Editor's Note: Recently, the 25th National Conference on Traditional Chinese Medicine and Hepatobiliary Diseases organized by the Chinese Association of Traditional Chinese Medicine was successfully held in Chongqing. The conference invited distinguished TCM masters, academicians, renowned TCM experts, and hepatology specialists from across the country to deliver academic reports, focusing on the hot and challenging issues in the diagnosis and treatment of liver diseases with TCM. At the conference, Professor Li Li from Beijing Hospital of Traditional Chinese Medicine, presented a report titled "Latest Advances in the Clinical Cure of Chronic Hepatitis B." The following is a summary of the report for our readers.

Clinical Cure Significantly Reduces Hepatocellular Carcinoma and Liver-related Mortality

Despite a significant decline in the global incidence of hepatitis B virus (HBV) infection over the past 30 years (4.51%), the number of deaths from HBV-related chronic liver disease increased by 14.36% from 1990 to 2019. HBV infection significantly increases the risk of hepatocellular carcinoma (HCC), with HCC risk being 25 to 37 times higher in HBsAg carriers compared to uninfected individuals. The 5-year incidence of HCC is 14.9% in untreated HBV patients and 10.7% in those receiving antiviral treatment. However, after achieving clinical cure through HBsAg clearance, the incidence of HCC drops to 0.6% to 1.88%, and the probabilities of cirrhosis, liver decompensation, and liver-related mortality are significantly reduced. The 2022 “Guidelines for the Prevention and Treatment of Chronic Hepatitis B” (hereafter referred to as the Hepatitis B Guidelines) recommend that for patients with HBV DNA below the quantification limit and HBeAg seroconversion, along with HBsAg levels below 1500 IU/mL after nucleos(t)ide analogs (NAs) treatment (advantageous population), adding pegylated interferon-alpha (PEG-IFNα) can be considered to pursue clinical cure. Achieving functional cure has become an international consensus.

Advances in Clinical Cure for NAs-treated Populations

Chinese researchers began exploring clinical cure for NAs-treated populations over a decade ago. The Anchor A study, supported by the national “13th Five-Year Plan” project (Han MF, et al. AASLD 2018; Abstract 29), found that in patients with baseline HBsAg levels below 3000 IU/mL and HBV DNA below 1000 copies/mL, 48 weeks or more of PEG-IFNα combined with NAs treatment achieved an HBsAg clearance rate of 20%. The New Switch study, the first domestic clinical study with HBsAg clearance as the endpoint (Hu P, et al. J Clin Transl Hepatol. 2018;6:25-34), reported an HBsAg clearance rate of 26.5% in patients with baseline HBsAg levels below 1500 IU/mL treated with PEG-IFNα combined therapy. The Clinical Cure (Zhu Feng) project is the largest real-world study to date on the clinical cure of chronic hepatitis B (CHB), showing that PEG-IFNα-based treatment significantly increased HBsAg clearance rates to over 30% in NAs-treated CHB patients. Subgroup analysis indicated that lower baseline HBsAg levels and faster HBsAg decline at 12 and 24 weeks of treatment correlated with higher clinical cure rates. For patients with baseline HBsAg levels of 200 IU/mL or less, the HBsAg clearance rate with PEG-IFNα combined treatment could reach 50%.

For CHB patients who do not achieve HBsAg clearance with initial treatment but show significant HBsAg decline, a phased approach to lower HBsAg levels could potentially achieve clinical cure in the future.

Advances in Clinical Cure for Inactive HBsAg Carrier State (IHCs)

The definitions of IHCs differ between the 2019 and 2022 versions of the Hepatitis B Guidelines. Common features include HBsAg levels below 1000 IU/mL, normal ALT, HBeAg-negative, HBeAb-positive, HBcAb-positive, and no or mild liver inflammation with varying degrees of fibrosis. The 2019 version includes individuals with HBV DNA below 2000 IU/mL. Current studies on the clinical cure of IHCs include some HBV DNA-positive patients. A study in Taiwan followed 1932 IHCs for an average of 13.1 years, finding that the risks of liver cancer and liver-related mortality in IHCs were 4.6 and 2.1 times higher, respectively, than in healthy individuals.

Overall, PEG-IFNα treatment has shown a relatively high clinical cure rate for IHCs advantageous populations. A meta-analysis (Song A, et al. Front Immunol, 2021,12:779347) reviewed articles on HBsAg clearance in IHCs published from January 2000 to August 2021, including randomized controlled trials and prospective or retrospective cohort studies with more than 20 IHCs who received PEG-IFNα, NAs, or no treatment. The analysis included IHCs with HBsAg positive for over 6 months, HBsAg below 1500 IU/mL, HBeAg-negative, HBeAb-positive or negative, HBcAb-positive, HBV DNA below 2000 IU/mL, normal ALT, and no cirrhosis on ultrasound or scan. The PEG-IFNα treatment group achieved an overall HBsAg clearance rate of 47% (95% CI: 31%~64%) after 48 weeks. Lower baseline HBsAg levels correlated with higher clearance rates, sometimes exceeding 90%.

Advances in Clinical Cure for HBeAg-positive Chronic HBV Infection and Indeterminate Phase

The 2022 Hepatitis B Guidelines renamed the “immune tolerant phase (IT)” as “HBeAg-positive chronic HBV infection,” characterized by high HBsAg and HBV DNA levels but normal ALT. The indeterminate phase (IP) refers to patients with HBsAg levels higher than the IHCs standard and normal ALT. Neither group is considered advantageous for clinical cure. The “Voyage” project, a multicenter cohort study led by the First People’s Hospital of Yunnan Province, evaluated the efficacy of different antiviral regimens in IT and IP patients.

Study 1 included treatment-naive IT patients aged 18 to 60 years, with the primary endpoint being the HBeAg clearance rate and the proportion of patients with qHBsAg below 3000 IU/mL at the end of treatment. After 48 weeks of treatment, 46.58% of the combination treatment group achieved qHBsAg below 3000 IU/mL, and 4.11% achieved HBsAg clearance.

Study 2 included treatment-naive IP patients aged 18 to 60 years, with qHBsAg above 3000 IU/mL and normal ALT, with the primary endpoint being the proportion of patients with qHBsAg below 1500 IU/mL at the end of treatment. At the end of treatment, 55.06% of the combination treatment group achieved qHBsAg below 1500 IU/mL, and 4.49% achieved HBsAg clearance.

Subgroup analysis showed that patients with qHBsAg below 1500 IU/mL had higher average ALT levels at weeks 12 and 24 compared to those with qHBsAg above 1500 IU/mL (P12 weeks=0.04; P24 weeks=0.002). Additionally, patients with ALT levels more than twice the baseline at weeks 12 and 24 were more likely to achieve qHBsAg below 1500 IU/mL at the end of treatment, with rates of 97.96% and 73.47%, respectively.

For IT and IP HBV patients, treatment can reduce HBsAg levels, and phased treatment might achieve a cure in the future.

Advances in Integrated Traditional Chinese and Western Medicine Clinical Cure Research for CHB

In recent years, research on the integrated treatment of chronic hepatitis B (CHB) with traditional Chinese and Western medicine has been limited. TCM treatments focus on promoting the reduction of HBsAg and HBeAg levels, improving liver function, reversing liver fibrosis, and mitigating the side effects of PEG-IFNα through methods like kidney and spleen tonification, detoxification, and supporting qi and blood. There is a lack of rigorously designed evidence-based studies with clinical cure as the endpoint. Future research should focus on leveraging the synergistic effects of TCM in enhancing the efficacy and reducing the toxicity of treatments for the clinical cure of hepatitis B.