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Review

Surveillance Following Hepatitis B Surface Antigen Loss: An Issue Requiring Attention

by
Shuai-Wen Huang
1,2,3,4,*,
Hong Long
1 and
Jia-Quan Huang
3
1
Department of General Practice, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China
2
Division of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China
3
Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China
4
Department of Nutrition, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China
*
Author to whom correspondence should be addressed.
Pathogens 2025, 14(1), 8; https://doi.org/10.3390/pathogens14010008
Submission received: 5 November 2024 / Revised: 25 December 2024 / Accepted: 27 December 2024 / Published: 27 December 2024
(This article belongs to the Special Issue Remaining Challenges of HBV Infection: Pathogenesis, Immune Response, Diagnosis and Therapeutic Strategies)
Browse Figure
Figure 1
<p>HBsAg loss implies stable immune control of HBV.</p> ">
Versions Notes

Abstract

:
Due to the lack of agents that directly target covalently closed circular DNA and integrated HBV DNA in hepatocytes, achieving a complete cure for chronic hepatitis B (CHB) remains challenging. The latest guidelines recommend (hepatitis B surface antigen) HBsAg loss as the ideal treatment target for improving liver function, histopathology, and long-term prognosis. However, even after HBsAg loss, hepatitis B virus can persist, with a risk of recurrence, reactivation, cirrhosis, and hepatocellular carcinoma. Therefore, follow-up and surveillance are still necessary. With increasing treatment options available for achieving HBsAg loss in patients with CHB, developing effective surveillance strategies has become crucial. Recent studies on outcomes following HBsAg loss provide new insights for refining current surveillance strategies, though further improvement is needed through long-term observation and follow-up.

1. Introduction

Owing to the comprehensive implementation of mother-to-child hepatitis B virus (HBV) prevention and hepatitis B vaccine immunization programs, there has been a significant decline in the incidence of new HBV infections. However, it is important to note that a substantial global burden involving individuals infected with HBV remains [1,2,3,4,5,6,7]. Thus, HBV infection continues to pose a significant public health challenge worldwide.
The course of HBV infection is primarily determined by the interplay between the virus and host, with age at the time of infection being widely recognized as a critical factor influencing chronicity [7,8]. In adults, HBV infection typically resolves spontaneously, as marked by the clearance of serum HBV DNA and emergence of hepatitis B core antibodies (anti-HBc), leading to loss of HBsAg and often accompanied by seroconversion to anti-HBs (antibodies to hepatitis B surface antigen). Conversely, perinatal transmission is associated with a higher risk of chronic infection characterized by persistent positivity for both HBsAg and/or HBV DNA, which accounts for most cases in highly endemic regions [7].
The objective of treating chronic hepatitis B (CHB) is to effectively suppress HBV replication and ultimately reduce the incidence of complications such as cirrhosis and hepatocellular carcinoma (HCC) [9,10,11,12]. Nevertheless, due to the lack of agents that directly target covalently closed circular DNA (cccDNA) and integrated HBV DNA in hepatocytes, a complete cure for CHB remains challenging [10,12,13]. HBsAg loss has been linked to improved liver function, histopathology, and long-term prognosis, making it an ideal treatment goal recommended by recent guidelines for preventing and managing CHB [11,12]. It is generally believed that only a small proportion of individuals with chronic HBV infection can achieve a spontaneous loss of HBsAg and attain a state similar to recovery from acute infection characterized by sustained and stable host immune control over HBV.
The loss of HBsAg is a complex immune process that involves cell-mediated immune responses, antibody production, the formation of immune memory, and overcoming immune evasion [14]. In some patients, the immune system is able to successfully clear HBV by recognizing and eliminating infected hepatocytes or neutralizing the virus, leading to the loss of HBsAg. However, this process is not always smooth. In CHB patients, immune tolerance may prevent the virus from being fully cleared [15]. Immune evasion, viral mutations, and the intensity of the immune response all play crucial roles in this process [14,16,17]. In most cases, HBsAg loss indicates stable immune control over HBV(Figure 1), which subsequently promotes the clearance of residual virus, including cccDNA and integrated HBV DNA.
Currently approved drugs for CHB mainly consist of nucleos(t)ide analogues (NA) and interferon drugs. Although NA are an effective treatment for CHB, achieving HBsAg loss with NA drug therapy is rare and may require long-term therapy [18]. Extended courses of treatment with NA, adherence to medication, and safety remain significant challenges in the management of CHB treatment. A limited course of NA therapy has been proposed as an alternative to long-term therapy with the potential to increase HBsAg loss [19,20], yet virological rebound and recurrence after discontinuation are almost universal [21]. Thus, achieving safe withdrawal from NA remains controversial. In 2005, pegylated interferon alpha (PEG-IFN-α) was approved for treating patients with CHB [22]. A limited course of PEG-IFNα-based therapy (sequential or in combination with NA) resulted in increased HBsAg loss. With progress achieved through clinical studies, rational optimization of PEG-IFNα-based treatment for select groups has significantly increased the loss of HBsAg [23,24,25,26,27,28]. Despite these promising results for future Peg-IFNα therapy, it is poorly tolerated due to the subcutaneous administration requirement and potential adverse reactions.
The current focus of drug development for hepatitis B encompasses two main aspects: targeting the life cycle of HBV and modulating the host immune system. Direct antiviral agents that specifically target the HBV life cycle include entry inhibitors [29], capsid inhibitors [30], small interfering RNAs [31], antisense oligonucleotides [32], and HBsAg inhibitors [33]. Indirect antiviral agents that modulate human immunity consist of therapeutic vaccines [34], monoclonal antibodies [35], and immune checkpoint inhibitors [36], among others. Several phase II/III clinical trials are being performed to simultaneously address both the HBV life cycle and host immune modulation. Some of these studies have demonstrated promising research progress and hold the potential to provide additional options for achieving HBsAg loss. For further details on the progress in the development of new hepatitis B drugs, some recently published review articles may be referred to [37,38,39].
Compared to sustained virological replication inhibition, HBsAg loss has been shown to effectively reduce the risk of hepatocellular carcinoma in patients with CHB [40,41,42,43]. However, due to the lack of effective means for complete eradication of cccDNA and integration into host genomic DNA, the hepatitis B virus can persist even after acute self-limited hepatitis B recovery or CHB infection, leading to HBsAg loss [13,44,45,46]. Consequently, seroreversion of HBsAg and reactivation of HBV can occur spontaneously or be triggered under specific conditions [13,47]. Furthermore, although the risk of hepatocellular carcinoma is significantly reduced following HBsAg loss, it remains a risk [48,49,50,51].
Clinical and animal experiments provide evidence indicating that traces of HBV DNA may persist in the liver for years or decades after HBsAg loss in acute or CHB and are associated with hepatic histological abnormalities [44,46,52,53,54,55,56]. Although HBsAg loss is an ideal endpoint for CHB infection, large-scale population cohort studies have confirmed that, after adjusting for confounding factors, the incidence of hepatocellular cancer (HCC) (HR: 7.95, 95% CI: 3.50–18.04) [57] and overall mortality risk [58] are higher in individuals after the resolution of an HBV infection than in those without previous HBV infection. Overall, the persistence of HBV leads to a continued risk of HBsAg recurrence, reactivation, cirrhosis, and hepatocellular carcinoma subsequent to HBsAg loss. Consequently, post-HBsAg loss follow-up and surveillance remain imperative.

2. HBsAg Recurrence or HBV Reactivation After HBsAg Loss

Loss of HBsAg generally indicates sustained immune control over HBV, but serological recurrence or reactivation may occur due to persistent viral presence and an imbalance between host immunity and viral replication. Biologics (such as CD20 monoclonal antibody), immunosuppressants (such as corticosteroids), chemotherapy agents, and anti-hepatitis C drugs can accelerate seroreversion or HBV reactivation in an immunosuppressive state [55,59,60,61,62,63,64,65]. Additionally, spontaneous HBV reactivation can occur without any specific trigger [66]. Nonimmunosuppressive states with seroreversion of HBsAg loss and hepatitis B virus reactivation following immunosuppression are described separately below.

2.1. HBsAg Recurrence in a Nonimmunosuppressive State

A recent large-scale community survey found that the 10-year cumulative seroreversion rate of HBsAg in the population after HBsAg loss was approximately 1.9%, with a higher rate observed in individuals who were anti-HBs negative than in those who were anti-HBs positive (10-year cumulative seroreversion rate: 2.9% vs. 1.4%). Notably, individuals who had previously received hepatitis B treatment showed a surprisingly high incidence of seroreversion, at 40.45%, with a higher incidence in the anti-HBs-negative group than in the anti-HBs-positive group (the 10-year cumulative incidence of seroreversion: 50.6% vs. 33.4%). Advanced age, surgical history, surface antibody negativity, HCV antibody positivity, and increased BMI and AFP levels are independent risk factors for seroreversion [67]. A large-scale inpatient study conducted in Hong Kong that excluded groups likely to be co-immunosuppressed (e.g., co-HCV, immunosuppressive, and biologics) reported that the incidence of seroreversion after spontaneous HBsAg loss during CHB was 2.1% and that the incidence of seroreversion after NA-induced HBsAg loss was 2.9% [68]. Although two studies based on community and hospital populations reported different conclusions regarding incidence and risk factors, it is generally accepted that seroreversion of HBsAg in the absence of an immunosuppressive state is transient with no obvious clinical symptoms and does not lead to true disease reactivation [67,68]. Smaller studies have suggested varying rates of seroreversion after NA-induced HBsAg loss, ranging from 3.9% (median follow-up of 26 months) [69] to 7.2% (mean follow-up of six years) [70]. Studies have also shown that liver cirrhosis is a risk factor for serologic reversal of HBsAg in patients with NA-induced HBsAg loss, though withdrawal of NA does not seem to be associated with serologic recurrence [69].
In recent years, sequential or combined administration of interferon and nucleos(t)ide analogue (NA) drugs has significantly enhanced the likelihood of HBsAg loss in individuals with CHB. The persistence of interferon-induced HBsAg loss has become a focal point of research. One study with a median follow-up period of 3.3 years demonstrated an approximate cumulative incidence rate of serologic recurrence after IFN-induced HBsAg loss of 9.6%, and low levels of hepatitis B surface antibody (anti-HBs) were identified as a significant risk factor for serologic recurrence [71]. Another prospective cohort study lasting 48 weeks reported a cumulative incidence rate of serologic recurrence after IFN-induced HBsAg loss of approximately 12.79%, with higher levels of anti-HBs along with post-HBsAg loss interferon consolidation therapy being predictive factors for sustained functional cure [72]. Additionally, lower levels of hepatitis B core antibody (anti-HBc) may be associated with an increased risk of serological recurrence [73]. According to recent literature published by Professor Ning Qin, short-term incidence rates for seroreversion following IFN-induced HBsAg loss are approximately 41.2%. Lower levels of hepatitis B core-related antigen (HBcrAg) and higher levels of anti-HBs reflect reduced intrahepatic cccDNA levels, more stable proportions of HBV-specific cytotoxic T lymphocytes, and sustained follicular T-helper and B-cell immune responses, which serve as effective indicators for predicting persistent surface antigen loss [74].
Table 1 summarizes the incidence rates and potential predictors for seroreversion after HBsAg loss. The reported incidence of serological HBsAg reversal varies among previous studies, as influenced by factors such as the study population, mode of infection, treatment duration, hepatitis B epidemic environment, and laboratory precision. In most cases, persistence is observed following HBsAg loss. Even if transient seroreversion occurs without obvious clinical symptoms in the absence of immunosuppression, these individual patients still have strong response rates to IFN or NA-based therapy [75].
Certain factors and models for predicting durable functional cures have been proposed, but there are inconsistencies in results between studies, and external validation remains weak due to the limited number of relapse cases with HBsAg loss. Further research is needed to identify high-risk groups for recurrence after HBsAg loss and to determine appropriate clinical treatment for those who experience relapse.

2.2. HBV Reactivation After HBsAg Loss in Immunosuppressed States

As there is currently no effective eradication therapy for HBV, a significant proportion of the general population remains at risk of HBV reactivation, particularly those who are either infected with or have been exposed to HBV but have achieved HBsAg loss. The potential consequences of such reactivation are especially concerning when these individuals undergo cancer chemotherapy, immunosuppression, or biological therapies for conditions such as rheumatism, malignancy, inflammatory bowel disease, skin disease, or solid organ or bone marrow transplantation [83]. Reactivation may occur due to decreased host immune control over the virus or increased viral replication resulting from immunosuppression [13]. Under such circumstances, serious adverse events, including liver failure and death, can ensue.
In a systematic meta-analysis, populations negative for HBsAg but positive for anti-HBc exhibited an approximate HBV reactivation rate of 6.5% when treated with immunosuppressants [84]. Among these populations, individuals with hematologic diseases (10.9%) and those receiving rituximab (9.7%) were found to have the highest risk of reactivation; baseline detectable HBV DNA and anti-HBs negativity were identified as significant risk factors for reactivation. Under severe immunosuppressive conditions, HBV reactivation can be fatal, as evidenced by the eventual death of 14.9% of patients experiencing such reactivation in the meta-analysis; however, the exact relationship between the cause of death and HBV reactivation remains inconclusive [84].
Guidelines from the American Gastroenterological Association recommend anti-viral agents for preventing viral reactivation in intermediate- and high-risk populations requiring long-term immunologic therapy against hepatitis B [85]. This recommendation is particularly relevant with high doses or prolonged courses of glucocorticoids and anthracycline derivatives (e.g., doxorubicin, epirubicin) in patients who are negative for both HBsAg and anti-HBs but positive for anti-HBc [86,87,88]. Although some of the literature suggests that individuals with detectable levels of anti-HBs have a relatively low risk of HBV reactivation, long-term immunologic therapy is not recommended by American Gastroenterological Association guidelines because a subset of anti-HBs-positive patients are still at risk; therefore, early prophylaxis with antivirals is strongly advised based on substantial clinical evidence and other guidelines to prevent serious adverse events [85,89,90,91].
Reactivation of HBV can occur in individuals who are negative for HBsAg, particularly those receiving anti-CD20 antibodies or undergoing hematopoietic stem cell transplantation. However, as newer targeted biological therapies emerge, it is important to understand which therapies may also predispose towards HBV reactivation. Table 2 summarizes immunosuppressive drugs or therapies that may be associated with HBV reactivation following HBsAg loss. It should be noted that these data and information may rapidly change due to the complex clinical application background, and risk ratings may need timely adjustment based on new clinical evidence.
A meticulous approach is needed to manage individuals with a history of HBV infection who are HBsAg-negative but anti-HBc-positive, especially in regions with high HBV prevalence. Although the risk of HBV reactivation is a concern for these individuals, it may not be appropriate to apply the same treatment to all HBV-infected individuals and HBsAg-positive patients without clear evidence to support it; treatment should be personalized. However, when facing extremely high risks of reactivation and severe adverse outcomes, prophylactic antiviral treatment should indeed be considered.
Additionally, aging individuals may experience HBV reactivation even without traditional triggers [66], but the effects of immunosenescence in such cases remain poorly understood and require further research. Few studies have assessed the risk of reactivation and treatment monitoring of HBV in elderly populations; thus, whether additional attention is needed for this group remains unclear.

3. Hepatitis B Virus Reinfection After HBsAg Loss

The issue of HBV reinfection remains a concern in the field of liver transplantation, particularly in areas with high hepatitis B prevalence and limited donor sources [84]. In certain cases, the selection of HBsAg-positive or anti-HBc-positive donors may be necessary, despite the infection potential. Distinguishing between reinfection and reactivation can be challenging in practice, and both are significant risks for transplant recipients due to persistence of the virus and long-term immunosuppressive therapy.
There have been reports of switching of HBsAg−/anti-HBc+/anti-HBs+ cases to HBsAg+ cases at 3.5 months after HBsAg+ donor liver transplantation due to the decrease in anti-HBs titer. Interestingly, however, HBsAg is cleared at 18 months after liver transplantation in patients with high anti-HBs titers [101]. This seems to suggest that this distribution of liver transplantation may be feasible, and although HBsAg+ donor liver transplantation may lead to reinfection, there is still a chance that individuals who have previously achieved HBsAg loss will regain relatively stable immunologic control of HBV. For anti-HBc+ donor liver transplantation, the rate of reinfection in HBsAg−/anti-HBc+/anti-HBs+ recipients is reportedly significantly lower than that of HBsAg−/anti-HBc−/anti-HBs+ recipients or HBsAg−/anti-HBc−/anti-HBs− recipients (1.4 versus 9.4 percent versus 13 percent), which may be associated with immune memory preservation after anti-HBs and previous hepatitis B infection [102].
Although reinfection with hepatitis B is generally less likely to occur after HBsAg loss due to the immune memory of previous HBV infection, the occurrence of reinfection after liver transplantation suggests that reinfection may in theory still occur after HBsAg loss; thus, reducing hepatitis B virus exposure may still bring benefits to the population achieving HBsAg loss.

4. Cirrhosis Combined with HBsAg Loss

Prior to the onset of cirrhosis, HBsAg loss is associated with a lower risk of developing cirrhosis [103]. However, particular attention should be given to those who experience HBsAg loss while already having cirrhosis, as they still have a high incidence of HCC even after HBsAg loss.
According to the literature, the proportion of patients with cirrhosis at the time of HBsAg loss is relatively high in the total population with HBsAg loss. A large cohort study from the Hong Kong Medical Authority showed that 6.3% (451/7124) of HBsAg-cleared HBV-infected patients had cirrhosis and that 3.5% (247/7124) had decompensated cirrhosis [104]. In a multicenter cohort study in South Korea, this figure was as high as 39.9% [69].
The incidence of cirrhosis after HBsAg clearance is relatively low [105], though the risk is still present [48,51,76], and some scholars believe that previous HBV infection may be the underlying cause of some cases of cryptogenic cirrhosis [106]. Early HBsAg loss is associated with less severe liver fibrosis [107,108,109]. Cirrhosis may occur during the HBV carrier phase of CHB infection and may also be associated with latent hepatitis B infection. A recent study based on liver biopsy proposed important risk factors for cirrhosis and tumor development in patients with nonalcoholic fatty liver disease previously infected with hepatitis B [110]. Similarly, some studies have confirmed that prior hepatitis B infection is associated with an increased risk of cirrhosis and liver cancer in patients with hepatitis C [111,112]. A study from Korea estimated the prevalence of cirrhosis after CHB clearance to be approximately 39.9%. Such higher prevalence may be related to the timing of cirrhosis, and the study did not make a strict distinction between cirrhosis occurring during the HBsAg carrier period of CHB infection and cirrhosis occurring after HBsAg clearance. The incidence of newly diagnosed cirrhosis following HBsAg loss is relatively low [50,76,107]; however, there remains a dearth of large-scale prospective cohort studies in this area. Table 3 presents a summary of the prevalence of cirrhosis in populations infected with HBV and demonstrating a loss of HBsAg.

5. Occurrence and Prediction of HCC After HBsAg Loss

The risk of hepatocellular carcinoma is significantly reduced after HBsAg loss, but numerous studies have shown that this risk still exists [113,115]. A large registry study of women of childbearing age suggests that even with the loss of HBsAg, the risk of HCC is much higher than that in the population without hepatitis B infection (HR = 7.95, 95% CI: 3.50–18.04) [57]. Based on the results of several recently published systematic meta-analyses, the incidence of HCC following HBsAg loss is approximately 1.86 to 2.29% [116,117,118], though a recent study from South Korea suggested that the incidence of HCC after HBsAg loss can be as high as 4.9% [119]. Such variation may be due to the prevalence of hepatitis B in the population and country involved.
The mechanisms underlying the development of hepatocarcinoma may involve the integration of HBV DNA into the host genome, and these genetic alterations can lead to the clonal selection of noncancerous hepatocytes with survival advantages, resulting in the development of liver tumors through the random insertion of HBV DNA into host hepatocytes [119,120]. It has also been suggested that the lower risk of hepatocellular carcinoma following HBsAg loss may be associated with incomplete HBsAg loss [121].
The development of HCC following HBsAg loss appears to be strongly associated with sex and age [42]. Studies suggest that the risk of HCC is higher in men and in those older than 50 years [42]. Cirrhosis and the development of diabetes mellitus are also risk factors for HCC [105]. Enhanced liver fibrosis testing may also play a role in the risk stratification of HCC [122].
Most models for predicting HCC are based on HBsAg-positive patients. However, only the CU-HCC and PAGE-B models have been cross-validated in HBsAg-negative populations [40,113]. Recently, Hyun Yang et al. proposed a predictive model for tumorigenesis in HBsAg-negative populations, but this model lacks effective external validation [119].

6. Surveillance Strategies Following HBsAg Loss

Continued surveillance is important to monitor for reactivation, relapse, reinfection, cirrhosis, or HCC, particularly in those with a history of chronic infection. For high-risk groups, regular testing for HBsAg, HBV DNA, anti-HBs, liver function, liver ultrasound, and AFP is still necessary to monitor viral response, liver health, and immune status. Emerging non-invasive biomarkers, such as HBV RNA [123], HBcrAg [74], HBsAg isoform quantification [124], high-sensitivity quantitative HBsAg [125], and HBV core antibodies [126], have gained attention for reflecting intrahepatic viral activity and assessing the likelihood of achieving partial or complete functional cure. However, most of these are still in the early research stages. The optimal frequency and methods for monitoring outcomes after HBsAg loss have yet to be determined, and their cost-effectiveness remains unknown. This underscores the need for further research.
The results from high-sensitivity HBsAg assays have prompted researchers to re-evaluate findings from previous studies. With improvements in measurement methods, it has recently become possible to detect trace amounts of HBsAg. In long-term observational studies, for example, patients previously judged as HBsAg-negative due to older, less sensitive methods may be considered HBsAg-positive with recent, more sensitive tests. In their review, Wang, Z.L. et al. discuss the potential of using high-sensitivity HBsAg assays as an indicator of complete cure [125]. However, even with high-sensitivity assays, cases of HBV reactivation have still been reported [127]. Research on long-term outcomes following HBsAg clearance using high-sensitivity tests remains limited. The optimal precision for detecting HBsAg remains unclear, and the health economic cost-effectiveness of these tests is yet to be established.
Indeed, current research suggests that HBsAg loss alone may not be sufficient to diagnose a complete cure for hepatitis B, as it does not necessarily indicate the elimination of all HBV-infected cells or the prevention of HBV reactivation. Although studies have explored various biomarkers and approaches, including high-sensitivity HBsAg assays and other viral markers, none have yet provided a universally accepted standard for diagnosing a complete cure. This gap highlights an ongoing need for further research and consensus in the field.
To design an implementation framework for monitoring after HBsAg loss, with a particular focus on its application in developing countries, we recommend adopting a prospective, longitudinal observational study design to track chronic hepatitis B patients who have cleared HBsAg. Future research should focus on evaluating the impact of long-term monitoring on patient health outcomes and exploring the feasibility and implementation barriers of monitoring protocols in countries with varying economic levels. Monitoring will include regular testing for HBV DNA, liver function, and imaging exams. The study will cover different monitoring periods, including early, intermediate, and long-term follow-ups, ensuring a comprehensive assessment of health changes after HBsAg clearance. Given the resource limitations in developing countries, the framework emphasizes delivering convenient monitoring services through primary healthcare settings, using cost-effective and simple testing methods, such as HBV DNA rapid tests, liver elastography, and ultrasound. The study will also place a strong emphasis on training healthcare providers and educating patients to improve adherence to long-term monitoring. Furthermore, collaborations with governments and international organizations will be explored to address economic burdens and ensure the sustainability of these monitoring programs in resource-limited settings. The results of this study will not only contribute to improving the management of hepatitis B patients’ health but also provide valuable insights for the formulation of global hepatitis B prevention and control policies.

7. Future Directions and Challenges

HBsAg loss is associated with improved liver function, histopathological improvement, and long-term prognosis and is the ideal treatment target recommended by the latest guidelines for the prevention and treatment of CHB. However, given the persistent challenges in completely eradicating the hepatitis B virus, it appears that individuals previously infected with the hepatitis B virus but achieving HBsAg loss require ongoing monitoring to facilitate timely personalized prevention and intervention measures for adverse outcomes. Nevertheless, current surveillance strategies following HBsAg loss necessitate further refinement and improvement. Future studies with long-term observation and follow-up of this population should be conducted to provide additional clinical evidence and guidance for developing effective surveillance strategies. In addition, further research is needed to identify suitable non-invasive biomarkers as surrogate indicators for sustained or complete cure of hepatitis B.

Author Contributions

Conceptualization, S.-W.H., J.-Q.H. and H.L.; writing—original draft preparation, S.-W.H., H.L. and J.-Q.H.; writing—review and editing, S.-W.H., H.L. and J.-Q.H.; supervision, S.-W.H., H.L. and J.-Q.H.; project administration, S.-W.H. and J.-Q.H.; funding acquisition, J.-Q.H. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the National Science and Technology Major Project, grant number 2018ZX10302204-001.

Conflicts of Interest

The authors declare no conflicts of interest.

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Pathogens 14 00008 g001
Figure 1. HBsAg loss implies stable immune control of HBV.
Figure 1. HBsAg loss implies stable immune control of HBV.
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Table 1. Incidence and predictors of seroreversion of HBsAg after HBsAg loss.
Table 1. Incidence and predictors of seroreversion of HBsAg after HBsAg loss.
AuthorWay to Achieve HBsAg LossFollow-Up (Years)Incidence of SeroreversionPredictors of Durable Functional Cure
ML Yeh [67]Unknown4.2 11.1% (84/7630)See text
T.C.Yip [68]Spontaneous 2.1% (75/3563)-
T.C.Yip [68]NAs -2.9% (14/475)-
M.A.Kim [69]NAs2.2 13.6% (10/276)-
G.Kim [70]NAs6 17.2% (8/110)-
Y. Wu [71]IFN or combined with NA therapy3.3 17.5% (18/238)Anti-HBs 3
M.H. Li [72]IFN/NAs add on IFN112.7% (22/172)IFN therapy > 12 weeks 4; Anti-HBs 3
Y. Wu [73]IFN or combined with NA therapy221.9% (16/73)Anti-HBc 5
D. Huang [74] NAs followed by IFN 0.541.6% (15/36)HBcrAg < 4 logU/mL & antiHBs > 2 log IU/L levels 6
X. Lin [75] IFN or combined with NA therapy4.2 18.9% (32/358)-
H.Chi [76]NAs 1.6 13.7% (2/54)-
MF. Han [77] NAs followed by IFN114.2% (1/7)-
X. LIN [75] IFN4.3 18.9% (32/358)Anti-HBs 3; Anti-HBc 5
G.Teuber [78]NAs combined with IFN3 12.1% (3/143)-
M. Li [79] IFN or combined with NA therapy28.2% (19/231)IFN therapy > 12 weeks 4;
N. Gao [80]IFN113.5% (30/222)Anti-HBs 3
A.S.Alawad [81]Spontaneous/NAs/IFN 9.6 24.6% (3/65)-
A.S.Lok [82]NAs/IFN/combined2 118.1% (10/55)-
1 Median follow-up time; 2 mean follow-up duration; 3 anti-HBs ≥ 100 IU/L; 4 IFN consolidation treatment is longer than 12 weeks; 5 those with higher anti-HBc titers may achieve more durable functional cure; 6 treatment endpoint HbcrAg < 4 log10 U/mL and anti-HBs > 2 log10 IU/L may result in a more durable functional cure.
Table 2. Immunosuppressive drugs or therapies associated with HBV reactivation after HBsAg loss.
Table 2. Immunosuppressive drugs or therapies associated with HBV reactivation after HBsAg loss.
CategoryDrug/TherapyPotential Clinical Application ScenariosHBV Reactivation
CD20 monoclonal antibodyRituximabHematological tumors, rheumatoid arthritis, idiopathic thrombocytopenic purpura, multiple sclerosis9.7% [84]
Tumor chemotherapeutic drugDoxorubicin, EpirubicinSolid and hematological malignancies11.3% [61]
Tumor chemotherapeutic drugPlatinum compoundSolid tumor3.0% [92]
TNF-α inhibitorsInfliximabInflammatory bowel disease, psoriasis, ankylosing spondylitis, rheumatoid arthritis0.0–0.4% [62,93]
Calcineurin inhibitorsCyclosporin, TacrolimusSolid organ transplantation, rheumatoid arthritis, psoriasis, aplastic anemia10.0% [94,95]
Chemokine inhibitorsMoglizumabRefractory adult T-cell leukemia/lymphoma12.5% [96]
Janus kinase inhibitorsBrectinibRheumatoid arthritis14.0% [94,97]
Cytokine inhibitorTocilizumabRheumatoid arthritis2.0% [94,98]
CAR-T therapyCAR-T therapyRefractory/recurrent diffuse large B-cell lymphoma3.3% [94,99]
Cortisol hormoneCortisol hormoneA variety of allergic diseases, widely used3.0% [94,100]
Immune checkpoint inhibitorsPD-1 inhibitorsTumor immunotherapy0.0–1% [94]
Table 3. Prevalence of cirrhosis in populations infected with HBV and exhibiting HBsAg loss.
Table 3. Prevalence of cirrhosis in populations infected with HBV and exhibiting HBsAg loss.
AuthorWay to HBsAg LossCirrhosis Before/After HBsAg LossCriterionNumber of PatientsPrevalence
T.C.Yip [104]Spontaneous/NAs-ICD code71246.3%
M.A.Kim [69]NAs-Imaging evaluation27639.9%
Y.Park [113]Spontaneous/antiviral therapy-Imaging evaluation and FIB-4120013.8%
Y.C.Chen [114]Spontaneous/NAs-Pathology/Imaging evaluation42210.2%
G.A. Kim [40]Spontaneous/NAs-Imaging evaluation82911.8%
Y. Arase [107]-After HBsAg lossPathology1640.0%
H.Chi [76]NAsAfter HBsAg lossImaging evaluation700.0%
Y.C.Chen [50]-After HBsAg lossImaging evaluation1891.6%
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Huang, S.-W.; Long, H.; Huang, J.-Q. Surveillance Following Hepatitis B Surface Antigen Loss: An Issue Requiring Attention. Pathogens 2025, 14, 8. https://doi.org/10.3390/pathogens14010008

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Huang S-W, Long H, Huang J-Q. Surveillance Following Hepatitis B Surface Antigen Loss: An Issue Requiring Attention. Pathogens. 2025; 14(1):8. https://doi.org/10.3390/pathogens14010008

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Huang, Shuai-Wen, Hong Long, and Jia-Quan Huang. 2025. "Surveillance Following Hepatitis B Surface Antigen Loss: An Issue Requiring Attention" Pathogens 14, no. 1: 8. https://doi.org/10.3390/pathogens14010008

APA Style

Huang, S. -W., Long, H., & Huang, J. -Q. (2025). Surveillance Following Hepatitis B Surface Antigen Loss: An Issue Requiring Attention. Pathogens, 14(1), 8. https://doi.org/10.3390/pathogens14010008

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