treatment of chb in china: experience and evidence from real-world...

Treatment of CHB in China:

Experience and evidence from real-world studies

Jidong Jia, MD, PhD， Shan Shan, MD, PhD

Liver Research Center，

Beijing Friendship Hospital, Capital Medical University

Jun.10, 20181

Outlines

• HBV treatment in China

• Antiviral therapy reserves fibrosis/ cirrhosis

• Antiviral therapy reduces the

• perspectives

3

HBsAg prevalence estimates for 2016

The Polaris Observatory Collaborators. Lancet Gastroenterol Hepatol 2018

6.1%(5.5%~6.9%) in China

2018 PEG-IFN, TDF/TAF, ETV

2015 ETV, TDF, PEG-IFN

2015 PEG-IFN, ETV, TDF,

2017 PEG-IFN, ETV, TDF/TAF,

2015 TDF, ETV

4

Recommendations of HBV Guidelines

5

TRADITIONAL EVIDENCE

REAL WORLD EVIDENCE

Clinical Trials

Claims

Clinical Setting

Pharmacy

Patient-power

What is real world evidence?

Network for Excellence in Health Innovation. Real world

evidence: a new era for health care innovation. September 2015

Trends in the number and reporting quality of the publications:

English publications Chinese publications

Zeng N, et al. Int J Infect Dis 2018; 67:58–64

7Zhang S, et al. Front Med 2017

Category Projects Major findings

Prevention of

transmission

•HBV vaccine, EPI

•Antiviral treatment in preventing MTIT

•Reduced HBV prevalence among age ＜15years

•Safe and greatly reduced MTIT to nearly 0

Treatment

•EFFORT

•EXCEL

•OSST or New Switch

•Peg-IFN add-on (ARES, PEGON)

•Peg-IFN for inactive sAg carriers

•Evaluated the efficacy and safety of the roadmap

strategy and reduced HBV resistance

•Demonstrated the reaponse-guided therapy

•Increases sAg loss and seroconversion

•Increases eAg and sAg loss and seroconversion

• Increases sAg loss and seroconversion

New

treatment

•HBsAg-anti-HBs therapeutic vaccine phase III

trial

•PreS1 therapeutic vaccine preclinical model

•GM-CSF adjuvant

• E6F6 antibody

•Fecal microbiota transplantation

•Core inhibitors

•CRISPR/Cas9

•No benefits

•Broke sAg tolerance and increased immune response to sAg

•Increased immune responses to sAg in model

•Restored immune response to sAg in model

•Promoted eAg seroconversion in patients

•Inhibited nucleocapsid assembly

•Mutated or eliminated cccDNA

Predictor

markers

•pgRNA

•qAnti-HBc

•HBcrAg

•Represented cccDNA, predicted off-treatment of NA timing

•Differentiated immune status, predicted eAg seroconversion

•Marker for cccDNA, predicted treatment outcome and HBV

reactivation

Recent advances in the clinical research of CHB in China

8

Number of published peer reviewed articles based on registries

and retrospective databases in China

Sun X, et al. BMJ 2018; 361:k1580. doi: 10.1136/bmj.k1580.

Outlines




• perspectives

Progression and regression of liver fibrosis

Regression

Fibrogenesis

Fibrolysis

Progression

Antiviral therapy reverses liver fibrosis & cirrhosis in CHB

Lok AS, et al. Nat Rev Gastroenterol Hepatol. 2013; 10:199-200.

Study Agents HBeAg Biopsy/NTreatment

period

Cases

achieved

decrease of

Ishak score

（%）

Ishak 5-6,

decrease ≥1

（%）

Dienstag

et al. 2003LAM + 63/267 3 12/19 (63%) 8/11 (73%)

Rizzetto

et al. 2005LAM - 48/76 3 8/18 (44%) 3/6 (50%)

Hadziyanni

s et al.2006ADV - 46/125 4-5 29/46 (63%) 3/4 (75%)

Chang et al.

2010ETV +/- 57/679 5 50/57 (88%) 4/10 (40%)

Marcellin

et al. 2012TDF +/- 348/641 5 176/348 (51%) 71/96 (74%)

Liaw, Y-F. J Hepatol. 2013;59:880-1. 11

Fib

rosis

Sta

ge

0w 78w 0w 78w

Perc

en

t o

f P

ati

en

ts

Pre-treatment:

P = 57.7%,

I = 29.6%,

R= 12.7%

HEPATOLOGYOfficial Journal of American Association for the Study of Liver Diseases

Sun Y, et al. Hepatology. 2017; 65:1438–50

Post-treatment:

P=11.3%,

I = 11.3%,

R=77.5%

P-I-R score for liver fibrosis

Predominantly Progressive （进展型）

Indeterminant（不确定型）

Predominantly Regressing （消退型）

• Wide/broad

• Loosely aggregated

• Moderate to

marked infiltrate of

inflammatory cells

• Thin/delicate

• Densely compacted

stroma

• Little or no inflammation

• could not be clearly

classified

13Sun Y, et al. Hepatology. 2017, 65: 1438-1450.

Post-treatment P-I-R score

n=71

Progressive

n=8

Indeterminate

n=8

Regressive

n=55

Ishak

(pre-post)

Increase,

n=3

Absolutely advancing

67% (2/3) 0 33% (1/3)

Stable,

n=35

Probably advancing

17% (6/35) 11% (4/35)

Probably

reversing

72% (25/35)

Decrease,

n=33 0

Probably

reversing

12% (4/33)

Absolutely

reversing

88% (29/33)

14

Post-treatment P-I-R vs Pre-post treatment Ishak scores

Sun Y, et al. Hepatology. 2017; 65:1438–50

Dynamic changes of LSM Predict Reversion of Liver Fibrosis in CHB

Non-reversion

Reversion

－Reversion was defined as Ishak score decrease ≥1

Kong YY, et al. Unpublished data

16

Platelets’ increase is associated with improvement of liver fibrosis

in entecavir-treated CHB patients with significant liver fibrosis

Wang L, et al. Hepatol Int 2018; Epub ahead of print

Outlines




• perspectives

18

Cumulative incidence of HCC in total patients during 10 years

4.24%

9.23%

15.09%

0.5 y 1.0 yJun 2004 1.5 y 10 y9.5 y

Anti-viral therapy (AVT) group: ADV 10mg qd

Non-antiviral therapy (Non-AVT) group

Zhang W et al. Medcine 2017; e8454

Zhang W, et al. Medicine 2017; 96:44(e8454)

Jia J, et al. JGH 2017

Effective viral suppression is necessary to reduce HCC development

in 120 cirrhotic patients with CHB: Results of a 10-year follow up

20

ETV

1 y 1.5 y 2 y0.5 y0 w 2.5 y 3 y

LAM + ADV

578 patients of

compensated

cirrhosis

LSM and APRI in cirrhotic patients with treatment

Unpublished data

21

Total hepatic

endpoints

Incidence of HCC Decompensation rate

Cumulative incidence of hepatic endpoints

Unpublished data

Dynamic changes of LSM predicts the incidence of LREs in ETV-treated patients

Wu S, et al. Liver Int 2017

Patients disposition in EVOLVE Study

Jia J, et al. Antiviral Therapy 2017

Effectiveness of NAs on HBV DNA suppression

Jia J, et al. Antiviral Therapy 2017

REALM: Global Prospective Observational Study

COEs, clinical outcome events; DMC, Data Monitoring Committee; SAEs, serious adverse events.a COEs reviewed by Events Adjudication Committee (EAC) for diagnostic consistency.

Targeted enrollment: 12,500 adult patients

1:1 randomization, stratified by country and prior HBV nucleos(t)ide experience

ETV0.5 or 1.0 mg once daily

Non-ETVOther available standard-of-care nuc

(selected by treating investigator)

■ Patients were accrued over 3 years, with up to 10 years of study follow up

■ Quarterly yearly assessments for COEsa and treatment-related SAEs

■ Data reviewed annually by DMC

Hou J-L, et al.; AASLD 2017. Abstract 28

Key Inclusion Criteria Key Exclusion Criteria

■ Male and female adults with CHB ■ Virologically controlled on current regimen

■ HBeAg+/- nuc naïve/experienced ■ Prior ETV use

■ Cirrhotic or non-cirrhotic ■ History of malignancies or dysplastic liver nodules(exception: non-melanoma skin cancers)

Patient Disposition

76 not treated31 not treated

2169 did notcomplete study

• 715 lost to follow-up• 673 withdrew consent• 262 death• 7 HCC• 9 non-HCC HBV

disease progression• 503 other

1734 did notcomplete study

• 587 lost to follow-up• 437 withdrew consent• 239 death• 8 HCC• 3 non-HCC HBV disease

progression• 460 other

37 not randomized

12522 enrolled

6238 randomized to non-ETV

6247 randomized to ETV

6216 treated withETV

Primary populationfor analysis

6162 treated withnon-ETV nucs

Primary populationfor analysis

4482 (72%)completed study

3993 (65%)completed study


Baseline Demographic and HBV Disease Characteristics

* Most common NAs were ADV, LdT or LAM. TDF was not available for HBV treatment at start of study.

ETV

N = 6216

Non-ETV*

N = 6162Age, median yr (range) 39 (16–88) 39 (16–86)Male gender, n (%) 4713 (76) 4672 (76)Race, n (%)

White 819 (13) 780 (13)Black/African American 59 (1) 68 (1)Asian 5221 (84) 5201 (84)Other 117 (2) 113 (2)

Geographic region, n (%)China 2659 (43) 2646 (43)Other Asia 2320 (37) 2304 (37)Europe 662 (11) 645 (10)North America 287 (5) 281 (5)South America 288 (5) 286 (5)

Historic HBeAg status, n (%)Positive 3375 (54) 3252 (53)Negative 2438 (39) 2441 (40)Other/unknown/not reported 403 (6) 469 (8)

Historica cirrhosis status, n (%)Absent 4956 (80) 4901 (80)Compensated 1044 (17) 1044 (17)Decompensated 216 (3) 217 (4)


Principal Analysis of Time to Adjudicated COEs: Primary Endpoints

Time to liver-relatedHBV diseaseprogression

Composite of:- HCC- non-HCC HBV disease progression

- liver-related death

Perc

en

tW

ith

Eve

nts 6

5

4

3

2

1

0

7

HR = 0.89 (CI, 0.77–1.03) P = 0.12

36 48 60 72 84 96 108 120Months

B/L 12 24

Number of Patients at Risk

ETVEvent/N = 350/6216

Non-ETVEvent/N = 375/6162

Pe

rce

nt

Wit

hEv

en

ts7

6

5

4

3

2

1

0



HR = 0.93 (CI, 0.80–1.08) P = 0.36

36 48 60 72 84 96 108 120Months

B/L 12 24


Time to overall malignantneoplasms

HR = 0.85 (CI, 0.71–1.01) P = 0.068

36 48 60 72 84 96 108 120Months

2

1

0B/L 12 24


Perc

ent

Wit

hEv

ents

3

4

5



Time todeath

ETV 6216 6009 5825 5663 5480 5291 5057 4684 3548 797 0 ETV 6216 5972 5799 5644 5464 5289 5058 4691 3559 801 0

Non-ETV 6162 5921 5683 5430 5193 4932 4625 4199 3178 737 0 Non-ETV 6162 5899 5649 5401 5163 4913 4615 4193 3163 731 0

ETV 6216 6045 5900 5766 5612 5438 5224 4867 3686 831 0

Non-ETV 6162 5956 5759 5534 5307 5071 4778 4346 3286 751 0

Hou JL et al. APASL 2011, Poster PP05-146.

Time to Adjudicated COEs: Secondary and Exploratory Endpoints

Time toHCC

Time tonon-HCC malignant

neoplasms

Time toliver-related death

Pe

rcen

tW

ith

Even

ts

0B/L 12 24 36

Number of Patients at RiskMonths

48 60 72 84 96 108 120



0.5

1

Months

0B/L 12 24 36


48 60 72 84 96 108 120

Perc

en

tW

ith

Eve

nts

1

2

3

4

5





CI, confidence interval; HCC, hepatocellular carcinoma; HR, hazard ratio.

Perc

en

tW

ith

Eve

nts

0B/L 12 24 36


0.5

1

1.5

2

48 60 72 84 96 108 120Months

Exploratory Endpoint:

Non-HCC HBV disease progression

N with Event:

ETV: 137 Non-ETV: 146

HR = 0.90 (CI, 0.71–1.14)

HR = 1.10 (CI, 0.82–1.48) HR = 0.87 (CI, 0.73–1.03)

HR = 0.91 (CI, 0.61–1.37)

ETV 6216 6045 5900 5766 5612 5438 5224 4867 3686 831 0

Non-ETV 6162 5957 5759 5534 5307 5071 4778 4346 3286 751 0

ETV 6216 6035 5880 5736 5575 5385 5172 4810 3642 820 0 ETV 6216 6019 5845 5693 5517 5344 5109 4740 3591 807 0

Non-ETV 6162 5948 5741 5508 5279 5034 4735 4300 3262 746 0 Non-ETV

6162 5930 5700 5454 5220 4967 4665 4243 3201 742 0

Hou JL et al. APASL 2011, Poster PP05-146.

Conclusions■ There were no significant differences between the ETV and non-ETV

groups in rates of malignant neoplasms, liver-related events of HBV

disease progression, or deaths

■ HCC was the most common malignancy in both treatment groups

– HCC incidence consistent with expectations for this population

– The most common non-HCC malignancies were gastrointestinal,

consistent with data from published studies in CHB

■ The composite endpoint of liver-related HBV disease progression

was observed more

frequently, regardless of treatment group, in the following

subgroups:

– Older patients, history of cirrhosis, and long-term cigarette smoking

■ More treatment-related SAEs were reported in the non-ETV vs ETV

group

– Difference primarily due to neuropathic and musculoskeletal events in

patients receiving L-nucleoside analoguesHou JL et al. APASL 2011, Poster PP05-146.

Outlines




• perspectives

33

Approved at the Sixty-ninth World Health Assembly

23–28 May 2016

TDF 1500 RMB/Mon ➔ 490 RMB/Mon

Medicine is not

luxury item.

➢Training courses （ 2015~2018）

for doctors in secondary

hospitals

➢31 provinces

~ 60 cities

~2000 hospitals,

~9000 doctors

Guidelines on the prevention and treatment of CHB

(2005, 2010, 2015)

Preliminary Data from China-Registry of Hepatitis B (CR-HepB)

Increasing use of the first-line NAs for CHB (2003-2016)

Lamivudine

Adefovir

Telbivudine

Tenofovir

Entecavir

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%

2016

2015

2014

2013

2012

2011

2010

2009

2008

2007

2006

2005

2004

2003

Shan S, et al. APASL 2017

37

Reduction of HBV-related deaths under different test-and-treat

strategies in China

Zhu J, et al. Medicine 2018; 97:16(e0484)

谢谢各位聆听！

treatment of chb in china: experience and evidence from real-world...

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