Prediction of response to entecavir therapy in patients with HBeAg‐positive chronic hepatitis B based on on‐treatment HBsAg, HBeAg and HBV DNA levels

Abstract

Quantitative hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) assays are emerging as effective tools of on-treatment predictors of response to antiviral agents, in addition to monitoring serum HBV DNA levels. However, the dynamic relationship between quantitative HBsAg, as well as HBeAg and HBV DNA, and the predictability of subsequent clinical outcomes during entecavir (ETV) therapy remain unclear. Eighty-two patients with HBeAg-positive chronic hepatitis B (CHB) received ETV therapy for ≥3 years. Virologic response (VR) after 3 years of ETV therapy was achieved in 73 (89.0%) patients. Among baseline and on-treatment factors, on-treatment HBV DNA levels performed better with respect to the prediction of response than HBsAg and HBeAg levels. Especially, the performance of absolute values of HBV DNA with respect to response was superior to HBV DNA decline from the baseline. The best predictive value was an absolute HBV DNA level of 2.3 log(10) IU/mL at month 6 (areas under the curve [AUROC], 0.977; 95% CI, 0.940-1.000; P < 0.001). HBeAg seroconversion after 3 years of therapy was achieved in 26 (31.7%) patients. On-treatment HBeAg levels performed better with respect to the prediction of seroconversion than HBsAg and HBV DNA levels. The best cut-off value for the HBeAg level at month 12 for the prediction of seroconversion was 0.62 log(10) PEIU/mL. Although the HBsAg level at baseline is often used to predict the antiviral potency of entecavir, on-treatment HBV DNA and HBeAg levels are more helpful for prediction of subsequent clinical outcomes in HBeAg-positive CHB patients with entecavir treatment.

On-treatment quantitative hepatitis B e antigen predicted response to nucleos(t)ide analogues in chronic hepatitis B

“…Our data showed that both HBeAg titer as well as its declined value at 24-wk were independent predictors for 96-wk HBeAg SC, and it strongly predicted HBeAg SC with an AUROC of 0.928 if combining HBeAg titer < -0.5 lg PEIU/mL and declined value > 2.2 lg PEIU/mL at 24-wk. A study from Shin et al[11] revealed that HBeAg titer < 0.62 lg PEIU/mL after 48 wk of ETV therapy was a strongest predictor for HBeAg SC at year 3 with an AUROC of 0.86 ( P < 0.001), which was inferior to the combined prediction validity of HBeAg level and declined value at 24-wk in our study (AUROC = 0.928). Our study presented that 88% (7/8) of patients with HBeAg titer < -0.5 lg PEIU/mL and declined value > 2.2 lg PEIU/mL at 24-wk achieved 96-wk HBeAg SC, whereas only 2% (1/51) of patients without meting above standards obtained HBeAg SC, thus got a NPV of 98%.…”

“…The average declines in anti-HBc levels were comparable between the two studies, although the baseline anti-HBc level was relatively higher in our study. Concerning the dynamic change of HBeAg, Shin et al[11] reported that HBeAg level reduced from baseline 2.23 lg PEIU/mL to 0.96 lg PEIU/mL after 96-wk ETV therapy and 17.1% (14/82) achieved HBeAg SC. In the present study, HBeAg level decreased from baseline 2.24 lg PEIU/mL to 96-wk 0.20 lg PEIU/mL and 19.7% (15/76) obtained HBeAg SC, which presented comparable HBeAg reduction and HBeAg SC rate as compared to Shin’s study.…”

“…However, HBV DNA levels and its declines would not associate with 96-wk VR and HBeAg SC anymore if all parameters including HBeAg levels and its declines were enrolled in multivariate analysis. Other studies also pointed out that HBeAg levels as well as its declines may maintain a better predictive value than HBV DNA to predict NAs treatment response in HBeAg-positive CHB patients[10,11]. HBeAg is generated by transcription and translation of HBV cccDNA, and previous studies had reported that serum HBeAg level was significantly correlated with intrahepatic HBV cccDNA ( r = 0.507, P = 0.010)[22].…”

HBsAg and HBcrAg as predictors of HBeAg seroconversion in HBeAg‐positive patients treated with nucleos(t)ide analogues

“…Factors in this study that did impact upon HBeAg seroconversion in univariate analysis included age, ALT, degree of fibrosis and baseline levels of HBV DNA and HBsAg. These have been identified before as baseline characteristics favouring HBeAg seroconversion, and likely reflect the presence of active pre‐existing immune responsiveness at the time of treatment initiation …”

Prediction of spontaneous HBeAg seroconversion in HBeAg‐positive chronic hepatitis B patients during the immune clearance phase

“…It was reported that during antiviral treatment, regardless of the nucleoside analog or IFN (PEG‐IFN), HBV DNA and/or HBeAg on‐treatment levels could accurately predict HBeAg seroconversion and long‐term treatment responses in HBeAg‐positive patients [Hsu et al, ; Mommeja‐Marin et al, ; van der Eijk et al, ; Yuen et al, ; Fried et al, ; Buster et al, ; Liaw et al, ; Shin et al, ]. However, our understanding of the prediction of spontaneous HBeAg seroconversion is limited.…”