Dr. Sujun Zheng: Advances in the Diagnosis and Treatment of Inactive HBsAg Carriers

Editor’s Note: According to estimates from the Polaris Observatory, the prevalence of inactive hepatitis B surface antigen (HBsAg) carriers in the general population in China was 6.1% in 2016, with approximately 86 million people chronically infected with HBV. This suggests that around 36.08% of these individuals are inactive HBsAg carriers (IHC), equating to about 30.96 million people. The definitions and treatment recommendations for IHC vary across national or regional chronic hepatitis B (CHB) guidelines. As research into the natural history of CHB deepens and antiviral treatment strategies evolve, the management of HBV infection is gradually changing. At a recent Beijing Hepatology Academic Annual Meeting, Dr. Sujun Zheng from Beijing You An Hospital, Capital Medical University, presented an insightful report on "Advances in the Diagnosis and Treatment of Inactive HBsAg Carriers." Here, we summarize the key points.

Definition of IHC

IHC, also known as HBeAg-negative chronic HBV infection, immune control phase, or inactive phase, is defined differently in various CHB guidelines globally. The definitions also differ between the 2019 and 2022 Chinese Hepatitis B guidelines. The “Guidelines for the Prevention and Treatment of Chronic Hepatitis B (2022 Edition)” define IHC as HBsAg <1000 IU/mL, HBV DNA negative, ALT normal, HBeAg negative, with no or only mild liver inflammation, though some degree of fibrosis may be present. The 2019 version included those with HBV DNA <2000 IU/mL in the definition.

Impact of HBV DNA Levels on Staging

The level of HBV DNA is closely associated with the eventual development of hepatocellular carcinoma (HCC). A prospective study conducted in Taiwan between 1991 and 2004 included 3,653 HBV-infected individuals with a mean follow-up of 11.4 years. It found that in patients who were HBeAg-negative, had normal ALT, and no cirrhosis at baseline, an HBV DNA level above 2000 IU/mL was significantly associated with HCC development (HR=4.5).

Based on HBV DNA levels, the revised classification divides the previous IHC population into two groups: (1) patients with HBV DNA negative or <20 IU/mL, now termed “new IHC”; and (2) patients with HBV DNA positive but <2000 IU/mL, categorized as “indeterminate phase.”

The “indeterminate phase” does not represent a distinct stage but indicates difficulty in clear staging: these patients cannot be clearly differentiated from HBeAg-positive chronic HBV infection or HBeAg-negative CHB. Compared with chronic HBeAg-positive or HBeAg-negative infection, “indeterminate phase” patients have a higher risk of disease progression and may require antiviral treatment. The necessity and feasibility of antiviral therapy in the “new IHC” population is an area of focus.

After the 2022 guideline update, the HBV DNA level for defining IHC is set as negative. Academician Hui Zhuang of Peking University Health Science Center pointed out that the 2022 guidelines’ staging of chronic HBV infection is inconsistent with international guidelines, which typically define IHC as having HBV DNA <2000 IU/mL. The new guideline’s approach lacks evidence-based medicine support. The immune control phase is generally characterized by HBsAg levels <1000 IU/mL, yet the proportion of initial treatment patients in this phase with specific HBV DNA levels remains unclear.

Number of IHC Patients in China

The “Starlight Project” is the largest clinical research project on IHC populations worldwide. As of May 6, 2024, 6,593 participants meeting inclusion criteria have been enrolled. Data shows that among IHC patients, 32.2% have HBV DNA ≤20 IU/mL, while 67.8% have HBV DNA >20 IU/mL. Patients with HBV DNA ≤20 IU/mL tend to be older, have higher HBsAg levels, LSM, and a greater prevalence of fatty liver.

The question of whether to treat IHC patients has been a hot topic in clinical practice. Research from Gulou Hospital indicates that 36% of CHB patients are in the immune control phase according to the 2019 guideline criteria. Data from the Chinese Clinical Hepatitis B Elimination Research Platform (CR-HepB) shows that about 24.31% of patients are in the immune control phase by the same standards.

In 2020, the HBsAg prevalence among people aged 1 to 69 in China dropped to 5.86%, suggesting around 75 million CHB patients in the country. If 24.31% to 36% meet the 2019 IHC criteria, this equates to 18 to 27 million individuals. Applying the “Starlight Project” data, where 32.2% of IHC patients have HBV DNA ≤20 IU/mL, 5.8 to 8.7 million people would meet the 2022 IHC definition.

Should all these patients go untreated? In the following lecture, Dr. Sujun Zheng further explored this question, sharing their team’s research findings. He also emphasized that the IHC definition should consider that some patients are not newly treated but have been off treatment for over six months; if they meet the criteria, they should also be considered “inactive HBsAg carriers.”

HBsAg Level Distribution in IHC Patients in China

Serum HBsAg levels help better distinguish IHC. The 2017 European Association for the Study of the Liver (EASL) guidelines define IHC as HBeAg-negative, anti-HBe-positive, with undetectable or low HBV DNA levels (<2000 IU/mL) and normal ALT levels (ULN~40 IU/mL). These patients typically have lower HBsAg levels (<1000 IU/mL).

The MAURIZIA study found that for HBV genotype D chronic infection patients, the diagnostic accuracy of IHC reached 94.3% when HBsAg (<1000 IU/mL) and HBV DNA (≤2000 IU/mL) were combined as diagnostic criteria.

Chien-Jen Chen’s research showed that combining HBsAg (<1000 IU/mL) and HBV DNA (<2000 IU/mL) achieved a diagnostic accuracy of 76% for IHC (HBV genotypes B and C). Using baseline HBsAg (<1000 IU/mL) and HBV DNA (<2000 IU/mL) together significantly reduced the long-term risks of liver cirrhosis (22%) and HCC (22%).

However, Dr.  Sujun Zheng pointed out that although combining serum HBsAg and HBV DNA levels helps better define the “virological stage of HBV infection,” these markers do not directly reflect the histological status of the liver.

“Starlight Project” data shows that 81.8% of IHC patients have baseline HBsAg levels <500 IU/mL. A meta-analysis by Dr.  Sujun Zheng ‘s team found that IHC patients with HBsAg <500 IU/mL had a high HBsAg clearance rate (59.6%) when treated with interferon, suggesting that IHC patients are a favorable group for pursuing clinical cure.

A meta-analysis included 11 studies conducted in Asia (10 in China), comprising 1,029 patients. The results showed that after 48 weeks of PEG IFNα treatment, the overall HBsAg clearance rate was 47%, with a seroconversion rate of 26%. The lower the baseline HBsAg level, the higher the clearance rate. Specifically, when HBsAg <10 IU/mL, the clearance rate reached 91.8%; when HBsAg <500 IU/mL, it was 59.6%. With extended treatment time, HBsAg clearance rates increased progressively: 29% at 24 weeks, 39% at 48 weeks, and 43% at 96 weeks.

Clinical Characteristics of Different ALT Treatment Thresholds in IHC Patients in China

Most international and domestic guidelines recommend starting CHB treatment at an ALT threshold of around 30 U/L for men and 20 U/L for women. For example, the 2024 World Health Organization (WHO) recommendations suggest that HBV DNA >2000 IU/mL and ALT levels above the ULN (30 U/L for men, 19 U/L for women) warrant treatment.

The 2022 “Expert Opinion on Expanding Antiviral Treatment for Chronic Hepatitis B” latest recommendations are:

1. For patients with positive serum HBV DNA and ALT levels persistently above the treatment threshold (30 U/L for men, 19 U/L for women) during at least three follow-up visits over a year, with each visit at least three months apart and other causes excluded, antiviral treatment is recommended.
2. For patients with positive serum HBV DNA, regardless of ALT levels, antiviral treatment is recommended if any of the following conditions are met: Family history of cirrhosis or HCC Age >30 years Non-invasive indicators or liver histology showing significant inflammation (G ≥2) or fibrosis (F ≥2).
3. For CHB patients who have been followed for over a year and whose HBV DNA and ALT patterns remain unclear and untreated, antiviral treatment is recommended.

“Starlight Project” data shows that 24.2% of IHC patients have normal high ALT levels (men 30-40 U/L, women 19-40 U/L), with higher HBV DNA, HBsAg levels, Fibroscan CAP values, and a higher prevalence of fatty liver (75.8%).

Dr. Sujun Zheng raised two points regarding ALT levels in IHC patients:

1. Should patients with HBV DNA <20 IU/mL and ALT persistently above the treatment threshold (30 U/L for men, 19 U/L for women) receive antiviral treatment as suggested in the new IHC definition?
2. What is the correlation between HBV DNA status (positive or negative) and liver inflammation and fibrosis in IHC patients?

Histological Characteristics of the Liver in IHC Patients in China

A study from Beijing You An Hospital included 208 patients meeting the following criteria: HBsAg <1000 IU/mL, HBeAg-negative, HBV DNA <2000 IU/mL, and persistently normal ALT (ULN: 40 U/L). Significant liver injury (EHI) was defined as the presence of significant inflammation (G ≥2) or fibrosis (F ≥2). The study found that 43.21% of patients with HBV DNA <20 IU/mL had liver fibrosis F ≥2, significantly higher than the 21.85% in those with HBV DNA between 20-2000 IU/mL.

The data also showed that in the IHC population, as age increases, HBV DNA and HBsAg levels gradually decrease, but the proportion of fibrosis F ≥2 increases. Among IHC patients over 30 years old, those with negative HBV DNA had a significantly higher proportion of fibrosis F ≥2 (42.1%) compared to those with positive HBV DNA (21.4%) (P=0.002). Patients with negative HBV DNA also had significantly higher liver stiffness values (LSM) and lower platelet counts (PLT).

“Starlight Project” data shows that 91.5% of IHC patients are over 30 years old, with higher ALT, LSM, and BMI values, lower HBsAg levels, and a higher prevalence of fatty liver.

Dr. Sujun Zheng offered two thoughts on the histological characteristics of IHC patients:

1. According to the new IHC definition, negative HBV DNA does not indicate good liver histological status; on the contrary, patients with negative HBV DNA have a significantly higher proportion of liver fibrosis F ≥2 than those with positive HBV DNA.
2. The IHC population over 30 years old accounts for over 91.5%, even with negative HBV DNA, making them a high-risk group for disease progression, and antiviral treatment should be recommended.

Clinical Cure Progress in IHC Patients

Multiple studies in China have confirmed high clinical cure rates based on PEG IFNα treatment for former IHCs. A study conducted at Beijing You’an Hospital between September 2011 and October 2013 included 144 IHCs (HBsAg <1000 IU/mL, HBV DNA <2000 IU/mL), with 102 in the treatment group and 42 in the control group. In the treatment group, patients with HBV DNA <20 IU/mL received PEG IFNα monotherapy for 96 weeks, while those with HBV DNA levels between 20-2000 IU/mL received PEG IFNα combined with adefovir dipivoxil (ADV) for 96 weeks. The control group received follow-up without treatment.

Results showed that the HBsAg clearance rates at 48 and 96 weeks in the treatment group were 29.8% and 44.7%, respectively, with seroconversion rates of 20.2% and 38.3%, significantly higher than in the control group. The HBsAg clearance rate in IHCs with HBV DNA <20 IU/mL who received PEG IFNα treatment for 96 weeks could reach 51.1%.

A prospective cohort study by Professor Cao Zhenhuan from You’an Hospital included 174 patients meeting the 2022 IHC definition (HBsAg <200 IU/mL, HBV DNA <20 IU/mL). Of these, 84 received PEG IFNα treatment for 96 weeks, and 90 were followed up without treatment for 96 weeks. The patients were divided into groups based on baseline liver fat attenuation parameter (CAP) values: none, mild, moderate, and severe fatty liver.

The results showed that at 48 weeks, the HBsAg clearance rate and seroconversion rate in the PEG IFNα treatment group were 30.77% and 23.08%, respectively; at 96 weeks, they were 57.69% and 55.13%. The cumulative HBsAg clearance rates at 96 weeks in IHCs with mild, moderate, and severe fatty liver were 71.42%, 74.07%, and 47.05%, respectively. These results suggest that patients meeting the 2024 IHC definition who have mild to moderate fatty liver have higher HBsAg clearance rates. “Starlight Project” data shows a 32.2% HBsAg clearance rate at 48 weeks of interferon treatment (116/360).

Another study by Dr. Xinyue Chen and  Dr. Sujun Zheng’s team showed that the clinical cure achieved through interferon treatment in IHC patients is durable, with long-term follow-up of up to 597 weeks indicating only about 9.66% of patients relapsed after discontinuation, with a lower relapse rate in those with anti-HBs >100 IU/L. Exploring new treatment strategies to increase anti-HBs seroconversion rates and levels is of great significance.

Dr. Xinyue Chen and Dr.Sujun Zheng’s team further explored the impact of combining Peg-IFNα with the hepatitis B vaccine on HBsAg seroconversion and patient immune function. The study divided patients into vaccine and non-vaccine groups, with 14 patients in each group. The vaccine group achieved a 100% HBsAg seroconversion rate at 24 weeks, significantly higher than the non-vaccine group’s 50% (P=0.006), indicating a significant advantage of the combined therapy in promoting HBsAg seroconversion. The vaccine group also showed a significant increase in B cells, plasma cells, and Tfh cells, with a significant decrease in Breg cells, reflecting the combined therapy’s positive modulation of the immune system, which helps enhance overall immune function.

A collaborative study led by Professors Lu Fengmin, Chen Xiangmei, Chen Xinyue, and Gao Zhiliang from Peking University, Beijing You’an Hospital, and Sun Yat-sen University’s Third Hospital, respectively, explored the relationship between TP53BP2 gene expression and HBsAg clearance in CHB patients treated with Peg-IFNα. The researchers found through a genome-wide association study (GWAS) that the rs7519753 C allele is significantly associated with HBsAg clearance (P=4.85×10-8) and that individuals carrying this allele have higher TP53BP2 expression levels in the liver (P=2.90×10-6). Further research showed that TP53BP2 enhances hepatocyte response to IFN-α by inhibiting SOCS2 expression, which may promote HBsAg clearance. This finding not only reveals the potential role of TP53BP2 in CHB treatment but also provides a theoretical basis for developing new treatment strategies in the future.

Conclusion

Dr. Sujun Zheng concluded:

1. Based on data from the Starlight Project, 32.2% of patients meeting the 2019 IHC definition have negative HBV DNA, suggesting that 5.8 to 8.7 million people in China meet the 2022 IHC definition.
2. According to the new 2022 IHC definition, negative HBV DNA does not represent good liver histological status; on the contrary, patients with negative DNA have a significantly higher proportion of liver fibrosis than those with positive DNA.
3. Over 91.5% of the IHC population is aged over 30 years, and antiviral treatment is recommended. The clinical cure rate with PEG IFN-based antiviral therapy in patients meeting the previous 2019 IHC definition can reach 32.2%, while those meeting the 2022 new IHC definition may have an even higher clinical cure rate, making treatment worthwhile.