恩替卡韦长期治疗核苷(酸)类药物初治HBeAg阳性慢性乙型肝炎患者的疗效和安全性

Long term efficacy of entecavir therapy on viral suppression in nucleoside-na?ve chronic hepatitis B patients

目的：了解恩替卡韦单药治疗至少5年对核苷（酸）类药物初治的 HBeAg 阳性慢性乙型肝炎患者的疗效和安全性。方法选择BMS463-012和BMS463-023研究项目在瑞金医院感染科入组的20例 HBeAg 阳性慢性乙型肝炎核苷初治患者。所有患者在第一阶段（第1～2年）口服恩替卡韦0．5 mg/d，第二阶段（第3～5年）口服恩替卡韦1．0 mg/d。检测并记录基线以及治疗48、96、144、192和240周时患者的ALT、HBV DNA、HBeAg和 HBsAg水平。如治疗240周时HBV DNA ≥300拷贝/mL，则进行基因序列测定以明确是否发生耐药。结果恩替卡韦治疗第48、96、144、192和240周，HBV DNA ＜300拷贝/mL的比例分别为60％、40％、50％、85％和85％，HBeAg消失率分别为15％、15％、20％、30％和65％。有3例患者在第192周发生 HBeAg 血清学转换。恩替卡韦治疗48周时血清 HBV DNA＜300拷贝/mL 与＞300拷贝/mL患者相比，240周病毒学应答率分别为100％和66．7％；240周 HBeAg 血清学转换率分别为27．3％和0。入组患者中基线ALT＞2倍和＜2倍患者相比，前者240周病毒学应答率为100％，后者为75％；前者240周 HBeAg 血清学转换率为37．5％，而后者为0。入组患者基线高病毒载量（＞10^8拷贝/mL）和低病毒载量（＜10^8拷贝/mL）比较，前者240周病毒学应答率为83．3％，后者为100％；前者240周 HBeAg血清学转换率为11．1％，而后者为50％。以上二者相比，均差异有统计学意义（P＜0．05）。基线、治疗48、96、144、192和240周血清 HBsAg 水平分别为（4．04±0．40）、（3．64±0．44）、（3．73±0．41）、（3．53±0．55）、（3．55±0．55）和（3．55±0．63）lg IU/mL。相对于基线，在第48周、144周、192周、240周 HBsAg效价有明显下降（P值分别为0．005、0．005、0．009、0．018）。治疗240周时 HBeAg消失和未消失的患者，其基线 HBsAg效价（3．95±0．54）lg IU/mL比（4．20±0．48）lg IU/mL，差异有统计学意义（P＝0．005）。在长达5年的恩替卡韦治疗过程中未出现任何严重不良事件。结论 HBeAg阳性慢性乙型肝炎核苷类初治患者接受恩替卡韦单药长期治疗能获得持久的病毒学抑制，5年未发生耐药。

Objective Durable hepatitis B virus （HBV）DNA suppression is important to antiviral effectiveness in chronic hepatitis B （CHB）. In this study,we analyzed the long-term efficacy and resistance profile of entecavir （ETV） monotherapy in 20 Chinese patients with nucleoside nave CHB treated for at least 5 years. Methods Twenty HBeAg positive patients with HBV DNA level 107 copies/mL and alanine aminotransferase （ALT）level 2-fold upper limit of normal （ULN）received ETV 0.5 or 1 mg/day for accumulated 5 years. Serum HBV DNA level,HBeAg status and HBsAg level were assessed at baseline and at year 1 ,2 ,3 ,4 and 5 . Gene sequencing was also conducted in the patients whose serum HBV DNA level 〉 300 copies/mL at year 5 . Results The ratio of HBV DNA undetectable （〈300 copies/mL）for these 20 patients were 60% ,40% ,50% ,85% and 85% at year 1,2,3,4 and 5 respectively. The ratios of HBeAg loss were 15% ,15% ,20% ,30% and 65% at year 1,2,3,4 and 5,respectively. Three of 20 patients （15% ）achieved HBeAgseroconversion at year 4 and 5 . Variables were compared between the patients whose serum HBV DNA 〈 300 copies/mL and those of patients 〉 300 copies/mL at week 48. Virological response rate was 100% and 66.7% at week 240 in the former＇s and the latter＇s,respectively;HBeAg seroconversion rate was 27.3% and 0 at week 240 in the former＇s and latter＇s, respectively. Virological response rate was 100% at week 240 in the patients whose ALT level 2-fold ULN,and was only 75% in the patients whose ALT level 〈 2-fold ULN;Meanwhile,the rate of HBeAg seroconversion was 37.5% and 0 in the former＇s and latter＇s. The rate of HBeAg seroconversion was 1 1 .1% at week 240 in the patients whose HBV DNA level〉10^8 copies/mL at baseline,and was only 50% in the patients whose HBV DNA level 〈10^8 copies/mL at baseline,the statistics had significant difference （P〈0.05）. The mean serum HBsAg levels of the patients were （4.04±0.40）log10 IU/mL,（3.64±0.44）log10 IU/mL,（3.73±0.41）log10 IU/mL,（3.53±0.55）log10 IU/mL,（3.55±0.55）log10 IU/mL and （3.55±0.63）log10 IU/mL at baseline and at year 1,2,3,4 and 5,respectively. HBsAg levels had a greater mean reduction at year 1 （P= 0.005）,3 （P= 0.005）,4 （P= 0.009）and 5 （P= 0.018）compared with baseline, respectively. The HBsAg titers at baseline were significantly different between the patients whose HBeAg loss （3.95 ± 0.54）log10 IU/mL and HBeAg non-loss （4.20±0.48）log10 IU/mL at week 240 （P= 0.005）. Non adverse effect was observed in this study. Conclusion These analysis demonstrates that long-term treatment of ETV monotherapy is effective in maintaining viral suppression. No ETV resistance substitution are detected in these patients.