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hbsag loss after 25years from natural hbeag seroclearance

Hepatitis B Surface Antigen Seroclearance: Relationship to Hepatitis B e-Antigen Seroclearance and Hepatitis B e-Antigen-Negative Hepatitis

James Fung, Danny Ka-Ho Wong, Wai-Kay Seto, Maggie Kopaniszen, Ching-Lung Lai and Man-Fung Yuen

Abstract
OBJECTIVES:

The objective of this study was to determine factors associated with hepatitis B surface antigen (HBsAg) seroclearance after hepatitis B e-antigen (HBeAg) seroclearance.

METHODS:

This is a cohort study of HBeAg-positive patients with HBeAg seroclearance. Factors associated with subsequent HBsAg seroclearance were examined.

RESULTS:

A total of 775 patients were included. At 1, 5, 10, 15, 20, and 25 years after HBeAg seroclearance, the HBsAg seroclearance rate was 0.3, 1.3, 3.0, 8.9, 15.7, and 23.6%, respectively. The rate of HBsAg seroclearance was highest in those who underwent spontaneous HBeAg seroclearance and required no treatment afterward (group 1), compared with those who underwent treatment-induced HBeAg seroclearance (group 2), and those who required antiviral therapy after spontaneous HBeAg seroclearance (group 3). At 25 years after HBeAg seroclearance, the HBsAg seroclearance rate was 38.0, 14.9, and 0% in groups 1, 2, and 3, respectively (P<0.001). There was no difference in the rate of HBsAg seroclearance between those who received interferon-based therapy compared with nucleos(t)ide analogs. The median HBV DNA level was similar between those with and without HBsAg seroclearance. The median HBsAg level was significantly lower in those who had HBsAg seroclearance compared with those who did not achieve loss of HBsAg (2.81 vs. 3.52 log IU/ml, respectively, P=0.009). The area under receiver operating characteristic curve for HBsAg at 1 year after HBeAg seroclearance for predicting HBsAg seroclearance was 0.742, with an optimal cutoff of 751 IU/ml.

CONCLUSIONS:

Spontaneous HBeAg seroclearance without need for subsequent antiviral therapy was associated with the highest rate of subsequent HBsAg seroclearance. Lower HBsAg levels were also associated with higher chance of HBsAg seroclearance.
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Avatar universal
thank you very much for this post, 200 pts is not a very big group but i think it is enough, just needs to be confirmed on more genotypes and somewhat also other studies had predictive levels like 10-200iu/ml for hbsag loss
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Avatar universal
This is interesting, as with all studies regarding natural clearing of HBsAg, it raises the same question: what causes the significant and progressive decline in HBsAg that leads eventually to clearance?
With this particular study, the interesting feature is the availability of serum HBsAg and hbvdna data up to 25 years ago. I wonder whether they came from stored serum samples?
I copied the discussion section from a 2012 paper, "A large case-control study on the predictability of hepatitis B surface antigen levels three years before hepatitis B surface antigen seroclearance†‡", by the same group of researchers in Hong Kong.
http://onlinelibrary.wiley.com/doi/10.1002/hep.25718/full

Our current study demonstrated the kinetics of serum HBsAg and HBV DNA levels preceding HBsAg seroclearance in a large population of CHB patients with HBsAg seroclearance. To our knowledge, this is a study with the largest number of patients with HBsAg seroclearance to date (n = 203).

Our present study outlines the changes in HBsAg kinetics before spontaneous HBsAg seroclearance. The enrollment of age- and sex-matched controls would allow us to optimally delineate the differences in serologic and virologic kinetics between the two patient groups. With 3 years of serial data, we were able to show a marked difference in HBsAg levels between patients with HBsAg seroclearance and controls. In our study, the median HBsAg levels of controls were between 366 and 846 IU/mL at different time points, levels which were similar to those reported in other studies on serum HBsAg levels in HBeAg-negative CHB.13-15 The results of our control group also provide additional insight into the natural history of HBsAg levels in HBeAg-negative CHB. Serum HBsAg levels decreased gradually over time and appears to be a much more stable marker than HBV DNA levels, which are known for their fluctuating nature.25

Our study confirms that serum HBsAg measurements can be an important tool for physicians in weighing the chances of HBsAg seroclearance in the long term. Because serum HBsAg decreases gradually with time, lower levels of HBsAg would eventually lead to HBsAg seroclearance. By achieving the highest AUC in our study (0.833), the absolute HBsAg level offers the best predictive value of eventual HBsAg seroclearance. From our study, HBsAg <200 IU/mL is already optimal in predicting eventual HBsAg seroclearance (Youden's index, 5.76), although HBsAg <100 IU/mL also had good predictive value (Youden's index, 5.42). Whether the slightly inferior predictive value of HBsAg <100 IU/mL (n = 151 in patients with HBsAg seroclearance) to that of <200 IU/mL (n = 170) is a result of the statistical underpower for detection needs further clarification.

The second-best method in predicting HBsAg seroclearance would be using the annual log reduction in HBsAg (AUC, 0.803). Serum HBsAg reduction is especially useful in patients with serum HBsAg ≥200 IU/mL (AUC, 0.867), when compared to HBsAg <200 IU/mL (AUC, 0.796). Therefore, adapting an annual 0.5-log reduction of HBsAg levels to predict subsequent HBsAg seroclearance is recommended in patients with baseline HBsAg ≥200 IU/mL. In the control group, annual 1-log reductions in HBsAg levels were uncommon, accounting for less than 5% for all time points, in contrast to 20.7%-48.7% of 1-log reductions noted in patients eventually clearing HBsAg. Thus, our study provides evidence that serial serum HBsAg measurements can be useful in identifying CHB patients with good immune control and eventual HBsAg seroclearance. From our study, an annual HBsAg reduction of 0.5 log already offers the best predictive value of HBsAg seroclearance, for all patients and also for patients with serum HBsAg ≥200 IU/mL.

Serum HBV DNA levels and their reductions were less useful in predicting HBsAg seroclearance. In addition, there was poor correlation between HBV DNA and HBsAg in both patient groups. It has been previously suggested that the relationship between viral replication and HBsAg production breaks down in HBeAg-negative CHB, probably because viral integration, a nonessential event in the life cycle of HBV, produces HBsAg in the absence of viral replication.12, 26 Also, HBsAg is produced in excess by replicating viruses. The significant decrease in HBsAg/HBV DNA ratios over time among patients with HBsAg seroclearance in our study implies a decrease in subviral particle production occurring in the absence of marked changes in viral replication before HBsAg seroclearance. Unlike the identification of inactive carriers,20 the combined analysis of HBV DNA and HBsAg levels in our study did not yield favorable AUCs and is less useful in predicting HBsAg seroclearance.

Among patients achieving HBsAg seroclearance, patients developing anti-HBs (n = 63) had a significantly younger age of HBsAg seroclearance (P = 0.013). Studies of vaccinated subjects show a higher rate of anti-HBs development among younger patients,27 although the implication of anti-HBs development in CHB patients with HBsAg seroclearance, and its association with HBsAg kinetics, needs further investigation. One study has shown the development of anti-HBs to have no influence over the subsequent occurrence of HCC.4

Besides providing important clinical data on serologic and virologic parameters before spontaneous HBsAg seroclearance, our present study also offers a reference for future studies investigating the usefulness of serum HBsAg measurements of CHB patients undergoing antiviral therapy. Serum HBsAg levels have already been shown to be useful in predicting favorable outcomes in Peg-IFN therapy.28, 29 In contrast, patients commenced on nucleoside analog therapy do not show significant decline in serum HBsAg up to 2 years,30 although a 0.5-log reduction in HBsAg is also predictive of subsequent HBsAg seroclearance.31 The achievement of low HBsAg levels or a strong reduction in HBsAg should thus be investigated in the future for suitability as treatment endpoints. Future studies should also consider matching baseline HBsAg and HBV DNA levels for a more detailed comparison of HBsAg kinetics.

A limitation of our study is that our patient population might not be totally representative of all treatment-naïve CHB populations, with no HBeAg-positive patients at initial presentation included. Although HBsAg loss is possible shortly after HBeAg seroconversion,16 the average age of HBeAg seroconversion in our population is 35 years32 and the average age of HBsAg seroclearance is 50 years4; hence, the proportion of patients with HBsAg seroclearance within 3 years of HBeAg seroconversion is likely to be small. Therefore, the validity of our study results, when applied to spontaneous HBsAg seroclearance, should not be affected by the absence of HBeAg-positive patients. In addition, HBV genotyping was not performed in all patients. Nevertheless, the lack of significant difference in genotype distribution among the two patient groups is in line with findings suggesting HBV genotypes as not being a key factor in determining HBsAg seroclearance.16 Further studies on this aspect are needed.

In conclusion, in CHB patients with spontaneous HBsAg seroclearance, low levels of serum HBsAg could be detected up to 3 years before HBsAg seroclearance and were more predictive of HBsAg seroclearance than low levels of serum HBV DNA. Serum HBsAg levels <200 IU/mL already offered a good prediction of eventual HBsAg seroclearance in 3 years. In patients with serum HBsAg ≥200 IU/mL, an annual 0.5-log reduction in serum HBsAg increases the prediction of HBsAg seroclearance. Both absolute and serial measurements of serum HBsAg would offer valuable clinical data in determining the probability of long-term seroclearance. These may also serve as good indicators for the consideration of treatment duration and cessation for CHB.
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Avatar universal
comment, interesting although i dont know if this can be real in clinical practice and any genotype

The area under receiver operating characteristic curve for HBsAg at 1 year after HBeAg seroclearance for predicting HBsAg seroclearance was 0.742, with an optimal cutoff of 751 IU/ml.

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1 Comments
Hello Stef. I have been diagnosed as hepa b positive last March 2019. My hbsag 250 coi hbeag 1332.94 s/co and my hbv dna was super high. Alt is 260 and Ast 200. My doctor prescribed tenofovir and last October 2020, my HBSAG <0.03 negative , HBEAG <0.04 negative but HBSAB 7.12. My LFT are all normal and undetectable hbv. Come December 2020 i did another test and everything remains the same except that my HBSAB becomes 11.22. Is there any possibility that i will become HBSAG positive again? Sag if im under stress?
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