Treatment in noncirrhotic and low-viral-load chronic hepatitis B

Abstract

Chronic hepatitis B virus (HBV) infection is a leading global cause of cirrhosis, liver-related mortality, and hepatocellular carcinoma (HCC).¹ Current first-line treatments for chronic hepatitis B (CHB) include nucleoside/nucleotide analogs (NAs) and pegylated interferon alpha. Previous studies have demonstrated that NAs can effectively suppress viral replication, achieve biochemical remission, improve liver histology, and lower the risk of HCC.^2-5

The decision to initiate NAs therapy is based on the severity of liver disease and inflammation status as well as viremia level.^{6, 7} In patients with cirrhosis or advanced fibrosis, treatment is generally recommended regardless of HBV DNA levels or serum alanine aminotransferase (ALT) levels. For non-cirrhotic patients, treatment is typically indicated when HBV DNA exceeds 2000 international units (IU)/mL and ALT levels are above the upper limit of normal.⁶ Conversely, in non-cirrhotic, hepatitis B e antigen (HBeAg)-negative patients with low viral loads (<2000 IU/mL) and normal ALT, antiviral therapy is usually not recommended.^{6, 7} However, the recent study by Jang and Dai offers the evidence that challenges long-standing thresholds for initiating antiviral therapy in CHB patients.⁸ This study retrospectively evaluated the impact of NAs on HCC incidence in non-cirrhotic, HBeAg-negative CHB patients with low viral loads.⁸ Among 63 patients aged over 50 years, those treated with NAs had a significantly lower risk of developing HCC compared to untreated counterparts, despite having higher baseline HBV DNA levels. These results underscore the oncogenic potential of even low-level viremia and suggest that current treatment guidelines may underestimate long-term cancer risk in this subgroup. Notably, post-treatment ALT levels decreased significantly (21.3 vs. 29.2 U/L), indicating that some of these patients may fall into the “gray zone,” characterized by borderline HBV DNA and ALT levels between inactive and immune-active HBeAg-negative CHB phases.

Although the study's relatively small sample size and retrospective design warrant cautious interpretation, its clinical implications are still noteworthy. Some guidelines recommend considering treatment even when full treatment criteria are not met, particularly in special scenarios, such as patients over 40 years of age, those with significant fibrosis or moderate liver necroinflammation, individuals with coinfections or extrahepatic HBV manifestations, or those with a family history of HCC.^{6, 7, 9} While a strong positive correlation exists between HBV DNA levels and HCC risk,¹⁰ potentially hepatocarcinogenic HBV integrations can occur across all phases of CHB, regardless of hepatitis activity or viremia levels.¹¹ Recent research further indicates that NAs therapy significantly reduces both integrated and non-integrated intrahepatic HBV DNA,¹² supporting its potential to lower HCC risk even in patients with mild ALT elevation, low viral load, and no cirrhosis.

As CHB management continues to evolve, the simplification and expansion of HBV treatment indications are influenced by clinical, financial, and practical factors.⁶ Among elderly patients with non-cirrhosis and low viral loads, a more individualized treatment approach may be warranted, potentially expanding the criteria for antiviral therapy to include those previously considered lower priority. Nonetheless, prospective studies with larger cohorts and extended follow-up are needed to confirm these findings and inform future treatment paradigms.

The author declares no conflicts of interest.