Editor's Note: The reduction of hepatitis B surface antigen (HBsAg) levels in treated chronic hepatitis B (CHB) patients is closely linked to decreased risks of cirrhosis and even liver cancer. However, spontaneous HBsAg clearance occurs in less than 1% of patients per year. As CHB prevention and treatment guidelines continue to evolve both domestically and internationally, more patients are now pursuing "functional cures" through nucleos(t)ide analogs (NAs) combined with or followed by pegylated interferon (PEG-IFN) treatment. This approach offers the possibility of reducing or eliminating long-term or lifelong medication use. Clinically, even when patients use similar regimens aimed at achieving a functional cure, many continue to struggle along the difficult path to achieving HBsAg seroclearance, let alone reaching the ideal treatment endpoint of HBs seroconversion. Thus, understanding and recognizing the potential factors influencing functional cure is crucial for timely evaluation and intervention. This article summarizes the possible factors affecting CHB functional cure based on both domestic and international research to date.

HBV-Related Factors

HBsAg is the key marker for achieving a functional cure. Research from abroad has found that baseline or post-treatment low levels of HBsAg, as well as a rapid reduction in HBsAg within the first 12 weeks of treatment, are closely associated with higher rates of HBsAg seroclearance. The following are predictive indicators that may assist in achieving a functional cure:

1. Middle Hepatitis B Surface Protein (MHBS) A retrospective analysis of 83 CHB patients treated with NAs or PEG-IFN found that during the period after HBsAg began to decrease and before its clearance (12.8 ± 8.7 months), MHBS, a component of HBsAg, cleared earlier. This suggests that quantifying MHBS could be a useful predictor of HBsAg seroclearance.
2. HBeAg Status Given the important role of HBeAg in chronic HBV infection, clinical observations have shown that many CHB patients who respond well to treatment experience HBeAg seroconversion before HBsAg clearance. One study of tenofovir disoproxil fumarate (TDF) therapy found that a reduction of serum HBeAg levels by ≥2.2 log PEIU/mL at week 24 was associated with higher HBsAg clearance rates in genotype A and D patients.
3. Serum Anti-HBc Levels A recent study revealed that higher baseline anti-HBc levels (≥4.4 log IU/mL in HBeAg-positive patients and ≥4.0 log IU/mL in HBeAg-negative patients) were linked to increased intrahepatic inflammation and higher HBsAg clearance rates in CHB patients treated with interferon.
4. Hepatitis B Core-Related Antigen (HBcrAg) HBcrAg reflects intrahepatic HBV cccDNA levels and transcriptional activity. Recent studies have shown that patients achieving functional cure with interferon-based regimens and meeting treatment discontinuation criteria often had low HBcrAg levels (<100 IU/mL), which correlated with higher HBsAg clearance rates.
5. Peripheral Serum HBV DNA Load A large-scale follow-up study demonstrated that baseline and on-treatment HBV DNA levels were associated with spontaneous HBsAg clearance. In patients treated with NAs and PEG-IFN, lower baseline and post-treatment HBV DNA levels were linked to faster HBsAg clearance and higher rates of anti-HBs seroconversion.
6. HBV Genotypes HBV genotype distribution varies across regions. For example, genotypes A and D are predominant in Europe, while genotypes B and C are more common in East and Southeast Asia. Research has shown that CHB patients with genotype C are more likely to achieve HBsAg seroclearance compared to those with genotype B. In a long-term study of HBeAg-negative CHB patients treated with TDF, HBsAg clearance was more frequent in patients with genotypes A and D. Additionally, a follow-up study of HBeAg-positive patients treated with interferon revealed that 47% of genotype A and 44% of genotype B patients cleared HBsAg within 78 weeks, compared to 28% of genotype C and 25% of genotype D patients.

Immune Modulation and HBV-Specific Immune Response

Although the mechanisms by which viral factors influence functional cure are not fully understood, observational studies suggest that antiviral drugs like NAs alone are insufficient to increase the probability of functional cure in CHB. The addition of immune-modulating agents such as interferon significantly boosts the chances of HBsAg seroclearance, highlighting the importance of activating the body’s antiviral immune response to achieve functional cure.

Research into the link between HBV and specific immune responses shows that during acute HBV infection, CD8+ T cells play a key role in HBV clearance. However, in chronic HBV infection, HBV-specific T cells become suppressed or exhausted. Studies have found that patients who achieve HBsAg seroclearance exhibit distinct CD4+ and CD8+ T cell profiles compared to those who do not, suggesting that restoring HBV-specific T cell function could be a potential pathway to achieving functional cure in HBV infection.

B cells also play a crucial role in immune responses against HBV. For instance, B cell depletion using rituximab increases the risk of HBV reactivation. In CHB patients, HBsAg-specific B cells show a decreased ability to secrete antibodies, while PD-1 blockade has been shown to restore the function of these cells.

Host Factors

Studies have shown that spontaneous HBsAg clearance is associated with age, with older patients having higher rates of HBsAg seroclearance. However, children treated with interferon show a decrease in HBsAg and higher rates of seroconversion at younger ages. Early treatment in children has been shown to yield higher HBsAg clearance rates, supporting the importance of timely intervention.

Additionally, immune responses, such as the elevation of ALT levels, indicate an immune-mediated attempt to clear HBV. In patients treated with PEG-IFN, early declines in HBsAg and elevated ALT levels have been identified as independent predictors of HBsAg seroclearance.

Impact of Treatment Regimens on Functional Cure

HBsAg is primarily derived from actively transcribed HBV cccDNA and integrated HBV DNA, with the latter being the main source in HBeAg-negative patients. The combination of NAs and PEG-IFN remains the most effective treatment strategy for achieving HBsAg clearance and anti-HBs seroconversion, leading to functional cure.

Research suggests that the use of PEG-IFN as part of a combined or sequential treatment approach after achieving viral suppression with NAs can lead to greater reductions in HBsAg and higher rates of functional cure.

In summary, while there have been successful cases of functional cure in CHB patients, several challenges remain, including limited drug options, low cure rates, significant side effects from interferon-based treatments, and low patient adherence. By understanding and addressing the factors that influence functional cure, clinicians can identify and manage the shortcomings in treatment, ultimately helping more patients complete their treatment and achieve better outcomes.