Moderate levels of serum hepatitis B virus DNA are associated with the highest risk of hepatocellular carcinoma in chronic hepatitis B patients

Globally, the second leading cause of cancer-associated mortality is hepatocellular carcinoma (HCC) and it is commonly caused by chronic hepatitis B (CHB). Studies have shown that an increase in the baseline serum levels of HBV DNA up to 10⁶ copies/mL (about 5 log₁₀ IU/mL) increases the risk of HCC in CHB patients, irrespective of HBeAg status and serum alanine aminotransferase (ALT) levels. However, in middle-aged and old patients with CHB and normal ALT levels, the relationship between very high levels of HBV DNA (especially >6 log₁₀ IU/mL) and HCC risk are still unclear. Studies have established that with normal ALT levels and high HBV replication, hepatocarcinogenesis could be underway. In contrast, the use of currently available nucleoside and nucleotide analogues in active-phase CHB patients for prolonged suppression of HBV replication reduces their risk of developing HCC. It is therefore important to ascertain the patients who have a high risk of developing HCC but do not currently qualify for treatment.

To establish the association between HBV DNA levels and HCC risk, Gi-Ae Kim, Gwang Hyeon Choi, Jonggi Choi and Young-Suk Lim from the Asan Medical Center, University of Ulsan College of Medicine in Republic of Korea together with Seungbong Han from Gachon University showed positive association between moderate serum levels of HBV DNA and the risk of HCC in CHB patients. The work is published in the Alimentary Pharmacology and Therapeutics.

The research team conducted a large-scale historical cohort study in non-cirrhotic CHB patients. The key finding of this study was that the risk of HCC was the highest at HBV DNA levels 6-7 log₁₀ IU/mL, and lowest at >8 log₁₀ IU/mL and ≤4 log₁₀ IU/mL. A total of 6949 patients were recruited and at the median 8.0 years of follow-up, the authors observed that 363 patients (5.2%) developed HCC. The annual incidence rate of HCC was found to be 0.63 per 100 person-years, and the estimated cumulative incidence rate at 3, 5 and 10 years, was 1.6%, 3.2% and 6.3% respectively. Multivariable Cox regression analysis conducted by the team showed that independent predictive factors that had a significant association with the HCC risk included older age, male sex, lower platelet count and HBV DNA levels. Whereas, ALT level and HBeAg status were not observed to be significant factors with an independent association with HCC risk.

A subgroup analysis of 3 different age groups (age <40, 40-49 and ≥50 years) showed a similarity in the association between HBV DNA levels and HCC risk for each age group and the entire cohort. The risk of HCC was found to be the highest at HBV DNA levels 6-7 log₁₀ IU/mL, and lowest at >8 log₁₀ IU/mL and ≤4 log₁₀ IU/mL, in all age groups. The association between HBV DNA levels and HCC risk these patients was found to be parabolic and not linear.

The findings from this important study may be applicable in the prevention of cancer in non-cirrhotic patients with CHB through early initiation of anti-HBV treatment based on serum HBV DNA levels. The authors recommend further studies aimed at refining the HCC risk prediction models using broad range of HBV DNA levels