von Wyl Viktor, Yerly Sabine, Böni Jürg, Bürgisser Philippe, Klimkait Thomas, Battegay Manuel, Bernasconi Enos, Cavassini Matthias, Furrer Hansjakob, Hirschel Bernard, Vernazza Pietro L, Rickenbach Martin, Ledergerber Bruno, Günthard Huldrych F
Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, Zurich, Switzerland.
Clin Infect Dis. 2008 Apr 15;46(8):1299-309. doi: 10.1086/528863.
The human immunodeficiency virus type 1 reverse-transcriptase mutation K65R is a single-point mutation that has become more frequent after increased use of tenofovir disoproxil fumarate (TDF). We aimed to identify predictors for the emergence of K65R, using clinical data and genotypic resistance tests from the Swiss HIV Cohort Study.
A total of 222 patients with genotypic resistance tests performed while receiving treatment with TDF-containing regimens were stratified by detectability of K65R (K65R group, 42 patients; undetected K65R group, 180 patients). Patient characteristics at start of that treatment were analyzed.
In an adjusted logistic regression, TDF treatment with nonnucleoside reverse-transcriptase inhibitors and/or didanosine was associated with the emergence of K65R, whereas the presence of any of the thymidine analogue mutations D67N, K70R, T215F, or K219E/Q was protective. The previously undescribed mutational pattern K65R/G190S/Y181C was observed in 6 of 21 patients treated with efavirenz and TDF. Salvage therapy after TDF treatment was started for 36 patients with K65R and for 118 patients from the wild-type group. Proportions of patients attaining human immunodeficiency virus type 1 loads <50 copies/mL after 24 weeks of continuous treatment were similar for the K65R group (44.1%; 95% confidence interval, 27.2%-62.1%) and the wild-type group (51.9%; 95% confidence interval, 42.0%-61.6%).
In settings where thymidine analogue mutations are less likely to be present, such as at start of first-line therapy or after extended treatment interruptions, combinations of TDF with other K65R-inducing components or with efavirenz or nevirapine may carry an enhanced risk of the emergence of K65R. The finding of a distinct mutational pattern selected by treatment with TDF and efavirenz suggests a potential fitness interaction between K65R and nonnucleoside reverse-transcriptase inhibitor-induced mutations.
人类免疫缺陷病毒1型逆转录酶突变K65R是一种单点突变，在增加使用替诺福韦酯（TDF）后变得更加常见。我们旨在利用瑞士HIV队列研究的临床数据和基因型耐药性检测来确定K65R出现的预测因素。
共有222例接受含TDF方案治疗时进行基因型耐药性检测的患者，根据K65R的可检测性进行分层（K65R组，42例患者；未检测到K65R组，180例患者）。分析该治疗开始时的患者特征。
在调整后的逻辑回归中，使用非核苷类逆转录酶抑制剂和/或去羟肌苷进行TDF治疗与K65R的出现相关，而任何胸苷类似物突变D67N、K70R、T215F或K219E/Q的存在具有保护作用。在21例接受依非韦伦和TDF治疗的患者中，有6例观察到了先前未描述的突变模式K65R/G190S/Y181C。对36例K65R患者和118例野生型组患者在开始TDF治疗后进行了挽救治疗。连续治疗24周后，K65R组（44.1%；95%置信区间，27.2%-62.1%）和野生型组（51.9%；95%置信区间，42.0%-61.6%）中人类免疫缺陷病毒1型载量<50拷贝/mL的患者比例相似。
在胸苷类似物突变不太可能出现的情况下，如一线治疗开始时或延长治疗中断后，TDF与其他诱导K65R的成分或与依非韦伦或奈韦拉平联合使用可能会增加K65R出现的风险。TDF和依非韦伦治疗选择出的独特突变模式的发现表明K65R与非核苷类逆转录酶抑制剂诱导的突变之间可能存在适应性相互作用。
