Llibre J M, Santos J R, Puig T, Moltó J, Ruiz L, Paredes R, Clotet B
Lluita contra la SIDA Foundation, Germans Trias i Pujol University Hospital, Ctra de Canyet s/n, 08916 Badalona, Barcelona, Spain.
J Antimicrob Chemother. 2008 Nov;62(5):909-13. doi: 10.1093/jac/dkn297. Epub 2008 Jul 23.
To evaluate the expected activity of etravirine in clinical samples, according to mutational patterns associated with decreased virological response (VR).
We identified 1586 routine clinical samples with resistance-associated mutations (RAMs) to nevirapine and efavirenz (K103N 60%, Y181C 37%, G190A 27%, V108I 13%). Concerning in vitro identified etravirine mutations, samples with F227C, Y181I, M230L or L100I plus K103N plus Y181C were considered highly resistant. Samples with two RAMs plus Y181C or V179D or K101E or Y188L were considered intermediate. The prevalence of 13 RAMs recently associated with decreased VR to etravirine in the DUET clinical trials was also investigated.
Most samples (69%) harboured more than one IAS-USA RAM to first-generation non-nucleoside reverse transcriptase inhibitors (NNRTIs): 42% harboured two RAMs, 21% three RAMs and 6% four or more RAMs. The prevalence of 13 specific etravirine RAMs was V179F 0.12%, G190S 3.9%, Y181V 0.1%, V106I 2.6%, V179D 1.6%, K101P 2.0%, K101E 10.1%, Y181C 36.9%, A98G 5.9%, V90I 6.9%, Y181I 3.6%, G190A 27% and L100I 9.1%. The five RAMs with the most impact on VR (V179F/D, G190S, Y181V and V106I) occurred less often. Overall, 8.2% of the samples had three or more etravirine RAMs and only 1.1% had four or more. In addition, patterns of RAMs previously associated with intermediate etravirine resistance were present in 26.2% of the samples, whereas 4.85% displayed patterns of high-degree resistance.
For RAMs associated with decreased VR, etravirine resistance in routine clinical samples was lower than previously reported. High-degree resistance was uncommon, even in patients with resistance to first-generation NNRTIs, whereas low-to-intermediate etravirine resistance was more common.
根据与病毒学应答（VR）降低相关的突变模式，评估依曲韦林在临床样本中的预期活性。
我们鉴定了1586份对奈韦拉平和依非韦伦具有耐药相关突变（RAMs）的常规临床样本（K103N占60%，Y181C占37%，G190A占27%，V108I占13%）。关于体外鉴定的依曲韦林突变，具有F227C、Y181I、M230L或L100I加K103N加Y181C的样本被视为高度耐药。具有两个RAMs加Y181C或V179D或K101E或Y188L的样本被视为中度耐药。我们还调查了在DUET临床试验中最近与依曲韦林VR降低相关的13种RAMs的流行情况。
大多数样本（69%）携带一种以上针对第一代非核苷类逆转录酶抑制剂（NNRTIs）的IAS-USA RAMs：42%携带两种RAMs，21%携带三种RAMs，6%携带四种或更多RAMs。13种特定依曲韦林RAMs的流行情况为：V179F为0.12%，G190S为3.9%，Y181V为0.1%，V106I为2.6%，V179D为1.6%，K101P为2.0%，K101E为10.1%，Y181C为36.9%，A98G为5.9%，V90I为6.9%，Y181I为3.6%，G190A为27%，L100I为9.1%。对VR影响最大的五种RAMs（V179F/D、G190S、Y181V和V106I）出现的频率较低。总体而言，8.2%的样本具有三种或更多依曲韦林RAMs，只有1.1%的样本具有四种或更多。此外，26.2%的样本中存在先前与依曲韦林中度耐药相关的RAMs模式，而4.85%的样本显示出高度耐药模式。
对于与VR降低相关的RAMs，常规临床样本中的依曲韦林耐药性低于先前报道。高度耐药并不常见，即使在对第一代NNRTIs耐药的患者中也是如此，而低至中度依曲韦林耐药更为常见。
