Long-acting injectable antiretrovirals for HIV treatment and prevention.
Long-acting injectable antiretrovirals for HIV treatment and prevention.
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DOI：
10.1097/coh.0000000000000002
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发表时间：
2013-11
影响因子：
4.1
通讯作者：
Pottage JC Jr
中科院分区：
文献类型：
--
作者：
Spreen WR;Margolis DA;Pottage JC Jr
长效抗逆转录病毒药物可提高治疗依从性，并为得不到充分服务的患者群体提供更多的治疗或预防干预机会。本文就小分子长效注射用抗逆转录病毒药物的研究进展作一综述。对联合抗逆转录病毒药物的需要和目前抗逆转录病毒药物的物理化学和剂量限制阻碍了将其重新开发为长效注射制剂的尝试。然而，利匹韦林（一种非核苷类逆转录酶抑制剂）和GSK 1265744（一种HIV-1整合酶链转移抑制剂）的固有特性使结晶纳米颗粒制剂能够进入临床试验。利匹韦林和GSK 1265744的研究性长效可注射纳米制剂是临床阶段开发的候选药物。两种药物的互补药理学特性-不同的作用机制、耐药性特征、代谢途径、缺乏药物相互作用和低每日口服剂量-提供了联合使用的可能性。每种长效制剂单独和联合使用的药代动力学和安全性的I期研究表明，每月给药方案可能用于HIV治疗。一项正在进行的口服GSK1265744和口服利匹韦林的IIb期试验正在评估这种双药方案维持病毒学抑制的效果;结果将为未来使用注射制剂的研究提供信息。其他临床前和临床研究表明，每种药物都可能用于HIV暴露前预防。
Long-acting antiretroviral (ARV) drugs may improve adherence to therapy and extend opportunities for therapeutic or prophylactic intervention to underserved patient populations. This review focuses on recent advances in the development of small molecule long-acting injectable ARV agents. The need for combination ART and physicochemical and dosing limitations of current ARV drugs impede attempts to redevelop them as long-acting injectable formulations. However, the intrinsic properties of rilpivirine, a nonnucleoside reverse transcriptase inhibitor, and GSK1265744, an HIV-1 integrase strand transfer inhibitor, have enabled crystalline nanoparticle formulations to progress to clinical trials. Investigational long-acting injectable nanoformulations of rilpivirine and GSK1265744 are clinical-stage development candidates. Complementary pharmacologic properties of both agents – different mechanisms of action, resistance profiles, metabolic pathways, lack of drug interactions and low daily oral doses – offer the potential for combination use. Phase I studies of the pharmacokinetics and safety of each long-acting formulation alone and in combination indicate that a monthly dosing regimen is possible for HIV treatment. An ongoing phase IIb trial of oral GSK1265744 and oral rilpivirine is evaluating this two-drug regimen for maintenance of virologic suppression; results will inform future studies using the injectable formulations. Additional preclinical and clinical studies indicate a potential use of each agent for HIV pre-exposure prophylaxis.