Editor's Note: Hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) presents a significant public health challenge in China, with the majority of HCC patients being diagnosed at an advanced stage. Postoperative survival rates for HBV-related HCC patients are often poor. Therefore, the prevention and treatment of HBV-related HCC urgently require comprehensive management. China has achieved remarkable success in primary prevention of hepatitis B. Regular screening and early treatment in high-risk populations are crucial to reducing HCC mortality. Antiviral treatment is an important measure for secondary and tertiary prevention of HBV-related HCC. At the 2024 World Hepatitis Day and the Elimination of Hepatitis Harm Action Conference, Dr. Yingli He from the First Affiliated Hospital of Xi'an Jiaotong University shared insights into antiviral treatment strategies for chronic hepatitis B (CHB) patients from the perspective of comprehensive liver cancer management.The Role of Nucleos(t)ide Analogs (NUCs) in Secondary Prevention of HBV-Related HCC
Chronic infections with HBV or hepatitis C virus (HCV) are major causes of HCC. The goal of secondary prevention for HBV-related HCC is to reduce or delay the onset of HCC in individuals with chronic HBV infection. By using antiviral therapy to suppress HBV replication to the lowest possible levels or achieve functional cure in CHB patients, and by clearing HCV in chronic hepatitis C (CHC) patients to achieve cure, the incidence of HCC can be significantly reduced. This approach is the most effective means of secondary prevention for HBV/HCV-related HCC.
Cirrhosis and high viral load are major risk factors for HCC, while a family history of HCC, alcohol consumption, smoking, and diabetes are additional promoting factors. Predictive models such as REACH-B, mPAGE-B, mREACH-B, and aMAP, which are based on factors like family history of HCC, HBsAg levels, HBV DNA levels, and HBeAg status, can help estimate the future risk of HCC progression in Asian CHB patients. The effectiveness of antiviral therapy is directly related to the control of risk factors such as HBV DNA, HBeAg, and HBsAg levels.
An HBV DNA level above 20 IU/mL can negatively impact the virological response to subsequent treatments. A retrospective cohort study in Hong Kong included 440 CHB patients who started on entecavir (ETV) therapy before September 2009. Among patients with poor virological response at 12 months, those who continued with the original treatment regimen were followed up every 3-6 months, with serum HBV DNA levels monitored at least every 6 months, over an average follow-up period of 34 ± 9 months. The study found that the cumulative virological suppression rate at 3 years was only 57.5%, significantly lower than in patients who responded well at 12 months (P < 0.001).
In standardized NUC treatment, achieving viral suppression to less than 20 IU/mL can significantly reduce the risk of disease progression. A retrospective cohort study from Hong Kong included 20,263 CHB patients who received at least 6 months of ETV and/or tenofovir disoproxil fumarate (TDF) treatment between 2005 and 2016. The study followed patients until death, HCC diagnosis, the last follow-up date, or up to 8 years. It evaluated the relationship between NUC treatment outcomes and the risk of HCC and liver-related events. The primary endpoint was HCC, while secondary endpoints included liver events and liver-related mortality. The results showed that controlling HBV DNA below 20 IU/mL significantly reduced the risk of HCC and liver-related death.
NUC treatment can significantly reduce the risk of HCC in cirrhotic patients. A retrospective cohort study analyzed two groups of CHB patients with cirrhosis. Cirrhosis was defined by histology, thrombocytopenia (platelet count <150×10^9/L), or imaging evidence of portal hypertension. The TDF group included patients from two Asian centers who received at least 12 months of TDF 300 mg/day treatment, while the control group included treatment-naïve patients who received routine clinical care. The study compared the 5-year cumulative incidence of HCC, overall mortality, and liver-related mortality between the two groups. The results showed that the 5-year cumulative incidence of HCC in untreated patients was 26.4%, whereas it significantly decreased to 13.5% in patients who received NUC treatment for 5 years.
A Chinese study included 1,453 treatment-naïve patients with compensated cirrhosis due to HBV who were treated with ETV or TDF for at least 12 months in nine hospitals across mainland China. The TDF group included 188 patients, and the ETV group included 1,265 patients. The primary endpoint was the incidence of HCC, while secondary endpoints included liver transplantation rates and mortality. The study found that TDF reduced the risk of HCC more effectively than ETV, particularly in patients with cirrhosis.
Researchers reviewed cohort studies conducted in Asia after 2019 with more than 500 patients, published in journals with an impact factor greater than 4, comparing the incidence of HCC between ETV and TDF treatments in CHB patients. More studies in Asia supported the superiority of TDF over ETV in reducing the incidence of HCC.
The Role of NUCs in Tertiary Prevention of HBV-Related HCC
The goal of tertiary prevention for HBV-related HCC is to reduce HCC recurrence, ensure the effectiveness of comprehensive HCC treatment, and extend patient survival. Antiviral therapy is one of the effective basic treatment measures after the onset of HBV/HCV-related HCC. It can alleviate liver damage caused by hepatitis viruses, reduce or even reverse liver fibrosis or cirrhosis, slow tumor progression, reduce HCC recurrence, protect liver function, ensure the effectiveness of other comprehensive treatments, and improve overall survival. Thus, it is a crucial measure for tertiary prevention.
The impact of NUCs on postoperative recurrence of HBV-related HCC varies. A historical cohort study from South Korea continuously enrolled 1,695 patients with HBV-related HCC who underwent curative liver resection and received ETV or TDF treatment between 2010 and 2018. The study found that ETV and TDF had different effects on the recurrence of HBV-related HCC after surgery.
A retrospective analysis using the Comprehensive Medical Database of National Taiwan University Hospital included 390 CHB patients aged 20 years and older who received ETV or TDF treatment for at least 3 months during curative treatment for HCC between 1986 and 2020. The median follow-up period was 29 months. The study compared the differences in HCC recurrence and mortality risks between ETV and TDF in patients who underwent curative treatment. The results showed that, compared to ETV, TDF treatment significantly reduced the risks of recurrence and mortality after curative liver resection for HBV-related HCC.
A meta-analysis searched MEDLINE, EMBASE, CENTRAL, and Science Direct, ultimately including nine studies with a total of 5,298 patients. The analysis aimed to evaluate the impact of ETV and TDF on recurrence and mortality rates after curative treatment for HBV-related HCC. The results showed that, compared to ETV, TDF treatment significantly reduced the risks of recurrence and mortality after liver resection or ablation for HBV-related HCC.
Conclusion
China still faces severe challenges regarding HBV-related HCC, necessitating comprehensive management strategies based on primary, secondary, and tertiary prevention. In primary prevention, hepatitis B immunization for newborns has significantly reduced the incidence and mortality of HBV-related HCC. In secondary prevention, timely initiation of antiviral therapy and standardized monitoring of viral suppression during NUC treatment can reduce the risk of disease progression. In tertiary prevention, nucleos(t)ide analogs are significantly more effective in reducing HCC recurrence and improving survival rates.
The nucleos(t)ide analog TDF has unique immunomodulatory mechanisms that can improve liver fibrosis and reduce the risk of HCC. By inhibiting Akt phosphorylation and downregulating the PI3K/Akt/mTOR signaling pathway, TDF exerts immunomodulatory effects. Compared to ETV, TDF treatment significantly reduces the risk of HCC, especially in patients with cirrhosis. Moreover, TDF treatment significantly lowers the risks of recurrence and mortality after liver resection or ablation for HBV-related HCC compared to ETV.
