Institute of Infection & Global Health, University of Liverpool, Liverpool, United Kingdom.
PLoS One. 2013 Jul 18;8(7):e69266. doi: 10.1371/journal.pone.0069266. Print 2013.
Non-nucleoside reverse transcriptase inhibitor (NNRTI)-resistant mutants have been shown to emerge after interruption of suppressive NNRTI-based antiretroviral therapy (ART) using routine testing. The aim of this study was to quantify the risk of resistance by sensitive testing and correlate the detection of resistance with NNRTI concentrations after treatment interruption and virologic responses after treatment resumption.
Resistance-associated mutations (RAMs) and NNRTI concentrations were studied in plasma from 132 patients who interrupted suppressive ART within SMART. RAMs were detected by Sanger sequencing, allele-specific PCR, and ultra-deep sequencing. NNRTI concentrations were measured by sensitive high-performance liquid chromatography.
Four weeks after NNRTI interruption, 19/31 (61.3%) and 34/39 (87.2%) patients showed measurable nevirapine (>0.25 ng/ml) or efavirenz (>5 ng/ml) concentrations, respectively. Median eight weeks after interruption, 22/131 (16.8%) patients showed ≥1 NNRTI-RAM, including eight patients with NNRTI-RAMs detected only by sensitive testing. The adjusted odds ratio (OR) of NNRTI-RAM detection was 7.62 (95% confidence interval [CI] 1.52, 38.30; p = 0.01) with nevirapine or efavirenz concentrations above vs. below the median measured in the study population. Staggered interruption, whereby nucleos(t)ide reverse transcriptase inhibitors (NRTIs) were continued for median nine days after NNRTI interruption, did not prevent NNRTI-RAMs, but increased detection of NRTI-RAMs (OR 4.25; 95% CI 1.02, 17.77; p = 0.03). After restarting NNRTI-based ART (n = 90), virologic suppression rates <400 copies/ml were 8/13 (61.5%) with NNRTI-RAMs, 7/11 (63.6%) with NRTI-RAMs only, and 51/59 (86.4%) without RAMs. The ORs of re-suppression were 0.18 (95% CI 0.03, 0.89) and 0.17 (95% CI 0.03, 1.15) for patients with NNRTI-RAMs or NRTI-RAMs only respectively vs. those without RAMs (p = 0.04).
Detection of resistant mutants in the rebound viremia after interruption of efavirenz- or nevirapine-based ART affects outcomes once these drugs are restarted. Further studies are needed to determine RAM persistence in untreated patients and impact on newer NNRTIs.
已显示,在使用常规检测中断抑制性 NNRTI 为基础的抗逆转录病毒治疗(ART)后,非核苷逆转录酶抑制剂(NNRTI)耐药突变体已经出现。本研究的目的是通过敏感检测量化耐药风险,并将耐药检测与治疗中断后的 NNRTI 浓度以及治疗重新开始后的病毒学应答相关联。
在 SMART 中中断抑制性 ART 的 132 名患者的血浆中,研究了耐药相关突变(RAM)和 NNRTI 浓度。通过 Sanger 测序、等位基因特异性 PCR 和超高深度测序检测 RAM。通过灵敏高效液相色谱法测量 NNRTI 浓度。
NNRTI 中断后 4 周,19/31(61.3%)和 34/39(87.2%)患者分别显示可测量的奈韦拉平(>0.25ng/ml)或依非韦伦(>5ng/ml)浓度。中断后 8 周中位数时,22/131(16.8%)患者显示存在至少 1 种 NNRTI-RAM,其中 8 例患者仅通过敏感检测检测到 NNRTI-RAMs。NNRTI-RAM 检测的调整后比值比(OR)为 7.62(95%置信区间 [CI] 1.52,38.30;p=0.01),NNRTI 浓度高于或低于研究人群中测量的中位数。错开中断,即在 NNRTI 中断后继续使用核苷(酸)逆转录酶抑制剂(NRTIs)中位数 9 天,并没有阻止 NNRTI-RAMs,但增加了 NRTI-RAMs 的检测(OR 4.25;95%CI 1.02,17.77;p=0.03)。重新开始 NNRTI 为基础的 ART(n=90)后,NNRTI-RAMs 的病毒学抑制率<400 拷贝/ml 为 8/13(61.5%),仅 NRTI-RAMs 为 7/11(63.6%),无 RAMs 为 51/59(86.4%)。NNRTI-RAMs 或仅 NRTI-RAMs 患者的再次抑制 OR 分别为 0.18(95%CI 0.03,0.89)和 0.17(95%CI 0.03,1.15),与无 RAMs 患者相比(p=0.04)。
在依非韦伦或奈韦拉平为基础的 ART 中断后的反弹病毒血症中检测到耐药突变体,会影响这些药物重新开始使用后的结果。需要进一步研究确定未经治疗患者中 RAM 的持续存在及其对新型 NNRTIs 的影响。