Clinical emergence of entecavir-resistant hepatitis B virus requires additional substitutions in virus already resistant to lamivudine
Clinical emergence of entecavir-resistant hepatitis B virus requires additional substitutions in virus already resistant to lamivudine
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DOI：
10.1128/aac.48.9.3498-3507.2004
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发表时间：
2004-09-01
影响因子：
4.9
通讯作者：
Colonno, RJ
中科院分区：
文献类型：
--
作者：
Tenney, DJ;Levine, SM;Colonno, RJ
恩替卡韦（ETV）对慢性感染野生型或拉米夫定（3TC）耐药（3TC(r)）乙型肝炎病毒（HBV）的患者显示出有效的抗病毒活性。在接受ETV II期临床试验的患者中，有2例先前治疗失败的患者在接受ETV治疗时出现了病毒学突破。从这些患者（任意指定的患者A和B）分离的菌株进行基因分析，以发现HBV逆转录酶（RT）的紧急替代，并在培养和HBV聚合酶测定中分析表型，以降低易感性。3TC治疗54周后，患者A （AI463901-A）接受0.5 mg ETV治疗52周，随后ETV和100 mg 3TC联合治疗89周。在ETV开始后133周出现病毒反弹。3TC(r) RT替代rtV173L、rtL180M和rtM204V在研究开始时存在，ETV-3TC联合治疗期间出现了额外的替代rtI169T和rtM250V。在体外降低ETV敏感性除了3TC(r)取代外，还需要rtM250V取代。对于肝移植患者B (AI463015-B)，先前的famciclovir、更昔洛韦、foscarnet和3TC治疗均失败，并且在研究开始时存在rtS78S/T、rtV173L、rtL180M、rtT184S和rtM204V的RT变化。1.0 mg ETV治疗76周后出现病毒反弹，在先前存在的3TCr背景下出现rtT184G， rtI169T和rtS202I替代。当rtT184G和rtS202I变化与3TCr替换联合使用时，体外敏感性降低幅度最大。总之，在延长治疗期间，在3TCr HBV背景下选择额外的RT替代，可能出现罕见的ETV耐药，导致ETV易感性降低和治疗失败。
Entecavir (ETV) exhibits potent antiviral activity in patients chronically infected with wild-type or lamivudine (3TC)-resistant (3TC(r)) hepatitis B virus (HBV). Among the patients treated in phase II ETV clinical trials, two patients for whom previous therapies had failed exhibited virologic breakthrough while on ETV. Isolates from these patients (arbitrarily designated patients A and B) were analyzed genotypically for emergent substitutions in HBV reverse transcriptase (RT) and phenotypically for reduced susceptibility in cultures and in HBV polymerase assays. After 54 weeks of 3TC therapy, patient A (AI463901-A) received 0.5 mg of ETV for 52 weeks followed by a combination of ETV and 100 mg of 3TC for 89 weeks. Viral rebound occurred at 133 weeks after ETV was started. The 3TC(r) RT substitutions rtV173L, rtL180M, and rtM204V were present at study entry, and the additional substitutions rtI169T and rtM250V emerged during ETV-3TC combination treatment. Reduced ETV susceptibility in vitro required the rtM250V substitution in addition to the 3TC(r) substitutions. For liver transplant patient B (AI463015-B), previous famciclovir, ganciclovir, foscarnet, and 3TC therapies had failed, and RT changes rtS78S/T, rtV173L, rtL180M, rtT184S, and rtM204V were present at study entry. Viral rebound occurred after 76 weeks of therapy with ETV at 1.0 mg, with the emergence of rtT184G, rtI169T, and rtS202I substitutions within the preexisting 3TCr background. Reduced susceptibility in vitro was highest when both the rtT184G and the rtS202I changes were combined with the 3TCr substitutions. In summary, infrequent ETV resistance can emerge during prolonged therapy, with selection of additional RT substitutions within a 3TCr HBV background, leading to reduced ETV susceptibility and treatment failure.