AbstractBackground: Spontaneous hepatitis B surface antigen (HBsAg) seroclearance is a rare event in patients with chronic hepatitis B virus (HBV) infections and there is little available literature on it. Objective: This study intended to identify determinants for HBsAg seroclearance in persons with chronic HBV using a large cohort of Chinese patients with 11 years of follow-up.Design/Methods: This secondary data analysis used the database of a prospective cohort study of 1863 subjects who had returned 11 years after initial cohort entry (1992-93) to undergo further testing of viral markers and HBsAg-status. Of those 1863 subjects, 341 (18.30%) had apparently cleared HBsAg by 2003. Spontaneous HBsAg seroclearance was investigated in terms of its relationship to age, HBeAg-status, gender, HBV-DNA viral load, and history of clinical hepatitis.Results: Of the 365 persons who were 50 years and older, 93 (25.47%) spontaneously cleared HBsAg. In contrast, only 248 (16.56%) of the 1498 subjects younger than 50 years of age cleared HBsAg (p<.0001). The incidence of HBsAg seroclearance was also significantly higher in persons who were HBeAg-negative compared to persons who were HBeAg-positive (21.52% vs. 13.17%; p <.0001). And HBsAg seroclearance incidence was higher in persons with a low-positive (21.37%) HBV-DNA viral load than in persons with either a negative (16.77%) or a high-positive (14.13%) viral load (p=.0009).Conclusions: Results suggest that the age of patients, HBeAg-status, and HBV-DNA viral load are determinants for spontaneous HBsAg seroclearance. However, gender and history of clinical hepatitis did not significantly influence the occurrence of HBsAg seroclearance.

Statement of the Problem

• Hepatitis B virus (HBV) infection is a major global public health concern because it is closely associated with serious outcomes, most notably liver cancer and cirrhosis.

• Worldwide Hepatitis B statistics:– > 2 billion people (1/3 of the world’s population) have been

infected at some point in their lives– 800 million current infected persons– 350 million current chronic carriers– 75% of all chronic carriers are in Asia– 50 million new cases/year– Accounts for 60-80 percent of liver cancer cases (the leading

cause of liver cancer) – Accounts for 500,000 to 1.2 million deaths per year (10th

leading cause of death worldwide)

Background and Significance

• Most (90%) HBV infections are acute and self-limited; – Hepatitis B surface antigen (HBsAg) is cleared from the infected

person’s blood within 6 months.

• And, 10% of all HBV infections become chronic (lifelong); HBsAg remains detectable in the blood.

• Still, a significant portion of the chronic hepatitis B population (~0.1-2%) spontaneously clears serum HBsAg per year.

• Previous studies have shown that certain factors (e.g. age, gender, HBeAg-status, HBV-DNA viral load) may influence the incidence of spontaneous clearance of HBsAg in the blood.

Project Aims

• Study seeks to identify determinants that will increase the incidence of spontaneous HBsAg seroclearance and, subsequently, decrease the occurrence of poor outcomes.– Contribute to current scant literature on HBsAg

seroclearance.

• Main hypotheses:1) Persons infected with chronic HBV who are ≥ 50 years of age

at cohort entry will be more likely to spontaneously clear HBsAg than their counterparts who are < 50 years of age at cohort entry.

2) Persons infected with chronic HBV who are HBeAg-negative at cohort entry will be more likely to spontaneously clear HBsAg than those who are HBeAg-positive at cohort entry.

Study Design and Methods

• This is a secondary data analysis performed on the database of a prospective cohort study.

• In 2003, 1863 randomly-selected Chinese chronic HBV carriers (out of an initial 18,000) returned, 11 years after initial entry into the study (1992-93), for further serum testing of viral markers and HBsAg-status.

• Of those 1863 patients, 341 (18.3%) had apparently cleared HBsAg by 2003.

• Statistical analysis was conducted by the x2 test, Student’s t test, and logistic regression by SAS v.8 statistical analysis software.

How Hepatitis B Progresses

Death Liver Scarrin g (Cirrh osis)

ChronicInfecti on

5%-10 %

LiverFailure

30%

Liver Cancer

AcuteInfecti on

LiverTransplantati on

23% of pati ents ha ve li verfailure w ithin 5 years ofdevelopin g cirr hosis

Persons infected with chronic HBV greatly suffer from liver cancer (5-10%), cirrhosis (30%), and liver failure (23%). Moreover, 1 in 4 of all chronically infected persons die from HBV-related illnesses. Increasing the incidence of clearance of HBsAg may decrease the occurrence of HBV-caused mortality and morbidity.

Demographics of Study Population

Characteristics Number % in populationMean age ± SD (yr)*

HBsAg-status (2003) Negative 341 18.30% Positive 1522 81.70%Age (yr.)* < 50 1498 80.41% >= 50 365 19.59%Sex Male 1051 56.41% Female 812 43.59%Occupation Non-Farmer 413 22.17% Farmer 1450 77.83%Smoking No 1206 64.73% Yes 657 35.27%Alcohol No 1180 63.34% Yes 683 36.66%History of clinical hepatitis* No 1333 71.55% Yes 530 28.45%Family history of liver cancer No 1638 87.92% Yes 225 12.08%HBeAg-status* Negative 976 59.37% Postive 668 40.63%HBV-DNA viral load* Negative 155 9.10% Low (+) 805 47.27% High (+) 743 43.63%History of blood transfusions No 1780 95.54% Yes 83 4.46%Interferon treatment No 1850 99.30% Yes 13 0.70%Lamivudine treatment No 1860 99.84% Yes 3 0.16%* At entry into the study

41.4 ± 8.8Range: 23-64

Significant Factors for Clearance of HBsAg

16.56

25.48

21.52

13.17

16.77

21.37

14.13

0

5

10

15

20

25

30

% of HBsAg-negative persons at cohort

follow-up (2003)

< 50 >= 50 Negative Positive Negative Low (+) High (+)

Age group (years) HBeAg-status HBV-DNA viral load

Baseline Factors (1992-93)

p < .0001

p < .0001 p=0.0009

Non-significant Factors for Clearance of HBsAg

18.84

17.61

18.83

16.98

16

16.5

17

17.5

18

18.5

19

% of HBsAg-negative persons at

cohort follow-up ( 2003)

Male Female No Yes

Sex History of Clinical Hepatitis

Baseline Factors (1992-93)

p=0.4966 p=0.3519

Odds Ratios for Clearance of HBsAg

1

1.526

1.643

1 1

1.347

0.957

1.028

1 10.959

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

1.8

Odds of Clearing HBsAg< 50>= 50 Negative Positive Negative Low (+) High (+)MaleFemale No Yes

Age group(years)

HBeAg-status

HBV-DNA viralload

Sex Historyof

ClinicalHepatitis

Baseline Factors

* Significant CI

**

Conclusions

• Results suggest that the age of patients and HBeAg-status are determinants for clearance of HBsAg.

• Persons older than 50 years of age and/or HBeAg-negative were more likely to spontaneously clear HBsAg than any other group.

• Although the % differences for clearance of HBsAg were significant for HBV-DNA viral load, this variable was not independent of other study variables.

• Gender and history of clinical hepatitis did not significantly influence the occurrence of spontaneous HBsAg seroclearance.

Recommendations

• Future studies should concentrate on determining the exact time infected persons contract chronic hepatitis B and the exact time they clear the virus.

• Hepatitis B vaccination is the most efficient method of preventing HBV and HBV-related illnesses, therefore, future policy should focus on:– Preventing mother-to-infant transmission through the

administration of HBV vaccines at birth– Increasing child vaccination coverage; and– Increasing adult vaccination coverage, especially in Asian

populations.

• Future policy should also focus on improving medical services, detection, and treatment for chronic HBV carriers, specially in Asian populations.

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