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Clinical Reports  
HBV CLinical Reports
ShenZhenLiuHuaHospital
Clinical Trial Report
Combination Treatment of Chronic Hepatitis B using YGK and Lamivudine
 

Introduction

Purpose

Perform a clinical trial that fulfills the 4 requirements based on the standards set by the ¡°15¡± Category National Scientific Achievement Project, section 7 ¨C Traditional Chinese Medicine treatment of Chronic Hepatitis B clinical trials (hereafter referred to as 15CNSAP).

Requirements

  1. Choosing a TCM drug that has high efficacy treatment potential for clinical trials in multiple sites
  2. HBeAg & HBV-DNA negativity rate as the main treatment success criteria
  3. A western drug, approved and available on the market, will be used as a comparative
  4. Analysis and discussion of TCM inhibition of viral replication efficacy rate in clinical trials

Brief Summary

This trial consists of 3 groups with a total of 135 patients

Group A
  • Combination Treatment Group (YGK & Lamivudine)
  • 48 patients
Group B
  • Lamivudine Control Group
  • 42 patients
Group C
  • YGK ControlGroup
  • 45 patients

After 4 weeks of treatment Group A has a 95.8% HBV-DNA negativity rate (46/48) and after 8 weeks HBV-DNA negativity rate is 100%. The data for Group A¡¯s HBeAg negativity rate for weeks 4, 8, 16 and 32 are as follows:

Group A: HBeAg negativity Rate ¨C P < 0.01
  • Week 4 ¨C 18.8% (9/48)
  • Week 8 ¨C 37.5% (18/48)
  • Week 16 ¨C 47.9% (23/48)
  • Week 32 ¨C 81.3% (39/48)

When Group A¡¯s results is compared to Group B¡¯s results, there is an observable improvement; P < 0.01. When compared to Group C¡¯s results, the improvement isn¡¯t as obvious; P > 0.05.

Group A: HBsAg negativity rate ¨C P < 0.01
  • Week 4 ¨C 4.2% (2/48)
  • Week 8 ¨C 18.7% (9/48)
  • Week 16 ¨C 37.5% (18/48)
  • Week 32 ¨C 50% (24/48)

Group A¡¯s results in this case is basically better than the results of Group B and C; P < 0.01
Tests performed at 24 weeks and 48 weeks after treatment has stopped showed that Group A¡¯s HBV-DNA maintained negative status for all the patients. In addition, HBeAg and HBsAg continued toturn negative in cases that were still positive at the end of the treatment periods. The conclusion we can draw from the data is that the combination treatment of chronic hepatitis B using YGK and Lamivudine has a high efficacy rate for the negativity of HBV-DNA, HBeAg and HBsAg in the blood serum and also beneficial long term results.

Table 1

Group

HBV-DNA
(Negative)

HBeAg
(Negative)

HBeAg
(Negative)
Chronic Carrier

HBV-DNA
(Negative)
Chronic Carrier

HBeAG
50% Chronic Viral Titer Reduction

15CNSAP

> 50%

> 50%

> 30%

> 30%

70%

A

100%

87.5%

87.5%

100%

87.5%

B

61.9%

0

0

0

0

C

93.3

71.1%

71.1%

93.3%

71.1%

The results from Group A and B, 48 weeks after treatment, has exceeded every criteria of the 15CNSAP standard. This is the first potential combination treatment using a western drug with TCM for the treatment of chronic hepatitis B. The result from this trial gives us a new direction of exploration for the treatment of other viral related or chronic diseases.

Trial Report

Brief Background

Reviewing the historic data on the progression of domestic and international development for the treatment of chronic hepatitis B, it is shown that TCM has a unique perspective and treatment methodology for the treatment of chronic hepatitis B. Especially when it comes to viral resistance mechanisms and intravenous delivery of TCM, these are the most exciting areas with a lot of growth potential.

Our hospital has been using YGK capsule and YGK intravenous injection liquid, developed by Gong Ming Pharmaceutical Ltd., in clinical studies. We discovered that YGK has good clinical results in the negativity of HBV-DNA, HBeAg and HBsAg in the blood serum. In order to further verify and increase the potential effectiveness of YGK, we conducted a YGK & Lamivudine combination treatment clinical trial during the periods of May 1998 to May 2000.

Patient Selection

Viable Candidates

  1. Patient must be diagnosed with chronic hepatitis B based on standards developed in 1990
  2. HBV-DNA in blood serum must be positive; Patient must also be HBV-DNA positive 3 weeks before the commencement of the trial
  3. HBeAg and HBsAg must be persistent positive; ALT levels must be fluctuating or persistent abnormal levels

Un-viable Candidates

  1. Ages below 18 or over 60. Women candidates cannot be pregnant or lactating.
  2. Has complications of coronary, lung, kidney, marrow, or mental diseases
  3. Unable to fulfill any of the viable candidate conditions, failure to take medication on time, unavailability during clinical trial period, inability to determine efficacy and effectiveness of treatment and influence of treatment effectiveness or efficacy and safety pre-cautions of any personnel involved.

    ¡¡¡¡¡¡ Grouping and Treatment Methodology

Grouping methodology

Randomized selection of candidates, choosing 135 viable candidates from the list, separated into groups A, B and C for clinical observation. Groups are then reviewed on sex, age, condition, progress of disease, etc. and then process through statistical analysis to ensure that the candidates are evenly distributed (P > 0.05). The purpose is to show that the groups are similar in their distribution of sex, age, condition, progress of disease, etc.

Group A is designated as the treatment group with 48 patients.
Group B and C are designated as the control groups with 42 and 45 patients respectively.

Treatment methodology

Group A
  1. 10ml of YGK intravenous injection liquid mixed with 500ml of 5% glucose solution applied intravenously once per day
  2. 6 YGK capsules (0.22g/capsule) 3 times a day
  3. 1 Lamivudine tablet (100mg/tablet) once per day
  4. Each treatment period is 4 weeks
  5. YGK intravenous injection liquid is applied for 2 treatment periods
  6. YGK capsules is applied for 8 treatment periods
  7. Lamivudine is applied for 4 treatment periods
Group B
  1. 1 Lamivudine tablet (100mg/tablet) once per day
  2. Each treatment period is 4 weeks
  3. Lamivudine is applied for 8 treatment periods
Group C
  1. 10ml of YGK intravenous injection liquid mixed with 500ml of 5% glucose solution applied intravenously once per day
  2. 6 YGK capsules (0.22g/capsule) 3 times per day
  3. Each treatment period is 4 weeks
  4. YGK intravenous injection liquid is applied for 4 treatment periods
  5. YGK capsules is applied for 8 treatment periods

Observation criteria and Efficacy evaluation Methodology

Observation criteria

  1. Blood serum of every patient in the trial is tested on the following items before the start of the trial, at weeks 4, 8, 16, and 32 during the trial and 24 and 48 weeks after the trial
    1. HBV-DNA
    2. HBeAg
    3. Anti-HBe
    4. HBsAg
    5. Anti-HBs
  2. ALT levels are tested for every patient before the start of the trial, at weeks 4, 8, 16, and 32 during the trial and 24 and 48 weeks after the trial.
  3. Doctors will observe, diagnose and record any side-effects from out-patient and home visits during the treatment periods. If any side-effects is determined, the proper measures will be taken.
 

Evaluation methodology

Tests will be performed at weeks 4, 8, 16, and 32 during the trial and 32 and 48 weeks after the trial. Once the entire observation and monitoring period has concluded, all the data will be compiled through statistical analysis. Comparative analysis will then be done on the compiled data based on the groups. Quantitative data will also be added to the qualitative data before making the final evaluation.

Observation Results

Treatment periods report and evaluation

Trial Data ¨C Week 4

Table 2

Group

# of Patients

ALT Normalization

HBV-DNA
(Negative)

HBeAg
(Negative)

Anti-HBe
(Positive)

HBsAg
(Negative)

A

48

47

46

9

9

2

B

42

28**

0**

0**

0**

0

C

45

38*

16**

3

3

0

* P < 0.05 compared to Group A** P < 0.01 compared to Group A

We can conclude from the data in Table 2, that after 4 weeks each group has an observable improvement, especially in the case of Group A.

ALT Normalization percentages
  • Group A ¨C 97.9% (47/48)
  • Group B ¨C 66.75% (28/42)
  • Group C ¨C 84.4% (38/45)
ALT Normalization rate comparative statistical analysis of Group A compared to Group B and C:

For

  • Group B
    • X2 = 15.75
    • P < 0.01
  • Group C
    • X2 = 5.39
    • P < 0.05

There is an observable improvement in ALT levels. ¡¡ ¡¡

¡¡¡¡¡¡¡¡¡¡¡¡¡¡ ¡¡¡¡

HBV-DNA negativity rate percentages
  • Group A ¨C 95.8% (46/48)
  • Group B ¨C 0% (0/42)
  • Group C ¨C 35.6% (16/45)
HBV-DNA negativity rate comparative statistical analysis of Group A compared to Group B and C:

For

  • Group B
    • X2 = 82.35
    • P < 0.01
  • Group C
    • X2 = 38.04
    • P < 0.01

There is a huge observable improvement in the negativity of HBV-DNA in Group A compared to that of Group B and C.

¡¡¡¡¡¡¡¡¡¡¡¡¡¡

HBeAg negativity rate percentages
  • Group A ¨C 18.8% (9/48)
  • Group B ¨C 0% (0/42)
  • Group C ¨C 6.7% (3/45)
HBeAg negativity rate comparative statistical analysis of Group A compared to Group B and C:

For

  • Group B
    • X2 = 8.55
    • P < 0.01
  • Group C
    • X2 = 3.07
    • P > 0.05

The negativity rate of Group A is observably higher than that of Group B and C. The difference is extremely noticeable when compared to Group B but negligible when compared to Group C.¡¡¡¡¡¡¡¡¡¡¡¡¡¡
¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡

HBsAg negativity rate percentages

  • Group A ¨C 4.2% (2/48)
  • Group B ¨C 0% (0/42)
  • Group C ¨C 0% (0/45)
HBsAg negativity rate comparative statistical analysis of Group A compared to Group B and C:

For

  • Group B
    • X2 = 1.80
    • P > 0.05
  • Group C
    • X2 = 1.95
    • P > 0.05

Although Group A has a higher negativity rate than that of Group B and Group C, the difference is negligible.


Summary

At this point in the trial, Group B has failed to produce a negativity result in a patient for HBV-DNA, HBeAg and HBsAg.

Trial Data ¨C Week 8

Table 3

Group

# of Patients

HBV-DNA
(Negative)

HBeAg
(Negative)

Anti-HBe
(Positive)

HBsAg
(Negative)

Anti-HBs
(Positive)

A

48

48

18

18

9

0

B

42

0**

0**

0**

0**

0

C

45

16**

11

11

0**

0

** P< 0.01 compared to Group A

From the data in Table 3, we can conclude that after 8 weeks, each group except for Group B continues to improve, especially in the case of Group A.

HBV-DNA negativity rate percentages
  • Group A ¨C 100% (48/48)
  • Group B ¨C 0% (0/42)
  • Group C ¨C 35.6% (16/45)

Group A has a total HBV-DNA negativity conversion (the last 2 patients) while Group B and C¡¯s HBV-DNA negativity remained unchanged from the previous treatment period.

HBeAg negativity rate percentages
  • Group A ¨C 37.5% (18/48)
  • Group B ¨C 0% (0/42)
  • Group C ¨C 24.4% (11/45)
HBeAg negativity rate comparative statistical analysis of Group A compared to Group B and C:

For

  • Group B
    • X2 = 19.62
    • P < 0.01
  • Group C
    • X2 = 1.86
    • P > 0.05

Group A continues to improve and maintains a lead over Group B and C. Group B has failed to produce any improvements yet while Group C has made improvements.


HBsAg negativity rate percentages
  • Group A ¨C 18.7% (9/48)
  • Group B ¨C 0% (0/42)
  • Group C ¨C 0% (0/45)
HBsAg negativity rate comparative statistical analysis of Group A compared to Group B and C:
  • Group B
    • X2 = 8.55
    • P < 0.01
  • Group C
    • X2 = 9.39
    • P < 0.01

Group A continues to improve while Group B and C has no improvements from the previous treatment period.

Summary

There is still no negativity result from Group B. Group A has also concluded the application of YGK intravenous injection liquid at this point in the trial.

 

Trial Data ¨C Week 16

Table 4

Group

# of Patients

HBV-DNA
(Negative)

HBeAg
(Negative)

Anti-HBe
(Positive)

HBsAg
(Negative)

Anti-HBs
(Positive)

A

48

48

23

23

18

5

B

42

26**

2**

0**

0**

0

C

45

36**

14

14

6**

0

** P < 0.01 compared to Group A

From the data in Table 4, Group A and C continues expected improvements based on the first 2 treatment periods. Group B is beginning to produce a little result at this stage.

HBV-DNA negativity rate percentages
  • Group A ¨C 100% (48/48)
  • Group B ¨C 61.9% (26/42)
  • Group C ¨C 80% (36/45)
HBV-DNA negativity rate comparative statistical analysis of Group A compared to Group B and C:

For

  • Group B
    • X2 = 22.32
    • P < 0.01
  • Group C
    • X2 = 10.60
    • P < 0.01

Group A is maintaining 100% persistent HBV-DNA negativity even with the discontinuation of YGK intravenous injection liquid. There is still an observable difference in performance between the groups.


HBeAg negativity rate percentages
  • Group A ¨C 47.9% (23/48)
  • Group B ¨C 4.8% (2/42)
  • Group C ¨C 31.1% (14/45)
HBeAg negativity rate comparative statistical analysis of Group A compared to Group B and C:

For

  • Group B
    • X2 = 20.79
    • P < 0.01
  • Group C
    • X2 = 2.79
    • P > 0.05

Group A and C continue to improve while Group B is beginning to show some results.

HBsAg negativity rate percentages
  • Group A ¨C 37.5% (18/48)
  • Group B ¨C 0% (0/42)
  • Group C ¨C 13.3% (6/45)
HBsAg negativity rate comparative statistical analysis of Group A compared to Group B and C:

For

  • Group B
    • X2 = 19.62
    • P < 0.01
  • Group C
    • X2 = 7.07
    • P < 0.01

Group A¡¯s results is observably much higher than that of the other groups. Group B still has not shown any progress in this category.

Summary

Group B has begin to show some more progress by week 16, however it is still very far behind the results of Group A. At this point in the trial, Group A has discontinued use of Lamivudine and Group C has discontinued use of YGK intravenous injection liquid.

Trial Data ¨C Week 32

Table 5

Group

# of Patients

HBV-DNA
(Negative)

HBeAg
(Negative)

Anti-HBe
(Positive)

HBsAg
(Negative)

Anti-HBs
(Positive)

A

48

48

39

39

24

12

B

42

38*

4**

4**

1**

1

C

45

42

28*

28*

16

7

* P < 0.05 compared to Group A** P < 0.01 compared to Group A

From the data in Table 5, expected improvements continues with Group B showing more promising results.

HBV-DNA negativity rate percentages
  • Group A ¨C 100% (48/48)
  • Group B ¨C 90.5% (38/42)
  • Group C ¨C 93.3% (42/45)
HBV-DNA negativity rate comparative statistical analysis of Group A compared to Group B and C:

For

  • Group B
    • X2 = 4.77
    • P < 0.05
  • Group C
    • X2 = 3.35
    • P > 0.05

Comparatively Group B¡¯s result after statistical analysis still lags behind the results of Group A and C. Despite the fact that Group A has discontinued use of Lamivudine and YGK intravenous injection liquid and Group C has discontinued use of YGK intravenous injection liquid.


HBeAg negativity rate percentages
  • Group A ¨C 81.3% (39/48)
  • Group B ¨C 9.5% (4/42)
  • Group C ¨C 62.2% (28/45)
HBeAg negativity rate comparative statistical analysis of Group A compared to Group B and C:

For

  • Group B
    • X2 = 46.26
    • P < 0.01
  • Group C
    • X2 = 4.19
    • P < 0.05

There are still observable difference in the results compared to Group A despite improvements in this category by Group B and C.

HBsAg negativity rate percentages
  • Group A ¨C 50.0% (24/48)
  • Group B ¨C 2.3% (1/42)
  • Group C ¨C 35.5% (16/45)
HBsAg negativity rate comparative statistical analysis of Group A compared to Group B and C:

For

  • Group B
    • X2 = 25.38
    • P < 0.01
  • Group C
    • X2 = 1.95
    • P > 0.05

All Groups have continued to improve with varying degrees of success. Group B¡¯s results has a huge difference compared to Group A while Group B¡¯s results is relatively closer to that of Group A¡¯s.

Summary

At this point in the trial, although Group B has varying degrees of success in producing negativity results, it is still very far behind the results of Group A and Group C, despite the fact that both Group A and C has reduce the number of types of drugs being applied to the patients to only YGK capsules.

Side-effects observation

Group A
  • Dull pain at point of injection
  • Dryness in mouth (Xerostomia)
Group B

Week 16

  • 8 patients experienced loss of appetite including loss of desire for anything greasy, discomfort near the liver area and abnormal fluctuation of ALT levels. Symptoms dissipated after 2 more weeks of further treatment and ALT levels normalized.
Group C
  • Dryness in mouth (Xerostomia)

Week 8

  • 17 patients experienced discomfort near the liver area, and abnormal fluctuation of ALT levels. Symptoms dissipated as treatment continued and ALT levels normalized.
 

Follow up observations after conclusion of treatment period

At 24 and 48 weeks after the conclusion of the treatment period, all patients involved were tested on all observation criteria.

Table 6

Group

# of Patients

HBV-DNA
(Negative)

HBeAg
(Negative)

Anti-HBe
(Positive)

HBsAg
(Negative)

Anti-HBs
(Positive)

Week 24

Week 48

Week 24

Week 48

Week 24

Week 48

Week 24

Week 48

Week 24

Week 48

A

48

48

48

42

42

42

42

29

29

29

29

B

42

38*

26**

4**

0**

4**

0**

1**

0**

1**

0**

C

45

42

42

32*

32*

32*

32*

18

18

11*

11*

* P < 0.05 compared to Group A** P < 0.01 compared to Group A
Group A
  • HBV-DNA has 100% persistent negativity 48 weeks after stopping treatment
  • HBeAg and HBsAg negativity persistence has been sustained as well.
  • Originally there were only 39 patients with negative HBeAg. When tested, 3 more patients had HBeAg turning negative after the treatment resulting in an 87.5% (42/48) negativity success, an increase of 6.2%
  • HBsAg negativity rate was also improved after the treatment period with 5 more patients¡¯ HBsAg turning negative for a 60.4% negativity success. This is an improvement of 10.4% compared to the data at the conclusion of the Treatment.
Group B
  • Experienced a decrease in negativity success rate all across the board.
  • 12 patients experienced a relapse back to HBV-DNA positive. A decline of 28.6% dropping from 90.5% to 61.9% (26/42).
  • HBeAg and HBsAg negative patients in this group all experienced a relapse back to positive
Group C
  • HBV-DNA sustained negativity persistence at 93.3% (42/45)
  • HBeAg negativity rate was also improved after the treatment period with4 more patients¡¯ HBeAg turning negative, an increase of 8.9% to 71.1% (32/45) from 62.2% (28/45)
    Comparative statistical analysis to Group A shows some obvious difference for X2 = 3.91; P < 0.05.
  • HBsAg also experienced negativity rate improvements, rising from 35.5% (16/45) to 40.0% (18/45), an increase of 4.5% or 2 patients.
    Comparative statistical analysis to Group A shows no obvious difference for X2 = 3.81; P > 0.05

Discussion, Analysis and Conclusion

The criteria to determine whether a treatment of chronic hepatitis B is successful should be based on the following results:

  1. Persistent negativity of HBV-DNA. HBV-DNA should be negative in the blood serum and liver cells.
  2. Negativity of HBsAg and the production of Anti-HBs
  3. Negativity of HBeAg and the production of Anti-HBe
  4. Inhibition of HBV replication
  5. Observable improvement to damaged Liver cells; ALT level normalization, Liver biopsy ¨C Damage due to Hepatitis reduced

The structure and replication process of HBV is very complicated. In addition the virus has a very close-knit relationship with the state of the immune system of the patient while it exists or is active in the patient. It is very difficult in clinical treatments to achieve the goal of full elimination of HBV or inhibit its replication. Therefore the treatment of chronic hepatitis B should focus on finding a point of entry in the replication process of the virus to inhibit the process, boosting the immune system, overcoming the immuno-tolerance of the virus, re-establish the balance of the immune system to achieve a well rounded treatment.

This trial used a combination treatment of Lamivudine and Gong Ming YGK for the treatment of chronic hepatitis B in an effort to fulfill the goals discussed in the paragraph before. Lamivudine is considered the representative of the 2nd generation of nucleoside analog drug development, its antiviral capabilities has garnered much attention. Lamivudine is a reverse transcriptase inhibitor which fulfils the role of inhibiting viral replication at the first phases of replication. Our trial data has shown that after 6 months of treatment, Lamivudine can reduce HBV-DNA with a 90.4% success rate, however HBeAg negativity rate is extremely low with only 9.5% success rate after a long period of treatment. The relapse rate is also extremely high once the treatment is stopped. This shows the Achilles heel of using 1 type of drug to inhibit viral replication at only 1 point in the process of viral replication. YGK contains 2 types of preparations; the YGK intravenous injection liquid has direct anti-HBV properties. According to Gong Ming Pharmaceuticals Ltd., YGK intravenous injection liquid can inhibit viral replication by preventing access to nucleotide substances and needed nutrients for replication. This forces the virus to die off naturally from a lack of nutrients needed for replication and survival. YGK capsules have an obvious effect in protecting liver cells, and restoring the immune system balance. By combining the 2 parts of YGK, anti-HBV, restoring liver functions and immune system balance can be achieved.

Our trial used Lamivudine to inhibit viral replication, and YGK intravenous injection liquid to prevent viral nutrition access to achieve a multi-point, multi-facet attack on HBV replication process, and with YGK capsules assisting in restoring immune system balance, an amazing 100% HBV-DNA negativity result was achieved in a matter of 8 weeks. Stopping the application of Lamivudine at week 16, we have already achieved a negativity success rate of 47.9% for HBeAg and 37.5% for HBsAg. Negativity success rate continued to rise despite the conclusion of the drug applications with a final negativity success rate of 87.5% for HBeAg and 60.4% for HBsAg. Using this combination treatment, not only can we shorten the length of time needed for the application of Lamivudine, it indirectly resolved the biggest problem of drug resistance that Lamivudine faces after prolonged use which usually results in poorer treatment results as the patient suffers a relapse. Using this method, we have observed the continuation of HBeAg, and HBsAg turning negative after the treatment has concluded, which bodes extremely well for long-term treatment effects. This trial has shown a new direction for the clinical treatment of chronic hepatitis B and is definitely worthy of further study.

End

Credits

Authors

Dr. Wang You Fu, Vice-Supervisor Doctor, ShenZhenLiuHuaHospital
(ÍõÓÓ·ò, ¸±Ö÷ÈÎҽʦ; ÉîÛÚÁ÷»¨Ò½Ôº)

Dr. Mu Wei Li, Vice-Supervisor Doctor, ShenZhenLiuHuaHospital ¨C Hepatology Department Head
(IJΰÀû, ¸±Ö÷ÈÎҽʦ; ÉîÛÚÁ÷»¨Ò½Ôº¨C ¸Î²¡¿ÆÖ÷ÈÎ)

Translation (English)

Warren Liu, East Wellsum (S) Industries Pte Ltd.

Points 1 ¨C 4: Zhang Yi Jun, Zhang Gu Sheng. Treatment of Hepatitis B Virus, Shanghai: Shanghai Scientific Technology Publishing, 2001; 72~82
ÕÅÒË¿¡, Õ¹ÈÉú. ÒÒÐ͸ÎÑ×ÉúÎïÖÎÁÆ, ÉϺ£: ÉϺ£¿ÆÑ§³ö°æÉç, 2001; 72~82

Point 5: Xu Bao Ping, Wang Wei An, et al. Alimentary system immunology, Beijing: Scientific Publishing, 2000, 357~364
Óౣƽ, Íõΰ°¶, µÈ. Ïû»¯Ïµ¼²²¡ÃâÒßѧ, ±±¾©: ¿ÆÑ§³ö°æÉç, 2000, 357~364

Main J Brown JL, Karayiannis P, et al. A double placer controlled study to assess the effect of famcicloviv on virus replication in patients with chronic hepatitis B infection J Hepatol, 1994; 21 (supplement)