中华肝脏病杂志
中華肝髒病雜誌
중화간장병잡지
CHINESE JOURNAL OF HEPATOLOGY
2012年
4期
280-284
,共5页
姬粉芝%王磊%杨保华%赵敬杰%刘峰%薛艳%李涛
姬粉芝%王磊%楊保華%趙敬傑%劉峰%薛豔%李濤
희분지%왕뢰%양보화%조경걸%류봉%설염%리도
肝炎病毒,乙型%核苷(酸)类似物%突变%治疗%焦磷酸测序
肝炎病毒,乙型%覈苷(痠)類似物%突變%治療%焦燐痠測序
간염병독,을형%핵감(산)유사물%돌변%치료%초린산측서
Hepatitis B virus%Nucleos (t) ide analogue%Mutation%Therapy%Pyrosequencing
目的 研究rtA181位点突变慢性乙型肝炎(CHB)患者的用药史、临床特点及个体化治疗效果. 方法 核苷(酸)类似物(NUCs)治疗中病毒学突破并检出rtA181突变的54例CHHB及相关肝硬化患者,检测其血清HBV DNA、HBsAg定量及ALT水平,焦磷酸基因测序法定量检测HBV的P基因区10个NUCs相关耐药突变位点.回顾性分析不同用药史患者的病毒变异模式,比较病毒学突破时与基线期、rtA181单个与多个位点突变时的HBV DNA载量,分析发生病毒学突破时,含rtA181T与含rtA181V位点突变患者的血清学指标.前瞻性队列研究分析不同个体化干预措施的疗效.正态分布的计量资料用t检验进行比较,不符合正态分布的数据用Mann-Whitney检验分析,两组间计数资料的比较采用x2检验或Fisher's精确概率法. 结果 54例rtA181突变的患者中,35例(64.8％)为包含rtA181T的突变.既往用药主要为阿德福韦酯和拉米夫定.应用多种NUCs者,多位点突变占57.6％ (19/33)；单一NUCs者,多位点突变占28.6％ (6/21),x2=4.342,P＜0.05.发生病毒学突破时,患者血清HBV DNA载量较初次NU Cs抗病毒治疗时低[(5.66±1.01)1og10拷贝/ml比(6.75±0.81)log10拷贝/ml,t=-4.210,P＜0.01],含rtA181T位点突变患者较含rtA181V位点突变患者HBsAg水平高[(3.80±0.45) log10 IU/ml比(3.46±0.60)1og10 IU/ml,t=2.109,P＜0.05].对患者分别给予加用或换用恩替卡韦和加用替比夫定治疗,随访满24周时,HBV DNA≥6 log10拷贝/ml的患者中,8例加用或换用恩替卡韦,4例加用替比夫定,其发生病毒学应答者分别为8例和3例,HBV DNA阴转者分别为3例和l例；HBV DNA＜6 log10拷贝/ml中,14例加用或换用恩替卡韦,7例加用替比夫定,其发生病毒学应答者分别为14例和5例,HBV DNA阴转者分别为12例和4例.结论 用药史与rtA181突变模式有一定关系,应用多种NUCs的患者,易出现多位点突变和多重耐药.加或换恩替卡韦干预治疗的疗效好于加用替比夫定方案.
目的 研究rtA181位點突變慢性乙型肝炎(CHB)患者的用藥史、臨床特點及箇體化治療效果. 方法 覈苷(痠)類似物(NUCs)治療中病毒學突破併檢齣rtA181突變的54例CHHB及相關肝硬化患者,檢測其血清HBV DNA、HBsAg定量及ALT水平,焦燐痠基因測序法定量檢測HBV的P基因區10箇NUCs相關耐藥突變位點.迴顧性分析不同用藥史患者的病毒變異模式,比較病毒學突破時與基線期、rtA181單箇與多箇位點突變時的HBV DNA載量,分析髮生病毒學突破時,含rtA181T與含rtA181V位點突變患者的血清學指標.前瞻性隊列研究分析不同箇體化榦預措施的療效.正態分佈的計量資料用t檢驗進行比較,不符閤正態分佈的數據用Mann-Whitney檢驗分析,兩組間計數資料的比較採用x2檢驗或Fisher's精確概率法. 結果 54例rtA181突變的患者中,35例(64.8％)為包含rtA181T的突變.既往用藥主要為阿德福韋酯和拉米伕定.應用多種NUCs者,多位點突變佔57.6％ (19/33)；單一NUCs者,多位點突變佔28.6％ (6/21),x2=4.342,P＜0.05.髮生病毒學突破時,患者血清HBV DNA載量較初次NU Cs抗病毒治療時低[(5.66±1.01)1og10拷貝/ml比(6.75±0.81)log10拷貝/ml,t=-4.210,P＜0.01],含rtA181T位點突變患者較含rtA181V位點突變患者HBsAg水平高[(3.80±0.45) log10 IU/ml比(3.46±0.60)1og10 IU/ml,t=2.109,P＜0.05].對患者分彆給予加用或換用恩替卡韋和加用替比伕定治療,隨訪滿24週時,HBV DNA≥6 log10拷貝/ml的患者中,8例加用或換用恩替卡韋,4例加用替比伕定,其髮生病毒學應答者分彆為8例和3例,HBV DNA陰轉者分彆為3例和l例；HBV DNA＜6 log10拷貝/ml中,14例加用或換用恩替卡韋,7例加用替比伕定,其髮生病毒學應答者分彆為14例和5例,HBV DNA陰轉者分彆為12例和4例.結論 用藥史與rtA181突變模式有一定關繫,應用多種NUCs的患者,易齣現多位點突變和多重耐藥.加或換恩替卡韋榦預治療的療效好于加用替比伕定方案.
목적 연구rtA181위점돌변만성을형간염(CHB)환자적용약사、림상특점급개체화치료효과. 방법 핵감(산)유사물(NUCs)치료중병독학돌파병검출rtA181돌변적54례CHHB급상관간경화환자,검측기혈청HBV DNA、HBsAg정량급ALT수평,초린산기인측서법정량검측HBV적P기인구10개NUCs상관내약돌변위점.회고성분석불동용약사환자적병독변이모식,비교병독학돌파시여기선기、rtA181단개여다개위점돌변시적HBV DNA재량,분석발생병독학돌파시,함rtA181T여함rtA181V위점돌변환자적혈청학지표.전첨성대렬연구분석불동개체화간예조시적료효.정태분포적계량자료용t검험진행비교,불부합정태분포적수거용Mann-Whitney검험분석,량조간계수자료적비교채용x2검험혹Fisher's정학개솔법. 결과 54례rtA181돌변적환자중,35례(64.8％)위포함rtA181T적돌변.기왕용약주요위아덕복위지화랍미부정.응용다충NUCs자,다위점돌변점57.6％ (19/33)；단일NUCs자,다위점돌변점28.6％ (6/21),x2=4.342,P＜0.05.발생병독학돌파시,환자혈청HBV DNA재량교초차NU Cs항병독치료시저[(5.66±1.01)1og10고패/ml비(6.75±0.81)log10고패/ml,t=-4.210,P＜0.01],함rtA181T위점돌변환자교함rtA181V위점돌변환자HBsAg수평고[(3.80±0.45) log10 IU/ml비(3.46±0.60)1og10 IU/ml,t=2.109,P＜0.05].대환자분별급여가용혹환용은체잡위화가용체비부정치료,수방만24주시,HBV DNA≥6 log10고패/ml적환자중,8례가용혹환용은체잡위,4례가용체비부정,기발생병독학응답자분별위8례화3례,HBV DNA음전자분별위3례화l례；HBV DNA＜6 log10고패/ml중,14례가용혹환용은체잡위,7례가용체비부정,기발생병독학응답자분별위14례화5례,HBV DNA음전자분별위12례화4례.결론 용약사여rtA181돌변모식유일정관계,응용다충NUCs적환자,역출현다위점돌변화다중내약.가혹환은체잡위간예치료적료효호우가용체비부정방안.
Objective To investigate chronic hepatitis B (CHB) patients infected with the antiviral-resistant rtAl81 mutation hepatitis B virus (HBV) who have been unresponsive to general therapy to determine the effects of individualized therapy.Methods Fifty-four patients with confirmed rtA181 mutation and who experienced virological breakthrough during nucleos(t)ide analogue (NUC) treatment were enrolled in this prospective cohort study.Their serum levels ofHBV DNA,hepatitis B surface antigen (HBsAg),and alanine transaminase (ALT)were tested.Each patient was genotyped by pyrosequencing for 10 mutation sites in the HBV P gene that have been previously correlated to NUC efficacy.Each patient's antiviral therapy and response history was analyzed in regard to their particular mutation pattern.The serological index was determined for carriers of the rtA181T/V mutation.The secondary individualized treatment included adding/switching to entecavir (ETV; group A) or adding telbivudine (LdT; group B) upon confirmation of drug resistance.Effect of individualized treatment was analyzed by T test and Mann-Whitney U test for continuous variables with normal or skewed distributions,respectively.Categorical variables were analyzed by the Chi-squared (x2) or Fisher's exact tests.Results The rtA181T mutation was found in 64.8％ (35/54) of patients with rtA181 mutation HBV.The most frequent previously administered medications were adefovir dipivoxil (ADV) and lamivudine (LAM).Multi-site rtA181 mutations occurred more frequently in the patients with multi-NUCs history (57.6％) than in those with single NUCs history (28.6％) (x2 =4.342,P ＜ 0.05).Serum HBV DNA level at virological breakthrough was lower than that at baseline of the first antiviral treatment (5.66 ± 1.01 vs.6.75 ± 0.81 log10 copies/ml; t =-4.210,P ＜ 0.01).The serum HBsAg level was hisher in carriers of the rtA181T mutation than in carriers of the rtA181V mutation (3.80 ± 0.45 vs.3.46 ± 0.60log10 IU/ml; t =2.109,P＜ 0.05).In patients with serum HBV DNA ≥ 6 log10 copies/ml at viral breakthrough,100％ (8/8) of patients in the secondary treatment group A and 75％ (3/4) patients in the secondary treatment group B exhibited virological response at week 24 after intervention.Undetectable HBV DNA was achieved in three patients of group A and one patient of group B.In patients with serum HBV DNA ＜ 6 log10 copies/ml at viral breakthrough,100％ (14/14) of patients in group A and 71.4％ (5/7) of patients in group B exhibited viological response at week 24 after intervention.The serum HBV DNA level decreased to undetectable levels in 12 patients of group A and four patients of group B.Conclusion The rtA181 mutation pattern correlates with previous antiviral therapy response.In addition,multi-site rtA181 mutations occur more frequently in patients with a history of multiNUCs therapy.Adding or switching rtA181 carriers to ETV produces a more robuts virological suppression than adding LdT.
