Risk of selecting de novo drug-resistance mutations during structured treatment interruptions in patients with chronic HIV infection
Risk of selecting de novo drug-resistance mutations during structured treatment interruptions in patients with chronic HIV infection
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DOI：
10.1086/432881
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发表时间：
2005-09-15
影响因子：
11.8
通讯作者：
Gatell, JM
中科院分区：
文献类型：
--
作者：
Arnedo-Valero, M;García, F;Gatell, JM
背景。在血浆药物水平降低的情况下，有组织的治疗中断（STI）可能允许病毒复制，有选择耐药性突变的风险。对于招募参加性传播感染研究的患者，在基线（接受任何治疗之前）、性传播感染之前和每次中断治疗后2周进行基因型耐药检测。在112个STI循环中的20个（18%）周期（95% CI, 11% - 26%）中，抗性突变被选中；6%的突变是新生突变（即在性传播感染开始之前未检测到），12%是存档突变（即在性传播感染之前已检测到的突变）。总体而言，35例患者中有9例（26%）在STI期间出现耐药性突变；5例（14%）为新生突变，4例（12%）为存档突变。在13名接受nnrti治疗方案的患者中，有3名（23%）患者出现了对非核苷类逆转录酶抑制剂（nnrti）产生耐药性的突变（所有突变均为新生突变）。接受拉米夫定方案治疗的18例患者中有9例（50%）出现了拉米夫定耐药突变（4例[22%]为新生突变，5例[28%]为存档突变）。35例NRTIs受体中有2例（6%）（1例[3%]为新生突变，1例[3%]为存档突变）选择了对核苷逆转录酶抑制剂（NRTIs）产生耐药性的突变（不包括M184V突变）。最后，在22例接受蛋白酶抑制剂治疗的患者中，没有一例选择具有蛋白酶抑制剂耐药性的突变。在大多数情况下，在第一个STI周期中选择了新生突变和存档突变，并且它们的数量在连续的周期中不会增加。当重新引入早期药物治疗方案时，所有患者的血浆病毒载量均降至检测不到的水平。在很大比例的患者（特别是接受nnrti或拉米夫定治疗的患者）中，在性传播感染期间选择了基因型突变。大约一半的选定突变是存档突变。与在性传播感染前感染野生型病毒的患者相比，具有存档突变的患者积累新突变的风险并不高。
Background. Structured treatment interruption (STI) may allow viral replication in the presence of decreased plasma drug levels, with risk of selection of resistance mutations.Methods. For patients recruited for an STI study, genotypic resistance testing was performed at baseline (before receipt of any treatment), immediately before the STI, and 2 weeks after each interuption of therapy.Results. During 20 (18%) of 112 STI cycles (95% CI, 11% - 26%), resistance mutations were selected; 6% of the mutations were de novo (i.e., not detected before the start of STI), and 12% were archived mutations (i.e., mutations already detected before the STI). Overall, resistance mutations during STI were selected in 9 ( 26%) of 35 patients; 5 (14%) of the mutations were de novo, and 4 (12%) were archived mutations. Mutations conferring resistance to nonnucleoside reverse-transcriptase inhibitors (NNRTIs) were selected in 3 (23%) of 13 patients receiving NNRTI-based regimens (all mutations were de novo). Mutations conferring resistance to lamivudine were selected in 9 (50%) of 18 patients receiving lamivudine-containing regimens (4 [22%] were de novo, and 5 [28%] were archived mutations). Mutations conferring resistance to nucleoside reverse-transcriptase inhibitors (NRTIs), excluding the M184V mutation, were selected in 2 (6%) of 35 recipients of NRTIs (1 [3%] of these mutations was de novo, and 1 [3%] was an archived mutation. Finally, mutations conferring resistance to protease inhibitors were selected in none of the 22 patients receiving protease inhibitors. In most cases, de novo and archived mutations were selected during the first STI cycle, and their number did not increase during successive cycles. Plasma viral load decreased to undetectable levels in all the patients when the earlier drug regimen was reintroduced.Conclusions. Genotypic mutations are selected during STI in a high proportion of patients (especially in patients receiving NNRTIs or lamivudine). Approximately one-half of selected mutations were archived mutations. Patients who had archived mutations did not have a higher risk of accumulating new mutations than did patients who were infected with wild-type virus before the STI.