BACKGROUND: We investigated hepatic histological changes in a cohort of HBeAg-negative chronic hepatitis B (CHB) patients (n=50) under long-term antiviral treatment in clinical practice.METHODS: Liver biopsies were obtained at baseline and after prolonged antiviral treatment with lamivudine (42/50), entecavir (6/50), telbivudine (1/50), or tenofovir (1/50). Due to viral resistance to lamivudine a nucleotide analog was added in 17 patients (adefovir n=11; tenofovir n=6). Twenty-two patients had initially received a 12-month course of pegylated interferon-α, followed by nucleos(t)ide analogs. Necroinflammatory activity was graded as 1-minimal (histological activity index [HAI]: 0-3), 2-mild (HAI: 4-8), 3-moderate (HAI: 9-12), or 4-severe (HAI: 13-18); staging was performed according to the METAVIR system.RESULTS: Twenty-seven patients were male and 23 female; mean age was 46.9±10.7 years. Mean interval between biopsies was 72.6±27.8 months. Improvement in activity was observed in 31/42 patients (74%) (mean drop -1.1 grade, SD=1.0), and in histological staging in 24/50 patients (48%) (mean drop -0.56 stage, SD=0.73). Importantly, the repeat biopsies of 5/10 patients with initial stage F4 were classified as F3 (n=3), F2 (n=1) or F1 (n=1). Worsening of staging was observed in only one patient. Development of resistance to lamivudine had no significant effect on stage improvement.CONCLUSIONS: Sustained hepatitis B virus suppression with antiviral treatment in HBeAg-negative CHB patients leads to reduction in necroinflammatory activity and improvement in staging, regardless of transient viral breakthrough. Potent antivirals in common clinical use for CHB can even lead to regression of fibrous septa and architectural improvement of cirrhotic livers.