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Background and Aims:  Few previous studies have reported on a combination response (hepatitis B virus (HBV) DNA undetected, alanine aminotransferase normalization and hepatitis B e antigen (HBeAg) seroconversion) following nucleos(t)ide analogue (NAs) long-term therapy in patients with chronic hepatitis B (CHB). This study aimed to investigate the combination response on long-term NAs therapy in patients with HBeAg-positive CHB and to determine whether prolonged therapy is beneficial for combination response, particularly in optimal patients (baseline alanine aminotransferase level ≥5 upper limit of normal and HBV DNA level &lt;10 9 copies/mL).  Methods:  In total, 280 HBeAg-positive CHB patients were enrolled in this study. Among them, 190 were treated with entecavir and 90 were treated with telbivudine.  Results:  The cumulative rates of combination response in the total number of patients were 8.6% at 1 year, 13.2% at 2 years, 19.1% at 3 years, 24.2% at 4 years and 26.0% at 5 years. In optimal patients, the cumulative rate of combination response was significantly higher than that in the non-optimal patients at 3 years ( p = 0.043); the trend of the cumulative rate was not strong at the later time. Interestingly, in optimal patients, combination response mainly occurred in the first 3 years. Multivariate analysis identified HBeAg/anti-HBe seroconversion at 1 year as the only factor for combination response in optimal patients (hazard ratio: 16.321; p = 0.000). During the 3 years, the proportion with aspartate aminotransaminase to platelet ratio index ≤0.5 increased from 15.6% at baseline to 71.3% at year 3.  Conclusions:  Upgrading the rate of combination response is limited by prolonging the treatment duration of NAs from 3 years to 5 years in HBeAg-positive CHB patients; a new switch treatment strategy modification should be considered, particularly in optimal patients.

Upgrade Combination Response Is Limited by Prolonged Nucelos(t)ide Analogue Therapy in HBeAg-positive Chronic Hepatitis B: A Real-life Study