Efficacy of standardized extract of Phyllanthus niruri , EPN 797 in inducing HBeAg clearance and seroconversion of HBV infection: three case reports

 

K.T. Singam

B.sc. MBBS [S’PORE], MCGP., DIP. STD./AIDS

K Singam And Associate Clinic, Sg. Pelek, Sepang, Selangor.

K. A. Ong

B. Pharm.[USM], Rph.

2Nova Laboratories Sdn. Bhd., Sg. Pelek, Sepang, Selangor.

 

ABSTRACT:

 

Active viral replication in hepatocytes is indicated by the presence of hepatitis B e antigen (HBeAg) in serum. HBeAg is thus a surrogate marker for the presence of hepatitis B virus DNA. There are recent data that show  the relationship between the risk of developing hepatocellular carcinoma (HCC) with the activity of the virus. There is a markedly increased risk of developing HCC in those individuals with chronic hepatitis B who are also e-antigen positive. We describe three cases where patients with positivity of HBeAg treated with the combination therapy of lamivudine 100mg and EPN 797 1500mg daily or monotherapy with EPN 797 1500 mg daily alone for a duration of treatment ranged from 3 to 7 months, had achieved HBeAg clearance in all three cases and seroconversion in 2 cases. Throughout the treatment period, these three patients had normal ALT level. These three cases suggested that the use EPN 797 alone or combination with lamivudine might be useful in inducing HBeAg clearance and seroconversion that could possibly reduce the risk of developing HCC.

 

Correspondent to:

Email     :              kuiannong@nova.com.my(K.A.Ong)

Tel          :               03-3141 3181

Fax         :               03-3141 1661

 

1.     INTRODUCTION

 

 

 

·        Hepatitis B virus (HBV) infection is a serious global health problem.

 

·        Recent data has shown there is a markedly increased risk of developing HCC in those individuals with chronic hepatitis B who are also e-antigen positive.1

 

·        EPN 797, is the standardized extract from Phyllanthus niruri, commercially available as Hepar-PTM capsule (250 mg of EPN 797), contains 4% of corilagin (a strong antiviral compound) and 18% of total Phyllanthus flavonoids (potent  inhibitor for hepatocyte lipid membrane peroxidation)

 

·        Dr. Baruch Blumberg, the 1976 Nobel Prize winner for his discovery of the HBV antigen, has found that Phyllanthus niruri could clear up the chronic carrier state of Hepatitis B.2

 

·        We describe three cases in which patients with positivity of HBeAg was treated with the combination therapy of lamivudine 100mg and EPN 797 1500mg daily or monotherapy with EPN 797 1500 mg daily alone for a duration of treatment ranged from 3 to 7 months, had achieved HBeAg clearance in all three cases and seroconversion in 2 cases.

 

 

 

 

 

 

 

 

2.0   CASE REPORT

 

Case 1:

 

Patient’s name : SLM                       Gender : Female                   Ethnic group : Chinese                     Age :  50

 

History of present illness : 

  • Known chronic HBV carrier for more than 15 years
  • Two of her children are also known carriers

 

Test

Time of testing

Reference range

November 99

August 02

(Treatment Initiation)a

May 03

Liver Function Test

Total protein

77

-

80

66-87 g/L

Albumin

41

-

42

38-50 g/L

Globulin

36

-

38

18-42 g/L

A/G Ratio

1.1

-

1.1

1.0-2-2

Total bilirubin

11.0

-

9

< 20.0 umol/L

ALT (SGPT)

51

-

54

8 – 54

AST (SGOT)

35

-

38

16 – 40

ALP

92

-

76

36-110 IU/L

GGT

37

-

47

8-35 IU/L

AFP

2.5

-

-

< 12 kU/L

Hepatitis B Serology

HBsAg

Reactive

Reactive

Reactive

 

HBsAb

Negative

Negative

Negative

 

HBeAg

Reactive

Reactive

Non-reactive

 

HBeAb

Negative

Negative

-

 

a Lamivudine 100 mg daily + EPN 797 500 mg three times daily

 

Case 2:

 

Patient’s name :  SPC                      Gender :  Female                  Ethnic group : Chinese                     Age :   38

 

History of present illness : 

  • Known chronic HBV carrier for more than 5 years

 

Test

Time of testing

Reference range

June 03

April 03

(Treatment Initiation)b

July 03

Liver Function Test

Total protein

84

-

82

66-87 g/L

Albumin

48

-

50

38-50 g/L

Globulin

36

-

32

18-42 g/L

A/G Ratio

1.3

-

1.6

1.0-2-2

Total bilirubin

10

-

16

< 20.0 umol/L

ALT (SGPT)

43

-

22

8 – 54

AST (SGOT)

36

-

22

16 – 40

ALP

19

-

42

36-110 IU/L

GGT

19

-

14

8-35 IU/L

AFP

1.0

-

0.7

< 12 kU/L

Hepatitis B Serology

HBsAg

Reactive

Reactive

Reactive

 

HBsAb

Negative

Negative

Negative

 

HBeAg

Reactive

Reactive

Non-reactive

 

HBeAb

Negative

Negative

Reactive

 

 

b EPN 797 500 mg three times daily

 

 

 

 

Case 3:

 

Patient’s name :  LCH                      Gender :  Female                  Ethnic group : Chinese                     Age :   74

 

History of present illness : 

  • Known chronic HBV carrier for more than 5 years
  • Husband died of HCC

 

Test

Time of testing

Reference range

February 02

March 02

(Treatment Initiation)c

July 02

Liver Function Test

Total protein

71

-

-

66-87 g/L

Albumin

42

-

-

38-50 g/L

Globulin

29

-

-

18-42 g/L

A/G Ratio

1.4

-

-

1.0-2-2

Total bilirubin

20

-

-

< 20.0 umol/L

ALT (SGPT)

21

-

13

8 – 54

AST (SGOT)

25

-

22

16 – 40

ALP

81

-

-

36-110 IU/L

GGT

14

-

-

8-35 IU/L

AFP

1.3

-

1.2

< 12 kU/L

Hepatitis B Serology

HBsAg

Reactive

Reactive

Reactive

 

HBsAb

Negative

Negative

Negative

 

HBeAg

Reactive

Reactive

Non-reactive

 

HBeAb

Negative

Negative

Reactive

 

 

c EPN 797 500 mg three times daily

 

 

4.0   DISCUSSION

 

 

 

4.1                   Phytopharmaceutical used:      

 

 

·        Phyllanthus niruri (local name: dukung anak) is a small plant from the family of Euphorbiaceae which is indigenous to Malaysia.

 

·        EPN 797 is standardized extract of Phyllanthus niruri which contains the following compounds:

a)    a bioactive polyphenol fraction consists of corilagin, geraniin and brevifolincarboxylic acid (antiviral compounds)

b)    a bioactive Phyllanthus flavonoids fraction containing rutin and other plant flavonoids (strong liver protection by acting as an inhibitor of hepatocyte lipid membrane peroxidation).

 

 

 

4.2                       Relationship of HBeAg seropositivity and HCC

 

·        The cumulative HCC risk from age 30  to 70 years has been estimated to be 87% for those with persistently seropositive on HBsAg and HBeAg, 12% for those with persistently seropositivity of HBsAg only, and 1% for those who were seronegative on HBsAg and HBeAg3.

 

 

 

 

 

4.3                       Definition of treatment end points

 

·        Important in the treatment of chronic HBV infection and the evaluation of the efficacy of therapeutic agent.

 

·        The treatment end points in hepatitis B are as follows4:

i)                   to normalize the ALT

ii)                 to decreased the HBV DNA to very low or undetectable levels by polymerase chained reaction (PCR)

iii)               to induce loss of e-antigen

iv)               to develop e-antibody if possible

v)                 to achieve histopathological improvement

 

 

    4.4                   Phases of Chronic HBV infection*.

 

Phases

HBsAg

HBeAg

HBV DNA (copies/ml)

ALT levels (IU/L)

Immunotolerant

+

+

105 - 1010

Persistently normal

Immuno-

active

 

Variation 1

(wild type)

+

+

 

 

104 – 108

 

 

Persistenly or intermittently elevated

Variation 2

(mutants)

+

-

Non-replicative

+

(may become negative over long-term)

-

102 – 105

 

Persistently normal

*This is a framework used by us and it may not be perfect.

 

 

4.6         Patients’s Response

 

·        The above patients are normally classified to be in the immunotolerant phase of HBV infection with very low rate of spontaneous HBeAg clearance.

·        In Case 1, initial response was shown by the clearance of HBeAg after 7 months of therapy.

·        The remaining two cases, response as shown by HBeAg seroconvertion was noted as early as 3 months in Case 2 and 4 months in Case 3 respectively.

 

4.7        Limitations of the above case reports.

 

·        Patients were not tested for HBV DNA, this had caused the incomplete evaluation of patients’ response.

·        Liver enzyme levels tested were at a single time point, this may cause misclassification of patients into different phases of HBV infection. This may lead to the  inappropriate interpretation of patient’s response.

 

5.0   Conclusion

 

·        The effect of EPN 797 in inducing HBeAg clearance in the immunotolerant phase may offer a new treatment option for this category of patients.

·        However, a number of better designed trials are underway to evaluate its therapeutic potential.

 

6.0   Reference

 

1.         You SL et al. Ann Med.2004; 36(3):215-24.

      2.         Thyagarajan SP, B.S Blumberg et al., Lancet, 1988. 2(8614): 764-6

      3.        Yang HI. et al. NEJM. 2002(Jul); 347: 168-74.

      4.        Conjeevaram HS. J Hepatol. 2003; 38: S30-S103