HBV Infection Associated with Increased Risk of Primary Extrahepatic Malignancies

The study that evaluated the associations of chronic hepatitis B and nucleos(t)ide analogue treatment with the risk of the development of extrahepatic malignancies point out to a need for more attention to the higher risk of extrahepatic malignancy in patients with chronic hepatitis B than in the general population. Long-term nucleos(t)ide analogue treatment was associated with lower risk of extrahepatic malignancy development among patients with chronic hepatitis B. The corresponding author, Dr. Jeong-Hoon Lee of the Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine in Seoul, South Korea and colleagues wrote in the article published on 13 May 2022 in the Journal of Clinical Oncology that patients with chronic hepatitis B should be advised to participate in screening programme for major cancers.

The authors wrote in the background that chronic hepatitis B is the most common chronic viral infection in the world. Hepatitis B virus (HBV) causes intrahepatic malignancy via direct and indirect mechanisms. Direct mechanisms involve HBV DNA integration in the host genome or transactivation of host oncogenes by HBV proteins and indirect mechanism concerns chronic inflammation because of recurrent hepatocyte injury and regeneration.

Anti-HBV treatment with nucleos(t)ide analogues that block HBV replication and suppress viral load can decrease the risk of hepatocellular carcinoma and intrahepatic cholangiocarcinoma, although risk reduction was significant mostly among patients with cirrhosis.

Recent epidemiologic studies reported associations between HBV infection and the risk of primary extrahepatic malignancies. HBV DNA particles were detected in cancer tissues of breast and central nervous system, and HBx protein was highly expressed in stomach and pancreatic cancers. Local inflammation was detected in extrahepatic tissues where HBV DNA was detected. 

In this study, the investigators compared the cumulative risks of primary extrahepatic malignancies in individuals without chronic hepatitis B (the control group), patients with chronic hepatitis B who did not receive nucleos(t)ide analogue treatment, and patients with chronic hepatitis B who received nucleos(t)ide analogue treatment. They conducted an analysis by using nationwide claims data from the National Health Insurance Service of South Korea.

In total, 90,944 newly diagnosed patients with chronic hepatitis B from 2012 to 2014 and 685,436 matched controls were included in the analysis. Patients with chronic hepatitis B were further classified as those treated with nucleos(t)ide analogue (6,539 patients) or untreated (84,405 patients). Inverse probability of treatment weighting analysis was applied to balance the treatment groups. Time-varying Cox analysis was performed to evaluate time-varying effect of nucleos(t)ide analogue treatment. The primary outcome was the development of any primary extrahepatic malignancy. Development of intrahepatic malignancy and death were considered as competing events.

During the study period with a median of 47.4 months, a total of 30,413 patients (3.9%) developed any extrahepatic malignancy. The group with chronic hepatitis B who did not receive nucleos(t)ide analogue treatment had a higher overall risk of extrahepatic malignancy than the group with chronic hepatitis B who received nucleos(t)ide analogue treatment (adjusted subdistribution hazard ratio [aSHR] 1.28; 95% confidence interval [CI] 1.12 to 1.45; p < 0.001) or controls (aSHR 1.22; 95% CI 1.18 to 1.26; p < 0.001).

There was no difference in the risk of extrahepatic malignancy between the group with chronic hepatitis B who received nucleos(t)ide analogue treatment and the controls (aSHR 0.96; 95% CI 0.84 to 1.08; p = 0.48).

In time-varying Cox analysis, the group of patients with chronic hepatitis B who did not receive nucleos(t)ide analogue treatment was associated with a higher risk of extrahepatic malignancy than the patients with chronic hepatitis B who received nucleos(t)ide analogue treatment patients (aSHR 1.37; 95% CI 1.23 to 1.52; p < .001).

The authors commented that there are several mechanisms by which HBV infection might increase the risk of extrahepatic malignancy. Direct HBV-induced carcinogenesis might occur in organs other than liver. Furthermore, HBV-induced inflammation might contribute to carcinogenesis outside the liver. Decreased NK cell function might play a role in extrahepatic malignancy development.

Randomised controlled studies might be warranted to explore whether nucleos(t)ide analogue treatment will reduce the risk of extrahepatic malignancy in patients with chronic hepatitis B outside the current treatment indication. It needs to be further validated in multinational or multiethnicity studies if these results are reproducible in other ethnicities and patients infected with HBV genotype other than genotype C, which is a major genotype in South Korea.

The study was previously presented in part at the European Association of the Study of the Liver International Liver Congress in June 2021.

The study was supported by the National IT Industry Promotion Agency grant funded by the Korea Ministry of Science and ICT, Liver Research Foundation of Korea, Seoul National University Hospital Research Fund, and Yuhan Pharmaceutical Company.

Reference

Lee DH, Chung SW, Lee J-H, et al. Association of Chronic Hepatitis B Infection and Antiviral Treatment With the Development of the Extrahepatic Malignancies: A Nationwide Cohort Study. Journal of Clinical Oncology; Published online 13 May 2022. DOI: 10.1200/JCO.21.01285

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