Real-world Study Evaluating the Long-term Outcomes of Pegylated Interferon α-2b Treatment in the Families With Clusters of HBV Infection and Unfavorable Prognosis - A Prospective, Controlled, Multicenter, Cohort Study

Study Backgrounds: Chronic hepatitis B (CHB) refers to an infectious disease characterized primarily by liver lesions that persist for more than six months, caused by the hepatitis B virus (HBV). According to the World Health Organization, in 2019, the global prevalence of HBsAg in the general population was 3.8%, with approximately 296 million chronic HBV infections, 1.5 million new HBV infections, and 820,000 deaths due to liver failure, cirrhosis, or hepatocellular carcinoma (HCC) related to HBV infection. Data released by the Polaris International Epidemiology Collaboration in December 2023 on the progress of eliminating hepatitis B in China showed that there are 79.742 million chronic HBV infections in China, with a diagnosis rate of only 24% and an annual treatment rate of only 15%, with more than 450,000 annual deaths related to hepatitis B. According to the National Disease Prevention and Control Bureau's report on nationally notifiable infectious diseases, there are about 1 million new cases of hepatitis B in China each year, with 1.05 million new cases in 2023, making it the fourth leading cause of death from infectious diseases in China.

HBV can trigger host antiviral immunity through direct and indirect mechanisms, leading to liver inflammation, fibrosis, and cirrhosis. Additionally, HBV DNA can integrate into the host genome, activating oncogenes, causing chromosomal instability, and epigenetic changes, ultimately leading to HCC. The risk factors for the development of cirrhosis mainly include host factors (older age, male, HBeAg seroconversion at \>40 years old, persistently elevated ALT), viral factors (HBV DNA \> 2,000 IU/mL, persistently positive HBeAg, C genotype), co-infections (HCV, HDV, HIV), and other liver damage factors (such as alcohol consumption or obesity). Without antiviral treatment, the annual incidence of cirrhosis in CHB patients is 2-10%. The annual incidence of decompensated cirrhosis progressing from compensated cirrhosis is 3-5%, with a 5-year survival rate of 14-35%. The annual incidence of HCC in non-cirrhotic HBV-infected individuals is 0.2-1.0%, while in cirrhotic patients, it is 3-6%. Factors such as age \>40, male, cirrhosis, family history of HCC, high-level replication of HBV, alcohol consumption, smoking, coexisting diabetes, obesity, and exposure to aflatoxins are all associated with a high incidence of HCC. In China, chronic HBV infection is the main cause of HCC, accounting for about 86% of HCC occurrences. As the fourth most common malignant tumor and the second leading cause of cancer-related deaths in China, HCC poses a serious threat to the lives and health of people. CHB and HBV-related diseases such as cirrhosis and HCC impose a huge disease burden on China, significantly affecting families and representing one of China's major public health challenges.

According to the Guidelines for the Prevention and Treatment of Chronic Hepatitis B (2022 Edition), the main goal of CHB treatment is to maximize long-term suppression of HBV replication, alleviate hepatocyte inflammation and necrosis, and liver fibrosis, thereby delaying and reducing the occurrence of liver failure, decompensated cirrhosis, HCC, and other complications. The current clinically used antiviral drugs for CHB mainly include nucleoside (tide) analogs (NAs) and interferon-α (IFN-α) (currently pegylated interferon-α). Antiviral therapy can slow the progression of CHB to cirrhosis and HCC. NAs mainly inhibit viral replication by blocking the reverse transcription process and are all oral medications, which are convenient to use and well-tolerated. However, since they cannot directly inhibit the transcriptional activity of cccDNA, they cannot effectively suppress the expression of viral proteins such as HBsAg, rarely achieving clinical cure. HBsAg decreases slowly during treatment, with an average annual seroconversion rate of 0-1.3% under long-term treatment, thus requiring long-term medication maintenance. Moreover, despite long-term NAs therapy with first-line drugs, there is still a stable and continuous risk of HCC over time, with an increasing annual incidence. Pegylated interferon α-2b (Peg IFN α-2b) is a first-line drug for the antiviral treatment of chronic hepatitis B, with main effects including anti-HBV, anti-fibrotic, antitumor, and immune regulation mechanisms. IFN-α exerts dual effects by enhancing host immune responses and direct antiviral actions at multiple levels. In addition to inhibiting the viral replication process, it affects the transcriptional inhibition of cccDNA, the degradation of cccDNA, and the clearance of HBV-infected cells, inducing a sustained immune response, which is more conducive to virus clearance. During treatment, HBsAg decreases more rapidly in some patients, with previous studies observing an HBsAg seroconversion rate of 2.8-7% at 48 weeks of IFN-α monotherapy, higher than that of NA monotherapy, and continued benefits after discontinuation of IFN-α. Therefore, IFN-α can promote the reduction of incidence and mortality related to liver cirrhosis and HCC. Additionally, IFN-α can inhibit tumor angiogenesis and tumor cell proliferation, which can explain its role in preventing the recurrence of HCC after surgery for HBV-related HCC and in preventing the occurrence of HCC in CHB patients. However, IFN-α preparations require subcutaneous injection and are relatively common in adverse reactions such as bone marrow suppression and flu-like symptoms, with relatively poor tolerance. The Guidelines for the Prevention and Treatment of Chronic Hepatitis B (2022 Edition) indicate that for eligible patients with CHB treated with NAs, the combination of Peg-IFN-α can lead to functional cure in some patients. Although antiviral treatment against HBV can significantly reduce the risk of liver cancer, it cannot completely avoid the occurrence of HCC. Current research on the advantages and disadvantages of different antiviral treatment regimens for CHB, especially the long-term prognosis differences in the incidence of decompensated cirrhosis and HCC after different antiviral treatment regimens, is insufficient.

HBV is mainly transmitted through mother-to-child, blood, and sexual contact, with mother-to-child transmission being the most common. In China, HBV infection is mainly through mother-to-child transmission, showing a family clustering phenomenon. In addition, the occurrence of cirrhosis and hepatocellular carcinoma also has a family clustering nature. Although free hepatitis B vaccination is implemented in various parts of China, due to unbalanced regional economic development, different levels of social education and culture, and uneven individual health knowledge, HBV infection cannot be completely blocked, leading to a significant family clustering of HBV infection, showing a trend of younger-age and high incidence. Many studies and guidelines have pointed out that a family history of HBV-related cirrhosis or HCC is an independent risk factor for the progression of liver disease and the occurrence of HCC. In a large cohort study of CHB patients, the odds ratio (OR) for HCC occurrence in non-cirrhotic patients with a family history of liver cancer was 32.9 times. A survey study of 102 family lineages at the First Affiliated Hospital of Xi'an Jiaotong University in China showed that the prevalence rates of cirrhosis among probands, first-degree relatives (siblings, parents, and children of the proband), second-degree relatives (siblings, parents, and children of the first-degree relatives), and non-relatives were 57.4%, 29.2%, 11.9%, and 8.7%, respectively. The prevalence rates of HCC were 28.7%, 21.8%, 1.4%, and 4.3%, respectively. The average ages at which cirrhosis was diagnosed in probands, first-degree relatives, and second-degree relatives were 57±9.91, 47±9.96, and 38±10.35 years, respectively. The average ages at which HCC was diagnosed were 60±7.92, 49±8.57, and 41±3.35 years, respectively. As the degree of kinship becomes more distant, the rate of HBV infection decreases, but the age of onset advances, the prevalence rates of cirrhosis and HCC decrease, and the prevalence rates of cirrhosis and HCC among different degrees of relatives in families with adverse outcomes of HBV infection are significantly higher than in the general population. Therefore, the risks and harms of HBV-related cirrhosis and HCC in families with unfavorable prognoses of HBV infection are significantly higher than in the general population.

Clinical practice has ample evidence showing that long-term antiviral treatment, whether with NAs or IFN-α, can reduce the risk of HCC in patients with chronic hepatitis B. The "Consensus on Secondary Prevention of Primary Liver Cancer (2021 Edition)" has indicated that the prevention of HCC in populations with chronic HBV/HCV infection and other chronic liver diseases is secondary prevention, and antiviral treatment for HBV is treatment to control the cause. Previous studies have shown that treatment based on PEG-IFN-α can further reduce the risk of liver cancer by more than 85% on the basis of NAs. Therefore, if antiviral treatment can be used as early as possible to achieve HBsAg seroconversion or serum conversion in patients with adverse outcomes of family clustering of HBV, it will reduce the risk of patients developing hepatitis B cirrhosis and HCC. Currently, there is insufficient research on the long-term prognosis differences in the incidence of decompensated cirrhosis and HCC after different antiviral treatment regimens in patients with CHB from families with unfavorable prognoses of HBV infection. There is an urgent clinical need for high-quality clinical studies with large samples and long-term follow-up to provide evidence-based support for the optimization of antiviral regimens.

This study aims to establish a prospective, controlled, multicenter, observational cohort study design to explore, in the context of families with unfavorable prognoses of family clustering of HBV infection, the impact of Peg IFN α-2b combined with NAs on the long-term outcomes of antiviral treatment for CHB, with cirrhosis and HCC progression as the main observation targets, compared with monotherapy with first-line NAs: referring to the use of entecavir (ETV), tenofovir disoproxil fumarate (TDF), tenofovir alafenamide fumarate (TAF), or tenofovir amibufenamide (TMF). The study intends to provide high-quality evidence-based medical evidence for the treatment and follow-up of CHB, explore the best clinical decisions, and provide globally promotable clinical data for the improvement and evaluation of this difficult-to-treat population.

The study plans to enroll patients from multiple research centers across the country, collecting data on antiviral (Peg IFN or NAs) treatments from CHB patients with a family history of unfavorable prognoses associated with HBV infection, and conducting a prospective real-world study. Standard methods are used in the study to collect data, conduct analysis, and evaluation. In this study, patients in each group choose different treatment plans based on the judgment of the clinician and the wishes of the patient. The treatment plans included in the study observation are combination therapy with Peg IFN α-2b and NAs (Peg IFN combination therapy group), and monotherapy with NAs (nucleos(t)ide monotherapy group), where interferon treatment is no less than 48 weeks. The initial therapeutic dose of Peg IFN α-2b and subsequent dose adjustment will be determined individually by the clinician based on the patient's specific condition. NAs include ETV, TDF, TAF, or TMF. During the study, if patients experience virological breakthrough, they may add or switch to other NAs treatments. This study does not conduct any interventions, only observes and records the treatment situation, collects data from laboratory tests, medical examinations, and other data at specified follow-up points, and record

• Overall survival time of patients in each treatment subgroup [Срок оценки: From enrollment to the end of treatment at 5 years and 7 years]
• the time of cirrhosis and HCC occurring in the non-cirrhosis population [Срок оценки: From enrollment to the end of treatment at 5 years and 7 years]
• the time of decompensated cirrhosis and HCC occurring in the compensated-cirrhosis population [Срок оценки: From enrollment to the end of treatment at 5 years and 7 years]
• the number and percentage of HBsAg seroconversion cases, the number and percentage of HBeAg seroconversion cases (for those who are HBeAg-positive) per 24 weeks [Срок оценки: From enrollment to the end of treatment at 5 years and 7 years]
• HBV DNA levels, HBsAg levels, and HBeAg levels per 24 weeks [Срок оценки: From enrollment to the end of treatment at 5 years and 7 years]