McGill University AIDS Centre, Lady Davis for Medical Research, Jewish General Hospital, Division of Experimental Medicine, Faculty of Medicine, McGill University, Montreal, Quebec, Canada.
Curr Opin Virol. 2012 Oct;2(5):656-62. doi: 10.1016/j.coviro.2012.08.007. Epub 2012 Sep 16.
Although all HIV drugs developed to date are prone to the problem of drug resistance, there is hope that second generation integrase inhibitors may prove to be relatively resilient to this problem and to retain efficacy over long periods. This review summarizes information about the integrase mutations identified to date and about why the most recently developed members of this drug class may be superior to earlier drugs. Several newly identified resistance mutations, such as G118R, R263K and S153Y, have been identified through tissue culture selection studies with second-generation integrase strand-transfer inhibitors (INSTIs). These new mutations add to our understanding of the three previously identified resistance pathways involving mutations at positions Y143, N155 and Q148. Biochemical analyses structural modeling, and deep sequencing are methods that currently help in the understanding of the mechanisms of resistance conferred by these various substitutions. Despite the fact that these new resistance mutations confer only low-level cross-resistance to second-generation drugs, the Q148 pathway with numerous secondary mutations has the potential to significantly decrease susceptibility to all members of the INSTI family of drugs. Selection of mutations in vitro with second-generation INSTIs suggests that only low level cross-resistance may exist between these new drugs and first-generation members of this class. The emergence of mutations at position Q148 should be monitored whenever possible and more data are needed to assess the long-term efficacy of second-generation INSTIs in patients who may have failed older INSTIs such as elvitegravir and raltegravir.
尽管迄今为止开发的所有 HIV 药物都容易出现耐药性问题，但第二代整合酶抑制剂有望在一定程度上解决这个问题，并在长时间内保持疗效。本文综述了迄今为止发现的整合酶突变信息，以及最近开发的此类药物为何可能优于早期药物。通过第二代整合酶链转移抑制剂（INSTI）的组织培养选择研究，发现了几种新的耐药突变，如 G118R、R263K 和 S153Y。这些新突变增加了我们对涉及 Y143、N155 和 Q148 位置突变的三种先前确定的耐药途径的理解。生化分析、结构建模和深度测序是目前有助于理解这些各种取代赋予的耐药机制的方法。尽管这些新的耐药突变仅对第二代药物产生低水平的交叉耐药性，但具有多种次要突变的 Q148 途径有可能显著降低对 INSTI 类药物所有成员的敏感性。第二代 INSTI 体外选择突变表明，这些新药与第一代成员之间可能仅存在低水平的交叉耐药性。只要有可能，就应监测 Q148 位置的突变，并需要更多数据来评估第二代 INSTI 在可能已经对埃替拉韦和拉替拉韦等旧 INSTI 产生耐药的患者中的长期疗效。
