摘要目的 探讨慢性乙型肝炎(CHB)经治患者核苷类药物(NA)再治疗的效果及其耐药情况.方法 104例研究对象为初次无间断NA单药治疗至少3个月、停药后再次NA治疗至少1年的CHB患者.分为3组:A组39例,停药时已达慢性乙型肝炎防治指南中的停药标准；B组33例,停药时未达到停药标准但HBV DNA＜1.0×103拷贝/mL；C组32例,停药时未达到停药标准且HBV DNA＞1.0×103拷贝/mL.比较基线ALT、HBV DNA、HBeAg水平对再治疗的影响,以及3组患者不同再治疗方案的累计耐药率.套式PCR检测HBV P基因区耐药变异位点.统计学处理采用Wilcoxon秩和检验与x2检验.结果 基线ALT＜1.3×正常值上限(ULN)的患者ALT复常时间为2个月,ALT≥1.3×ULN的患者ALT复常时间为4个月,差异有统计学意义(Z=2.281,P=0.023);基线HBV DNA＜5 lg拷贝/mL的患者病毒学应答时间为1个月,HBV DNA≥5 lg拷贝/mL的患者为2个月,差异有统计学意义(Z=2.054,P=0.040);基线HBeAg阴性者病毒学应答及ALT复常时间分别为1个月和3个月,均早于HBeAg阳性者的2个月和4.5个月(Z=2.580、2.304,均P＜0.05).A组患者再治疗时病毒学应答时间及HBeAg血清学转换时间均比初次治疗快,分别为(1.61±1.76)、(3.38±3.34)个月和(3.48±4.06)、(9.92±11.22)个月(Z=-2.854、-1.094,均P＜0.05).A组病毒学应答时间早于B、C组,分别为(1.61±1.76)、(3.13±3.06)和(3.41±3.26)个月(Z=-2.025,P＜0.01；Z=2.474,P＜0.05).A组累计HBeAg血清学转换率高于B、C组,分别为80.0％、36.8％和37.5％(x2=4.368、5.100,均P＜0.05).共有13例发生耐药,4例检测到基因型耐药；继续原方案治疗C组累计耐药率明显高于A、B组,分别为44％、9％和0(x2=5.019、6.588,均P＜0.05)；采用无交叉耐药位点NA联合治疗方案的14例患者未发现耐药.结论 对于符合抗病毒治疗的CHB经治患者,停药后再治疗时间越早越好；没有交叉耐药位点的NA联合治疗方案可以降低经治患者的耐药风险.

abstractsObjective To evaluate the efficacy and drug resistance profiles of nucleosides (NA) retreatment in NA experienced chronic hepatitis B (CHB) patients. Methods Totally 104 NA experienced CHB subjects were enrolled in this study.All these subjects had received at least 3 months NA monotherapy and stopped the treatment,and then received NA retreatment for at least one year.The subjects were divided into three groups according to the following criteria:reached the therapy endpoint of China guideline when they stopped NA-naive treatment (group A,n =39); did not reach the therapy endpoint when they stopped NA-naive treatment but hepatitis B virus (HBV) DNA＜1.0× 103 copy/mL (group B,n=33); and with HBV DNA＞1.0× 103 copy/mL (group C,n=32).The efficacy and drug resistance profiles of retreatment were compared among three groups. The effects of baseline alanine aminotransferase (ALT) levels,HBV DNA levels and HBeAg titers on the retreatment efficacies were analyzed. The mutations of HBV P gene were detected by nested polymerase chain reaction (PCR) and direct sequencing.The data were analyzd by Wilcoxon test and x2 test.Results The time to ALT normalization in patients with baseline ALT＜ 1.3 × upper limit normal (ULN) was shorter than that in patients with ALT≥1.3×ULN (2 months vs 4 months; Z=2.281,P=0.023).The time to virological response in patients with baseline HBV DNA＜5 lg copy/mL was shorter than that in patients with HBV DNA≥5 lg copy/mL (1 month vs 2 months; Z=2.054,P =0.040). The time to virological response and ALT normalization in baseline HBeAg negative were both shorter than those in patients with baseline HBeAg positive patents ( 1 month vs 3 months and 2 months vs 4.5 months,respectively; Z=2.580 and 2.304,respectively; both P＜0.05). The subjects in group A achieved virological response and HBeAg seroconversion after retreatment earlier compared to previous NA-naive therapy ([1.61 ± 1.76] months vs [3.48±4.066]months and [3.38 ± 3.34] months vs [9.92-11.22] months,respectively; Z=-2.854 and-1.094,respectively; both P＜0.05).The cumulative HBeAg seroconversion rate in group A was higher compared to those in group B and group C (80.0％ vs 36.8％ and 37.5％,respectively; x2 =4.368 and 5.100,respectively; both P＜0.05).Thirteen patients developed clinical resistance and four of them developed genotypic resistance proved by PCR direct sequencing.Among the patients retreated with the same regimen as previous in the C group,the cumulative resistance rate was highest compared to group A and B (44％ vs 9％ and 0,respectively; x2 =5.019 and 6.588,respectively;both P＜0.05).No resistance was detected in the 14 patients retreated with combined NA treatment without cross resistance.Conclusions For NA experienced CHB patients who fulfill the indication of antiviral therapy,the retreatment should be started as earlier as possible. Retreatment with NA combination without cross resistance can prevent (reduce) the risk of developing drug resistance.