Clinical benefit of dolutegravir in HIV-1 management related to the high genetic barrier to drug resistance
Clinical benefit of dolutegravir in HIV-1 management related to the high genetic barrier to drug resistance
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DOI：
10.1016/j.virusres.2016.07.006
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发表时间：
2017-07-15
期刊：
影响因子：
5
通讯作者：
Wainberg, Mark A.
中科院分区：
文献类型：
--
作者：
Brenner, Bluma G.;Wainberg, Mark A.
这篇文章回顾了为什么整合酶抑制剂现在应该常规地构成一线抗逆转录病毒治疗HIV疾病的一部分的原因。与大多数其他类别的抗病毒化合物相比，使用这些通常耐受良好的药物产生的耐药性要小得多。此外，整合酶抑制剂家族的药物不太容易出现传播性耐药性的问题，这是由于HIV基因组中有各种各样的替代，可以通过性行为从一个人传播到另一个人。然而，不幸的是，整合酶抑制剂在一线治疗中的使用可能不会很快在发展中国家实现，非核苷类逆转录酶抑制剂仍然是初始治疗的主要手段，主要是由于成本原因。只要这种情况继续下去，耐药性和传播性耐药性问题将在这些环境中普遍存在。目前的证据还表明，使用多替格拉韦作为一线整合酶抑制剂可能会限制耐药性的发展，其程度超过使用该药物家族的其他成员。这可能是由于涉及多替格拉韦的特殊耐药模式，因此与对该化合物的耐药相关的突变实际上可能以深远和独特的方式降低HIV复制能力以及整合酶酶活性。这给人们带来了潜在的希望，即在一线治疗中使用多替格拉韦实际上可能成为实现HIV疾病功能性治愈这一长期追求的目标的一部分。(C) 2016 Elsevier B.V.版权所有
This manuscript reviews the reasons why Integrase inhibitors should now routinely constitute a part of first line antiretroviral therapy for the treatment of HIV disease. The use of these drugs that are generally well tolerated has resulted in far less drug resistance than was the case with most other categories of antiviral compounds. In addition, the integrase inhibitor family of drugs has been less prone to the problem of transmitted drug resistance which is due to a wide variety of substitutions in the HIV genome that can be sexually transmitted from one person to another. However, the use of integrase inhibitors in first line therapy may unfortunately not soon happen in developing country settings where non nucleoside reverse transcriptase inhibitors continue to be a mainstay of initial therapy, primarily for reasons of cost. As long as this situation continues, problems of drug resistance and transmitted drug resistance will be common in such settings. Current evidence also suggests that the use of dolutegravir as a first line integrase inhibitor may limit development of drug resistance to an extent that exceeds the use of other members of this family of drugs. This may be due to particular patterns of resistance involving dolutegravir, whereby the mutations that are associated with resistance against this compound may actually diminish both HIV replication capacity as well as integrase enzymatic activity in a far-reaching and unique manner. This gives potential hope that the use of dolutegravir in first line therapy could actually form part of the long-sought goal of attainment of a functional cure for HIV disease. (C) 2016 Elsevier B.V. All rights reserved.