1、 最小的最小的DNA病毒之一病毒之一-约约3.2kb 变异率较高的变异率较高的DNA病毒病毒-准种准种 高效利用自身复制模板高效利用自身复制模板 特殊稳定形式特殊稳定形式-cccDNAHBsAg 被被膜膜部分双链部分双链 DNAA(n)感染性感染性HBV病毒颗粒病毒颗粒(-)-DNA感染性感染性HBV病毒颗粒病毒颗粒mRNAcccDNADNA 多聚酶多聚酶逆逆转转录录酶酶被包裹的前基被包裹的前基因组因组 mRNALai et al.,J Med Virol 2000LVDLVDETCETCLdTLdTClevudineClevudineADVADVTDFTDFETVETVL-L-核核 苷苷无环
2、磷酸盐化合物无环磷酸盐化合物环戊烷环戊烷/烯烯耐药的分子基础抗HBV核苷类药物的分类目前已知不同核苷类药物的耐药位点845 a.a.845 a.a.终末蛋白终末蛋白间隔区间隔区POL/RTPOL/RTRNaseHRNaseHA AB BC CE ED D 1 1183183349 349(rt1)(rt1)692(rt 692(rt 344)344)YMDDYMDDF_V_LLAQ_F_V_LLAQ_I(G)I(G)II(FII(F)拉米夫定耐药拉米夫定耐药 L80V/IL80V/I L180M M204V L180M M204V/I/I A181VA181V替比夫定耐药替比夫定耐药 L180
3、ML180M M204I M204I阿德福韦耐药阿德福韦耐药V84MV84M A181T/V A181T/V V214A V214A N236T N236T S85AS85A Q215SQ215S恩替卡韦耐药恩替卡韦耐药 S184GS184G S202I S202I M250V M250VLDVrLDVr（204V+L180M)+204V+L180M)+I169TI169T阿德福韦、拉米夫定L180M+M204V+N236T多药耐药阿德福韦、拉米夫定rtA181T/V共享耐药无环磷酸盐化合物(阿德福韦,替诺福韦)rtN236T 236L-核苷(拉米夫定、替比夫定)环戊烷/烯（恩替卡韦）rtM2
4、04V/I204引起耐药突变位点途径 LAM-R ETV-R in LAM-refractory ptsIncidence of Resistance(%)71%020406080Year 1 Year 2Year 3Year 4LAM29%ETVYear 532%ETV-R in HBeAg+/-naive patientsLdt21.6%ADV-R in HBeAg-Ldt-R in HBeAg+Ldt-R in HBeAg-1.1%ADV8.6%有效控制耐药有效控制耐药:如何将耐药风险降到最低点如何将耐药风险降到最低点?L-核苷类药物(LDV/LdT)耐药早期加药救助治疗策略 保护保护2
5、04204途径对中国的乙肝治疗更重要途径对中国的乙肝治疗更重要Future directionsFor the clinician:When should resistance testing be ordered?Should treatment be changed based based on clinical data (virologic breakthrough)or must it be confirmed?Algorithm based approach relying on genotypic and phenotypic data,clinical databases and expert advice For clinical trials:Incorporation of genotypic testing in design of clinical trials and prior to initiation of therapy in treatment nave patients Combination therapy versus sequential monotherapy Combination antiviral and immunotherapy regimens谢谢 谢谢
