核苷和核苷酸类药物治疗慢性乙型肝炎停药标准的探讨

Criteria for withdrawal of nucleos( t) ide analogues and their clinical significance in treatment of chronic hepatitis B

目的探讨核苷和核苷酸类药物（NAs）治疗慢性乙型肝炎（CHB）停药后病毒学复发与停药时HBs Ag定量、HBV DNA载量的关系。方法收集2010年1月-2014年6月于济宁市传染病医院门诊经NAs治疗达到《慢性乙型肝炎防治指南（2010年版）》制订的停药标准计划停药的CHB患者205例。停药前检测HBs Ag定量、HBV DNA载量,其中HBV DNA〈103IU/ml的采用Roche COBAS Taq Man 480ⅡPCR进一步检测高灵敏度HBV DNA载量。停药后随访1年,HBV DNA载量〉103IU/ml定义为病毒学复发。计数资料组间比较采用χ^2检验和Fisher精确检验。结果停药1年所有CHB患者的总病毒学复发率为65.9%（135/205）。20%（41/205）患者HBV DNA〉103IU/ml。HBs Ag定量≤100 IU/ml患者的复发率为23.9%（11/46）,〉100 IU/ml患者的复发率为78.0%（124/159）,两组比较差异有统计学意义（χ^2=46.4,P〈0.000 1）。高灵敏度HBV DNA载量〈20 IU/ml患者的复发率为56.4%（62/110）,≥20 IU/ml患者的复发率为76.8%（73/95）,两组比较差异有统计学意义（χ^2=9.5,P=0.002）。同时符合HBs Ag定量≤100 IU/ml、高灵敏度HBV DNA定量〈20 IU/ml的患者复发率为14.3%（5/35）,余下患者复发率为76.5%（130/170）,两组比较差异有统计学意义（χ^2=49.9,P〈0.000 1）。结论达到我国《慢性乙型肝炎防治指南（2010年版）》制订的停药标准停止抗病毒治疗后,CHB的复发与停药时HBs Ag定量、HBV DNA载量有一定关系,参考HBs Ag定量和（或）高灵敏度HBV DNA载量作为抗病毒治疗的停药指标,如HBs Ag定量≤100 IU/ml、高灵敏度HBV DNA载量〈20 IU/ml可达到最大的安全停药。

Objective To investigate the association of virologic relapse after withdrawal of nucleos（ t） ide analogues（ NAs） with HBs Ag quantitation and HBV DNA load at withdrawal in patients with chronic hepatitis B（ CHB）. Methods A total of 205 CHB patients who were treated with NAs in the outpatient service of Jining Infectious Diseases Hospital from January 2010 to June 2014,met the criteria for drug withdrawal in Guidelines for Prevention and Treatment of Chronic Hepatitis B（ version 2010）,and planned to stop the drugs were enrolled.HBs Ag and HBV DNA load were measured before drug withdrawal,and COBAS Taq Man 480 Ⅱ PCR was performed for patients with HBV DNA 103 IU / ml to measure highly sensitive HBV DNA load. The patients were followed up for 1 year after drug withdrawal and HBV DNA 103 IU / ml was defined as virologic relapse. The chi- square test and Fisher＇ s exact test were used for comparison of categorical data between groups. Results At 1 year after drug withdrawal,the overall virologic relapse rate in all CHB patients was 65. 9%（ 135 /205）,and 20%（ 41 /205） had HBV DNA 103 IU / ml. In the patients with HBs Ag quantitation ≤100 IU / ml or 100 IU / ml,the virologic relapse rate was23. 9%（ 11 /46） and 78. 0%（ 124 /159）,respectively,with a significant difference between the two groups（ χ^2= 46. 4,P〈0. 000 1）. In the patients with highly sensitive HBV DNA load 20 IU / ml or ≥20 IU / ml,the virologic relapse rate was 56. 4%（ 62 /110） and 76. 8%（ 73/95）,respectively,with a significant difference between the two groups（ χ^2= 9. 5,P = 0. 002）. The patients with HBs Ag quantitation ≤100IU / ml and highly sensitive HBV DNA load 20 IU / ml had a relapse rate of 14. 3%（ 5 /35）,and the other patients had a relapse rate of 76. 5%（ 130 /170）; the relapse rate showed a significant difference between the two groups（ χ^2= 49. 9,P〈0. 000 1）. Conclusion After the patients meet the criteria for drug withdrawal in Guidelines for Prevention and Treatment of Chronic Hepatitis B（ version 2010） and stop the antiviral therapy,the relapse of CHB is associated with HBs Ag quantitation and HBV DNA load at withdrawal. With reference to HBs Ag quantitation and / or highly sensitive HBV DNA load as the criteria for withdrawal of antiviral therapy,such as HBs Ag quantitation ≤100 IU / ml and highly sensitive HBV DNA load 20 IU / ml,patients can achieve the safest drug withdrawal.