Editor's Note: Achieving a functional cure for chronic hepatitis B (CHB) has become the recognized ideal treatment goal in both domestic and international guidelines, as it significantly reduces the risk of liver cancer and other long-term adverse outcomes for CHB patients. How to better pursue functional cure using existing antiviral drugs has become a hot topic in current research. Recently, Dr. Jie Li from Nanjing Drum Tower Hospital delivered an insightful presentation titled "Focusing on Cutting-Edge Information - Preparing for the Functional Cure of Chronic Hepatitis B." The content of her presentation is summarized below.1. HBsAg Clearance Significantly Reduces the Risk of HCC and End-Stage Liver Disease in CHB Patients
A study in Chinese Taiwan recruited patients with CHB-related liver cirrhosis who achieved virological suppression with nucleos(t)ide analogues (NAs) (n=805, virological suppression group) and patients who achieved HBsAg clearance (n=165, HBsAg clearance group) from two medical centers and the REVEAL-HBV cohort. The cumulative incidence of hepatocellular carcinoma (HCC) was compared between the two groups. Through propensity score matching (PSM) analysis, it was found that the annual incidence of liver cancer in the HBsAg clearance group was only 0.46%, significantly lower than the 3.2% in the virological suppression group (P=0.0035). This finding highlights the critical role of HBsAg clearance in preventing HCC.
A 2023 meta-analysis, which included 50,354 patients with a follow-up of 350,734 person-years, assessed the relationship between HBsAg clearance and long-term clinical outcomes. The results showed that HBsAg clearance not only significantly reduced the risk of HCC but also greatly decreased the risks of cirrhosis (72% risk reduction, IRR: 0.28), liver cancer (73% risk reduction, IRR: 0.27), and liver-related mortality (83% risk reduction, IRR: 0.17).
2. Evaluating the Efficacy of Functional Cure with Existing Treatment Regimens
In a large study from Chinese Taiwan involving 1,075 HBeAg-negative patients treated with NAs, five patients achieved HBsAg clearance during treatment. Of the 691 patients who discontinued NAs according to the Asia-Pacific guideline standards, 42 achieved HBsAg clearance after a median follow-up of 155 weeks. Cox regression analysis compared the baseline and treatment characteristics of patients with and without HBsAg clearance, finding that greater HBsAg decline during treatment (>1 log10 IU/mL) was a predictor of HBsAg clearance (HR 2.34, 95%CI: 1.2~4.57, P=0.0126).
Dr. Li summarized the clinical cure efficacy of NAs, including entecavir (ETV), tenofovir disoproxil fumarate (TDF), tenofovir alafenamide (TAF), and tenofovir methoxy fumarate (TMF), and interferon-α (IFN-α) for CHB patients, aiming to provide readers with an understanding of how to better achieve functional cure using existing antiviral drugs.
A retrospective study involving 891 CHB patients without cirrhosis treated with ETV (n=556) or TDF (n=335) found that the cumulative HBsAg clearance rates at 3, 5, and 7 years were 7.7%, 13.2%, and 22.6% in the ETV group, compared to 12%, 20.9%, and 35.4% in the TDF group. The cumulative HBsAg clearance rate was significantly higher in the TDF group than in the ETV group (P=0.019). After propensity score matching, the difference remained statistically significant (P=0.0015).
A meta-analysis systematically reviewed studies involving patients treated with ETV who switched to TDF versus those who continued ETV treatment. The analysis included 10 studies with a total of 1,588 patients. The results indicated that TDF was more effective than ETV in reducing HBsAg levels (MD=0.04 IU/mL, 95%CI: 0.02~0.05, P<0.00001).
Another study found that TDF could induce high expression of IFN-λ3, which activates the JAK-STAT-ISRE signaling pathway, increasing the expression of ISGs such as MX1, OAS, and IFR7, thereby further inhibiting HBsAg production. This study offers new perspectives and strategies for CHB treatment.
In a multicenter, randomized controlled trial involving 240 HBeAg-negative patients who received PEG-IFNα-2a (180 μg/week) ± lamivudine (LAM, 100 mg/day) for 48 weeks, a 5-year follow-up showed that HBsAg clearance rates increased from 3% at 24 weeks post-treatment to 8.7% at 3 years and 12% at 5 years, indicating a modest improvement with the addition of interferon but still suboptimal.
Dr. Li acknowledged that combining NAs with PEG-IFN remains a suboptimal choice. An open-label study randomized 740 CHB patients to receive TDF+PEG-IFN combination therapy for 48 weeks, TDF+PEG-IFN for 16 weeks followed by TDF monotherapy for 32 weeks, TDF monotherapy for 120 weeks, or PEG-IFN monotherapy for 48 weeks. At week 120, the highest HBsAg clearance rate was in the combination group (10.4%), significantly higher than the monotherapy groups (P<0.001).
Another study randomized patients to receive PEG-IFNα-2b+ETV or PEG-IFNα-2b+TDF for 48 weeks. The TDF combination group showed a greater HBsAg decline (-1.799±0.3063 vs. -1.078±0.2028 log10 IU/mL, P=0.0491) compared to the ETV combination group.
Overall, the HBsAg clearance rate was highest with TDF monotherapy (3%~11%), followed by ETV (1.4%~5.1%), with TAF at just 1%. IFN monotherapy achieved a clearance rate of 3%~7%. Combination therapy of NAs with IFN showed higher clearance rates, with initial combination therapy achieving 8%, switch therapy 14%, and add-on therapy 8%. However, these combination regimens are not universally applicable, and individualized treatment decisions should be based on patients’ HBsAg dynamics. Additionally, while combination or sequential therapy offers some benefit, they are not prioritized in current guidelines. There remains a pressing need for new antiviral drugs to achieve functional cure.
3. Exploration and Prospects of New Drugs for Functional Cure
Dr. Li introduced two main categories of drugs currently being explored for functional cure: virus-targeting drugs and immune-modulating drugs. Virus-targeting drugs aim to inhibit key steps in the viral lifecycle, such as adsorption, entry, uncoating, reverse transcription, and integration, thereby effectively suppressing viral replication. Immune-modulating drugs focus on activating and enhancing the host immune system to more efficiently clear the virus.
Current strategies to achieve functional cure focus on three core approaches: inhibiting replication, reducing antigen levels, and stimulating immunity. Drugs that inhibit replication include NAs, capsid assembly modulators (CAMs), and nucleic acid polymers (NAPs); those that reduce antigen levels include small interfering RNA (siRNA) and antisense oligonucleotides (ASO); and those that stimulate immunity include PEG-IFN, TLR7/8 agonists, anti-PD-1 (PD-L1) antibodies, and therapeutic vaccines.
Dr. Li emphasized the potential of small nucleic acid drugs (siRNA and ASO) in reducing HBsAg, making them a hot topic in new drug development for CHB. These drugs exert RNA interference, precisely targeting HBV mRNA and pgRNA, effectively reducing HBV antigen production and viral replication. Small nucleic acid drugs currently under development have entered Phase I, II, and III clinical trials, showing great potential in treating CHB by reducing HBsAg levels.
Dr. Jie Li pointed out that functional cure is the treatment goal for CHB, and achieving sustained response after HBsAg clearance can significantly reduce the risk of HCC, end-stage liver disease, and other adverse outcomes in CHB patients. However, the clinical benefits of monotherapy with NAs or IFN are limited, necessitating optimization of existing antiviral therapies to provide more options for functional cure. At the same time, the development of new anti-HBV drugs is urgently needed, and several investigational drugs have shown great promise in achieving functional cure for CHB patients, offering hope for the future of anti-HBV therapy.
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