Yang Yongping

the Beijing 302nd Hospital of PLA, Beijing, China

中国人民解放军第三O二医院

Novel Ideas and Options for Traditional Chinese

Medicine Induced Regression of Advanced Liver Fibrosis

& Cirrhosis in Chronic Hepatitis B

Thoughts on the treatment of CHB with oral antiviral drugs in the past decade

C.-L. Lin et al. Alimentary Pharmacology and Therapeutics 2016; 44: 213–222

1. Clinical cure : HBeAg/HBsAg loss or seroconversion for HBeAg-positive patients, and HBsAg loss or

seroconversion for HBeAg-negative patients, undetectable HBVDNA, no eradicate intrahepatic HBV cccDNA;

2. Cure of HBV： HBeAg/HBsAg loss or seroconversion for HBeAg-positive patients, and HBsAg loss or

seroconversion for HBeAg-negative patients, undetectable HBVDNA, achieving HBV cccDNA clearance;

3. The post-antiviral era: Regression of liver fibrosis or cirrhosis and completely eliminates the risk of long-

term liver cancer caused by HBVDNA integration.

Anna S. Lok,et al. Journal of Hepatology 2017 , 67:847–861

Novel Therapies for Hepatitis B Virus Cure – Advances and Perspectives

2018/6/10C.-L. Lin et al. Alimentary Pharmacology and Therapeutics 2016; 44: 213–222

Hope and Action of Traditional Chinese Medicine in Novel Therapies for Hepatitis B Virus Cure

1. Traditional Chinese medicine (TCM), one of the oldest medical systems in theworld, is based on its own unique principles and comprehensive theory. Today, itplays an indispensable role in the Chinese health care system, and its impactworldwide is increasing.

2. In the world of medicine, TCM has developed into the only medical systemcomparable to modern medicine.

3. Traditional Chinese medicine has solved many problems that western medicinecannot solve, showing its irreplaceable nature.

4. TCM will be an important contributor to the future development andintegration of medicine.

1. Ann Intern Med 2017. doi:10.7326/M16-2977

2. World Health Organization. WHO traditional medicine strategy: 2014-2023. 2013;

http://apps.who.int/iris/bitstream/10665/92455/1/9789241506090_eng.pdf3. Traditional Chinese Medicine (TCM) for fibrotic liver disease: hope and hype. J Hepatol 2014;61: 166-8

1. Body is visible, with Yin

and Yang;

2. Human health depends on

the balance of “Yin qi” and

“Yang jing” in the body;

3. The source of cure for

disease, which is Yin and

Yang;

In the yellow emperor's Canon

“ Yin” and “Yang” symbolize the balance and harmony between two opposing forces

in human body. These forces are universal in our immune system. The balance

between regulatory T cells and reactive cells, for example, is important in maintaining

homeostasis

2018/6/10Marx JL. The Yin and Yang of Cell Growth Control. Scince 1986; 323:1093-1095

“The Yin and Yang of Cell Growth Controll” is published in Science 1986.

This is the first time the theory of “Yin” and “Yang” has been published in a top

international scientific journal. It proves the value of the theory of Yin and

Yang in modern medicine.

Balancing Efficacy of and Host Immune Responses to Cancer Therapy:

the Yin and Yang Effects

NATURE REVIEWS |CLINICAL ONCOLOGY 2016, 13:611-626

Fig. 1

Journal of Hepatology 2014 61, 166-168DOI: (10.1016/j.jhep.2014.03.009)

Journal of Hepatology 2014 61, 166-168DOI: (10.1016/j.jhep.2014.03.009)

Traditional Chinese Medicine (TCM) for fibrotic liver disease: Hope and

hype TCM’ holism: Western Medicine (WM):

Nature and humanity Mechanical

reductionism

Compound medicine model Linear pure biomedical

science

TCM’ individual: WM’ individual:

syndrome differentiation Personalized treatment

TCM’ language: WM’ language:

Qi, Luo and Xue Evidence-based

medicine

TCM’ prescription :

the “chief” or the king, WM’ prescription:

“adjuvant” or “minister” , Etiology and

pathogenesis

the “assistant”, the “guider”

medicine.

Cure idea: Cure idea:Different diseases are treated Target and drug selection

How to Dialogue for Traditional Chinese Medicine and Modern Western Medicine

Traditional Chinese Medicine Modern Western Medicine

Life substance or energy that preserve life

Circulating channels for Life substance

or energy that preserve life

Transport carrier Life substance or

energy that preserve life

Hope of Traditional Chinese Medicine in the New Treatment of CHB

1. the Chinese government has begun to initiate a national safety plan in 2011;

2. investing in the modernization of TCM ($100 million from the NationalNatural Science Foundation in 2012), to promote research on lead compoundidentification and mechanisms of action, on a better standardization and wellcontrolled clinical trials;

3. a major national infectious disease project was added to evaluate the clinicalefficacy of Chinese medicine for blocking and reversing CHB-related liverfibrosis in 2013;

4. CONSORT Extension for Chinese Herbal Medicine Formulas 2017:Recommendations, Explanation, and Elaboration in Ann Intern Med. 2017,doi:10.7326/M16-2977

How can the efficacy and safety of Traditional Chinese Medicine regression of liver fibrosis be demonstrated through clinical trails

中国人民解放军第三O二医院

Regression of Liver Cirrhosis by Traditional

Chinese Medicine, Biejia-Ruangan Tablet (RGT),

in Patients with Chronic Hepatitis B: A

Multicenter, Randomized, Double-blind, Placebo-

controlled Trial[2013ZX10005002]

Historical origin for Commpound Biejia-Ruangan Tablet

1. a quintessence of TCM which represents China’s 5000 years philosophy pursuing the

harmony of nature and human, was used in the rural area of northern China for the

treatment of “liver stiffness and ascites ” for generations;

2. In 1967, the usefulness of RGT was accidentally witnessed by a group of Chinese

hepatologists;

3. In 1997, a randomized, double-blind clinical trial enrolling 420 CHB patients proved

that long-term RGT treatment resulted in histology-proved regression of

fibrosis/cirrhosis in 40.4% patients. Based on these data, in 1999, the Chinese Food

and Drug Administration (CFDA) approved RGT as the first TCM regime for the

treatment of liver fibrosis/cirrhosis caused by various chronic cirrhotic liver diseases;

4. To date, RGT has been used in China for almost two decades in more than 1,000,000

patients with chronic cirrhotic liver diseases;

The high-pressure liquid chromatography chemical fingerprint for the ethanol extract of RGT

（1）RGT contains at least 32 anti-fibrotic compounds；（2）some compound can reduce the expression of

tissue inhibitor of metalloproteinase (TIMP-1), andtype Ⅰ and Ⅲ procollagen by fibroblasts cells；

（3）strong inhibition of TGF-β/Smad inducedfibrogenesis and suppression of hepatic stellate cell(HSC) proliferation；

RGT contains multiple anti-fibrotic

components

1. Xiao X-h. Journal of Chromatography B 2016;1026: 145-151.

2. Zhou J. Chinese journal of integrative medicine 2015;21: 152-156.

3. Yang F-R. World J Gastroenterol 2013;19: 5326-33.

4. Niu JZ. World J Gastroenterol 2004;10:1487-1494

Fingerprint of Curcuma zedoaria

Curcuma zedoariae (Chinese drugs)

Dried roots of turmeric plant warm turmeric gold (Curcuma wenyujin Y.H.Chen et

C.Ling), named “ Wenzhou’ Rhizoma zedoariae”, place of origin: Wenzhou, Zhejiang

province, China.

The Chinese pharmacopoeia, 2015

Fingerprint of Radix Paeoniae rubra

Radix Paeoniae rubra (Chinese drugs)Dried roots of the paeonia lactiflora of ranunculaceae or “Sichuan” Paeonia veitchii

Lynch, excavation of Spring and autumn, place of origin: Wenzhou, Zhejiang province,

China.

The Chinese pharmacopoeia, 2015

Design based on international recognized criteria of clinical trail

to regression of hepatic fibrosis

•Patients with single etiology (study on hepatitis B related hepatic fibrosis (HB-HF))

•observation of disease progression during the whole course of disease

•Classification of HF including mild, moderate and severe stage, and more than 25%

patients with cirrhosis

•Reduces the liver-relating mortality

•Inhibits the progression from HF to cirrhosis, and reduces the morbidity of cirrhosis

•Reversed part of patients’ HF successfully, especially part of patients with cirrhosis

•Improved hepatic vascular structure and liver function of patients with cirrhosis

Patients’ inclusion criteria

Terminal criteria

• hard index: changes of liver tissues before and after treatment

• Soft index: FDA approval bio-marker to forecast progression of disease and efficacy

Evaluation criteria

临床试验注册

WHO注册号：ChiCTR- TRC-13003581

国际临床试验注册(Clinical Trail)号：NCT 01965418

1.TCM syndrome type :

syndrome of stagnation pf liver

qi and spleen deficiency, static

blood blocking collaterals; or

syndrome of static blood

blocking collaterals, Qi and

blood deficiency, Yin deficiency

of liver and kidney.

2. HBsAg Positive，HBVDNA

≥104

copies/ml，or≥2000 IU/ml;

3. Ishak：F≥3,

4. 18-65 years old, no limitation

of gender

Group 1: ETV+RGT

simulated agent(n=500)

Group 2: RGT+ETV (n=500)

Double-blind double-dummy treatment for 72w

组三：

Randomn=18

0

1. Major indexes

（1）hepatic biopsy twice bfore and after

treatment;

（2）LSM-FS;

(3)Scoring of TCM syndrome

（4）Scoring of TCM constitution

2. Minor indexes

（1）biochemical indexes

（2）liver function

（3）ultrasound of liver and spleen

（4）important clinical events

Flow chart of clinical efficacy evaluation on TCM RGT on the

regression of Hepatitis B related liver fibrosis

Flow chart

CharacteristicRGT+ Entecavir

(n=500)

Placebo+ Entecavir

(n=500)p value

Age (Mean±SD,Median) 41.9±9.7 (42.0) 41.7±10.0 (42.0) 0.75

Gender (Male/Female) 348/152 351/149 0.84

WBC (109/L) 5.5±1.7 5.5±1.7 0.99

HGB(g/L) 142.7±16.7 144.2±16.1 0.15

PT(s) 12.6±1.7 12.7±1.7 0.63

Normal ALT (n, %) 178(35.6%) 171(34.2%) 0.22

Bilirubin (umol/L) 16.8±15.1 17.2±17.1 0.71

Album (g/L) 41.8±4.6 43.5±25.2 0.15

Plate (109/L) 161.7±59.8 162.3±60.1 0.89

HBV-DNA (1og10 copies/ml) 6.9±1.7 6.9±1.6 0.87

HbeAg Positive (n, %) 290(58%) 291(58.2%) 0.95

Thicken Spleen(n,%) 279(56%) 290(58%) 0.23

Knodell Necroinflammatory Score 6.8±2.4 6.9±2.5 0.58

3-6/7-10/11-14 225/238/37 214/249/37 0.64

Ishak Fibrosis Score 4.6±1.2 4.5±1.2 0.35

3/4/5/6 118/117/106/159 142/104/96/158 0.40

Demographic and Baseline Characteristics of the Enrolled

Patients

HE

(100×)

Reticular fiber(100×)

Masson

(100×)

Ishak Score：G3F4

Evaluation of secondary hepatic biopsy for baseline and 72w

after double-blind treatment, which was performed by 3

pathologists from third party for independent observation.

16G hepatic biopsy needle:

（Single Action Biopsy Device,20mmx15mm,USA)

Baseline biopsy samples : the median length of 18.5 mm (range, 14.0-

26.0 mm; 77.9% ≥ 18 mm, 4.7% ≤ 15 mm), and on average

specimens contained 12 portal tracts (range, 10-15);

week 72 biopsy samples : the median length of 18.5 mm (range,

14.0-25.0 mm; 81.5% ≥ 18 mm; 4.0% ≤ 15 mm) and on average 12

portal tracts (range, 10-14).

RGT Synergistically Enhances Entecavir (ETV)-induced Regression of

Advanced Fibrosis in Patients with Chronic Hepatitis B

RGT+ETV vs. ETV of changes in Ishak fibrosis scores at baseline and at week 72

RGT +ETV: n = 358

PLC +ETV: n = 347

After treatment of RGT combination with ETV week 72, in 36.9% ofpatients with cirrhosis, regression of hepatic fibrosis was significant, andIshak score was less than or equal to 4, no longer cirrhosis.

Results of liver histological improvement of RGT combined with ETV in the treatment of CHB at week 72

Is there a definite linear relationship between hepatic histological improvement and regression of hepatic fibrosis?

RGT+ETV or ETV (n=705)

Necrinflammatory improvement

Regression of hepatic fibrosis

ETV (n=347)

Necrinflammatory improvement

Necrinflammatory improvement

Regression of hepatic fibrosis

Regression of hepatic fibrosis

ETV+RGT (n=358)

Sensitivity analysis of the regression of liver fibrosis andimprovement of hepatic tissue inflammation

Effect of RGT combined with ETV on the spleen thickness of patients with CHB for week 72

44.2%30.9%

11.5%

23.8%

syndrome types

(TCM)

Regression of liver fibrosis n（%） Blocking of liver fibrosis n（%）

ETV RGP+ETV P value ETV RGP+ETV P value

Qi and Yin

deficiency

0 103(46.82) 122(54.71) 0.1065 197(89.55) 202(90.58） 0.7525

1 13(20.23) 22(46.81) 0.1320 36(83.72） 40(85.11） 1

Blood Stasis

and block

Meridians

0 89(41.78) 101(52.06) 0.0466 188(88.26) 174(89.69） 0.7520

1 27(54.00) 43(56.58) 0.8552 45(90.00) 68(89.47) 1

Liver Stasis

and Spleen

deficiency

0 65(42.76) 99(57.89) 0.0075 132(86.84) 157(91.81) 0.1518

1 51(45.95) 45(45.45) 1.0000 101(90.99) 85(85.86) 0.2813

Liver and

kidney Yin

deficiency

0 114(45.06) 139(54.51) 0.0338 226(89.33) 229(89.80) 0.8855

1 2(20.00) 5(33.33) 0.6592 7(70.00) 13(86.67) 0.3577

10.28%

15.13%

9.45%

Analysis on the regression of hepatic fibrosis of HCB with different TCM

syndromes by syndrome differentiation and treatment

EventsRGT+ETV

(n=500)

Placebo+ETV

(n=500)P value

Adverse events 385 (78%) 366 (73.2%) 0.32

Serious adverse events 44 (8.8%) 43 (8.6%) 0.88

Discontinuation due to adverse events 1 (0.2%) 1 (0.2%) 1.00

ALT > 2× baseline and > 10× ULN 17 (3.4%) 19 (3.8) 0.52

Death 1 (0.2%) 3 (0.6%) 0.23

Table 2. Summary of Cumulative Safety Data

Conclusions

1. It is the first multi-center random clinical trail to assess clinical efficacy of RGT on the

regression of liver fibrosis involving a large amount of cases according to international

recognized criteria of clinical trail on blocking and reversing hepatic fibrosis.

2. It was confirmed that RGP combination with ETV can increase 13% （RGT+ETV:59% vs.

ETV:46%, p=0.0147）, especially 23.18% of patients with significant fibrosis up to no or mild

fibrosis after treatment week 72.

3. For patients with advanced fibrosis, RGT combination with ETV can increased 15.23%

（ RGP+ETV:57.87% vs. ETV:42.64%, p=0.0268 ), especially, 53.7% of patients with cirrhosis were

reversed hepatic cirrhosis after treatment, which made up the limitation of nucleoside drug to

reversing the advanced fibrosis.

4.The options is more fit for CHB patients with stagnation of liver qi and spleen deficiency (A) or

sydrome of static blood blocking collaterals (B), whose reversing HB ratio increased 15.13% (A:

p=0.0075) and 10.28% (B: p=0.0466), respectively. It showed superiority and characters of RGP

on blocking and regression the advanced fibrosis.

Unite for a greater victory

Thank you for your attention

汇报人：杨永平中国人民解放军第三O二医院