Institute of Human Virology, University of Maryland School of Medicine, Medicine, Baltimore, MD, USA.
McGill University AIDS Centre, Lady Davis Institute, Montréal, Quebec, Canada.
J Antimicrob Chemother. 2017 Sep 1;72(9):2570-2573. doi: 10.1093/jac/dkx195.
To compare the effectiveness of HIV integrase inhibitor monotherapy between raltegravir and dolutegravir as an approach to simplify therapy.
We evaluated and compared the efficacy of 20 week monotherapy with dolutegravir or raltegravir in humanized mice (HSC-NSG) infected with HIVBaL. Plasma HIV RNA was measured by quantitative RT-PCR (limit of detection of 150 copies/45 μL of plasma) and drug levels by LC-MS/MS. Escape viruses were genotyped and analysed for replication capacity and drug susceptibility in tissue culture.
Drug-untreated control mice maintained constant viraemia throughout the study. Virus isolates from these mice were susceptible to both raltegravir (EC50 of <8 nM) and dolutegravir (EC50 of <1 nM). Mice treated with raltegravir or dolutegravir had plasma drug levels comparable to those in humans. Monotherapy with raltegravir initially suppressed HIV viraemia, but failed to maintain suppression in 4/4 mice. Viruses from raltegravir failing mice developed mutations G140G/S and Q148H/K, and were resistant to both raltegravir (EC50 values of >100 nM) and dolutegravir (EC50 values ranging from 8.8 to 13.3 nM). Monotherapy with dolutegravir suppressed viraemia in 5/5 of mice, but viraemia rebounded in one animal. The virus from this mouse had mutations E138K, G140S, Q148H, N155H and S230R, was highly resistant to both raltegravir (EC50 of >1000 nM) and dolutegravir (EC50 of 550 nM), and replicated to levels similar to those of control viruses in PBMCs.
Monotherapy with either raltegravir or dolutegravir does not consistently maintain HIV suppression, suggesting that dual therapy may be required in simplification strategies.
比较 HIV 整合酶抑制剂拉替拉韦与多替拉韦单药治疗作为简化治疗方案的效果。
我们评估并比较了人源化小鼠（HSC-NSG）感染 HIVBaL 后，20 周多拉替拉韦或拉替拉韦单药治疗的疗效。采用定量 RT-PCR（检测限为 45μL 血浆中 150 拷贝）和 LC-MS/MS 检测血浆 HIV RNA 和药物水平。对逃逸病毒进行基因分型，并在组织培养中分析其复制能力和药物敏感性。
未用药对照小鼠在整个研究过程中保持恒定的病毒血症。这些小鼠的病毒分离株对拉替拉韦（EC50 ＜8 nM）和多替拉韦（EC50 ＜1 nM）均敏感。接受拉替拉韦或多替拉韦治疗的小鼠的血浆药物水平与人类相当。拉替拉韦或多替拉韦单药治疗初期均能抑制 HIV 病毒血症，但 4/4 只小鼠未能维持抑制。拉替拉韦耐药小鼠的病毒发生 G140G/S 和 Q148H/K 突变，对拉替拉韦（EC50 值＞100 nM）和多替拉韦（EC50 值 8.8-13.3 nM）均耐药。多替拉韦单药治疗抑制了 5/5 只小鼠的病毒血症，但有 1 只动物的病毒血症反弹。该小鼠的病毒发生 E138K、G140S、Q148H、N155H 和 S230R 突变，对拉替拉韦（EC50 值＞1000 nM）和多替拉韦（EC50 值 550 nM）均高度耐药，在 PBMC 中的复制水平与对照病毒相似。
拉替拉韦或多替拉韦单药治疗均不能持续抑制 HIV，提示简化治疗方案中可能需要双药治疗。
