubin

• APRI: AST to Platelet Ratio Idex

• FIB-4: Age, ALT, AST, Platelet

• Reflect alterations in hepatic function (more on diagnosis of cirrhosis)

• Routinely available

• Usually no extra cost

Meta-analysis of APRI for F2 fibrosis/cirrhosis in CHB

Xu XY, et al. PlosOne 2014

F≥2 F4

Meta-analysis of FIB-4 for F2 and F4 in CHB

Xu XY, et al. PlosOne 2014

F≥2 F4

The predictive ability of APRI, FIB-4 and AST/ALT,

for ≥F3 fibrosis in 2372 US patients with CHC

Holmberg SD, et al. CID 2013

FibroTest /Fibrosure for significant fibrosis (F2-4)

or cirrhosis (METAVIR F4)in CHB

Significant fibrosis (F2-F4) Cirrhosis (F4)

Salkic NN, et al. AJG 2014

AUROC=0.84 (95 % CI: 0.78 – 0.88)

AUROC=0.87

(95 % CI: 0.85 – 0.90)

Meta-analysis of FibroTest for significant

fibrosis and cirrhosis in CHB

Xu XY, et al. PlosOne 2014

F≥2 F4

AUROCs for ELF and TE diagnosis of significant

fibrosis (F≥2) (A) and cirrhosis (F4) in CHC

F≥2 F=4

(ELF: HA+PIIIP+TIMP-1)

Fernandes FF, et al. JCG 2015

Imaging Assessments For Liver Fibrosis

• Ultrasound elastography Transient elastography (TE)

Fibroscan- EchoSense

Real-time elastography (RTE)

HI Vision-Hitachi

Shear Wave Elastography(SWE)

VTTQ(ARFI)- Siemens system

Shear Wave Elastography-SuperSonic system

ElastQP-Phillips system

• Magnetic Resonance Elastography (MRE)

Ferraioli G, et al. J Ultrasound Med 2014

Normal Values

Meta-analysis of AUROCs TE for significant fibrosis

and cirrhosis in CHB

Cho YE, et al. PloS ONE 2012

TE for each METAVIR fibrosis stage

in 469 patients with CHB

Jia JD, et al. JGH 2015

AUROC of TE, FIB-4 and APRI for the diagnosis of F ≥ 2

and F4 METAVIR stages in 469 CHB patients

F ≥ 2 F4

Jia JD, et al. JGH 2015

AUROC for 10 models, according to METAVIR Fibrosis

Stages in 259 CHB patients

Cheng J, et al. PLoS ONE 2015

Real-Time Elastography (RTE, Hitachi) for F1-F4 fibrosis in CHB

Wu T, et al. Dig Dis 2014

AUROC for LFI from RTE (Hitachi) and LSM from TE (Fibroscan) for

diagnoses of fibrosis ≥F2 and cirrhosis (F4) in CHB

F=4 F≥2

Meng F, et al. J Ultrasound Med 2015

3 major techiques for Sear Wave Elastography (SWE)

Super-Sonic system (Sear Wave Elastography)

Siemens system (ARFI, VTTQ=Virtual

Touch Tissue Quantification)

Phillips System (ElastPQ)

Ferraioli G, et al.

J Ultrasound Med 2014

ROC for SWE (ARFI, Siemens) and TE for diagnosis

of significant fibrosis (F≥2) in CHB

Friedrich-Rust M, et al. JVH 2013

AUROC for SWE (SuperSonic) in 303 Chinese patients with CHB

Zeng J, et al. Eur Radiol 2014

AUROC for SWE (SuperSonic) for identifying ≥F2 and

F4 in patients with CHC

F≥2 F=4

Samir AE, et al. Radiology 2015

Venkatesh SK, et al. Magn Reson Med 2014

Correlations between MRE and Metavir score

in 32 patients with CHB.

Venkatesh SK, et al. Magn Reson Med 2014; 72:1123–1129

Meta-analysis: Composite box plot graph showing MRE

values for various stages (METAVIR) of fibrosis

Singh S, et al. CGH 2014

Meta-analysis: Diagnostic Performance of MRE

for Fibrosis of Different Etiology

Singh S, et al. CGH 2014

Changes of LSM in CHB after NA therapy

The mean interval between two LSMs was 411.5 ±149.5 (180-1,062) days

Kim JK, et al. J Korean Med Sci 2014

Changes of LSM after ETV therapy

P<0.01

P<0.01

n-=233 n-=13

( with mean interval of 52.8 and 61.9 weeks in the 2 groups)

Kuo YH, et al. PloS ONE 2014

Changes of Ishak score and APRI and FIB-4

in CHB patients on TDF therapy

Kim WR, et al. J Hepatol 2015

APRI FIB-4

Multivariate analysis of negative prognostics

of sustained virologic response in CHC

on dual or triple therapy

N=65 N=20

Stasi C, et al. WJG 2015

LSM by TE and LFI by RTE correlates treatment

response by antiviral therapy in CHC patients

• LSM and LFI correlated well before and after therapy

(r = 0.567, p = 0.003 and r = 0.576, p = 0.002,

respectively).

• In the group without a sustained virological

response (SVR), LSM increased in 4 of 5 patients.

• In the SVR group, both LSM and LFI decreased in all

patients except 1 (18/19, 94.7%)

• In the patient with an increase in LSM despite

achieving SVR, LSM decreased quickly after alcohol

cessation.

Yada N, et al. Oncology 2014

MALDI-TOF MS Identified Serum Peptide Pattern for Prediction of HBV-Cirrhosis

Complete mass spectrum of

serum samples between

HBV-cirrhosis and non-LC groups

in the 800–10,000 m/z range.

Red line=HBV-cirrhosis group

Blue line=non-LC group.

Cao Y, et al. BioMed Research International

High Throughput LC-IMS-MS Identified relative log2 intensity proteins with

significant differential abundance in CHC

Baker ES, et al. Molecular & Cellular Proteomics 2014

EASL-ALEH Proposed algorithm for Tx-naïve patients with CHC ± HIV

EASL-ALEH. J Hepatol 2015

EASL-ALEH Proposed algorithm for Tx-naive patients with CHB

EASL-ALEH. J Hepatol 2015

Thank you for your attention!