替诺福韦治疗慢性乙型肝炎核苷类似物经治患者48周的疗效分析

Efficacy of 48-week tenofovir disoproxil fumarate therapy in patients who were unresponsive to nucleoside- analogue treatments

目的探讨替诺福韦（TDF）在慢性乙型肝炎（CHB）经治患者中实际临床应用的疗效特点及其安全性。方法回顾性分析TDF单独治疗30例CHB经治患者48周，比较治疗前后第4、12、24、36、48周时HBVDNA水平、HBVDNA下降水平及累积下降水平，HBVDNA不可检测率、HBVDNA阴转中位时间及观察终点时Au？复常率、HBeAg血清转换率（HBeAg-R％）、病毒学应答率（VR）、病毒学突破率（VBT）及不良事件发生率。计量资料采用t检验，计数资料采用x^2检验，HBVDNA累积不可检测率采用生存分析Kaplan-Meimer方法。结果第4、12、24、48周的HBVDNA下降幅度分别为（2．11±0．38）log10IU／ⅡⅡ、（0．93±0．31）log10Iu／ml、（0．75±0．20）log10IU／ml、（0．16±0．19）log10IU／ml、（0．14±0．25）log10IU／ml，均较基线水平有明显下降（t值分别为5．582、9．303、3．123、10．759、12．202，均P〈0．01），HBVDNA水平、下降及累积下降水平在第4、12、24周差异均有统计学意义（均P〈0．05），而第24、36、48周各时间点差异无统计学意义（均P〉0．05）。第4周与第24、36、48周HBVDNA不可检测率比较，差异有统计学意义（分别为P〈0．01、P=0．007、P=0．001）。第48周HBVDNA累积不可检测率为96．7％。HBVDNA阴转中位时间为10．4（3．43～34．0）周。ALT复常率从第4周的40．0％上升到第48周的100％，且第4周与第12、24、36、48周比较，差异均有统计学意义（均P〈0．05）。随访终点时VR为88．90／0（8／9），HBeAg血清转换率为6．67％（2／30），VBT为0。治疗后各时间点肌酸激酶（CK）超过正常值上限（ULN）2倍的比例平均为9．18％，CK超过2×ULN比例在治疗前后差异均无统计学意义（P=0．087）。治疗后出现血清肌酐上升超过ULN比例为0。结论对于核苷类药物经治的CHB患者，TDF仍能早期快速抑制HBVDNA复制，且ALIT复常率高，耐受性好，不良事件发生率低。

Objective To evaluate the efficacy and safety of tenofovir disoproxil fumarate （TDF） in patients with chronic hepatitis B （CI-IB） after failure of nucleoside-analogues （NAs）. Methods A total of 30 CHB patients who had been previously treated with NAs and had subsequently completed a 48-week course of TDF were retrospectively investigated. Patients＇ data of HBV DNA level （log10 copies/ml） and rate of undetectable HBV DNA at treatment weeks 0 （baseline）, 4, 12, 24, 36 and 48 were collected for evaluation. The lower limit of HBV DNA detection was 100 IU/ml. The serum alanine aminotransferase （ALT） normalization rate, hepatitis B e antigen （HBeAg） seroconversion rate, viral breakthrough （VBT） rate, viral response （VR） rate, and adverse events were determined upon treatment completion. Statistical analyses were carried out using the Student＇s t-test, the 2,2 test or the Kaplan-Meier method. ResuRs Over the 48-week treatment period, HBV DNA levels declined significantly from baseline （week 4：（2.11 ± 0.38） log10 IU/ml, t = 5.582; week 12：（0.93 ± 0.31） log10 IU/ ml, t = 9.303; week 24：（0.75 ± 0.20） log10 IU/ml, t = 3.123; week 36：（0.16 ± 0.19） log10 IU/ml, t = 10.759; week 48：（0.14 ± 0.25） log10 IU/ml, t = 12.202） （all P 〈 0.01）. However, the rates of HBV DNA reduction and of cumulative reduction were comparable at weeks 24, 36 and 48 （all P 〉 0.05）. The most robust decline in I-IBV DNA levels was observed at week 4 （（2.11± 0.38） log10 IU/ml） and the highest cumulative HBV DNA reduction was observed at week 24 （（3.79 ± 0.37） log10 IU/ml）. The rate of undetectable HBV DNA at week 4 （26.7%） was significantly lower than that at weeks 24 （87.5%, P 〈 0.01）, 36 （80.0%, P = 0.007）, and 48 （88.9%, P = 0.001）. The median time to achieving undetectable I-IBV DNA was 10.4 weeks （range： 3.43-34.0 weeks）. At week 48, the rates ofVR, HBeAg seroconversion, and VBT were 88.9%, 6.7%, and 0% respectively. During treatment, the levels of creatine kinase were more than two times the upper limit normal in 9.2% of the patients, and were comparable at each time point examined （all P 〉 0.05）. All patients showed a normal level of serum ereatinine throughout the treatment period. Conclusion For CHB patients with non-response to NAs, TDF can suppress HBV DNA replication very quickly and achieve a high rate of ALT normalization with a low rate of adverse events.