Non-linear association of baseline viral load with on-treatment hepatocellular carcinoma risk in chronic hepatitis B

Objective The association between baseline pretreatment serum HBV DNA levels and on-treatment hepatocellular carcinoma (HCC) risk remains controversial in patients with chronic hepatitis B (CHB). We aimed to investigate the association between baseline HBV viral load and on-treatment HCC risk in CHB patients without cirrhosis. Design Using a multicentre historical cohort study including 4693 hepatitis B e antigen (HBeAg)-negative and HBeAg-positive, adult CHB patients without cirrhosis who initiated antiviral treatment, HCC risk was estimated by baseline HBV viral load as a categorical variable. Results During a median of 7.6 years of antiviral treatment, 193 patients developed HCC (0.53 per 100 person- years). Baseline HBV DNA level was independently associated with on-treatment HCC risk in a non-linear, parabolic pattern. Patients with moderate baseline viral loads (5.00–7.99 log 10 IU/mL) exhibited the highest HCC risk (HR, 2.60; p<0.001), followed by those with low viral loads (3.30–4.99 log 10 IU/mL; HR, 1.66; p=0.11). Patients with high viral loads (≥8.00 log 10 IU/mL) presented the lowest HCC risk. Particularly, patients with baseline HBV DNA levels 6.00–6.99 log 10 IU/mL had the highest on-treatment HCC risk (HR, 3.36; p<0.001) compared with those with baseline HBV DNA levels≥8.00 log 10 IU/mL. These findings were more prominent among HBeAg-positive patients, younger patients, or those with less advanced hepatic fibrosis. Conclusion Patients with moderate baseline viral load, particularly around 6 log 10 IU/mL, demonstrated the highest on-treatment HCC risk, despite long-term antiviral treatment. Early initiation of antiviral treatment, tailored to viral load, should be considered to minimise HCC risk in adult CHB patients without cirrhosis.