Characterization of HIV-1 Resistance to Tenofovir Alafenamide In Vitro
Characterization of HIV-1 Resistance to Tenofovir Alafenamide In Vitro
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DOI：
10.1128/aac.01151-15
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发表时间：
2015-10-01
影响因子：
4.9
通讯作者：
Callebaut, Christian
中科院分区：
文献类型：
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作者：
Margot, Nicolas A.;Johnson, Audun;Callebaut, Christian
替诺福韦丙氨酰胺(TAF)是HIV-1核苷酸逆转录酶(RT)抑制剂替诺福韦(TFV)的研究前药，与目前的前药富马酸替诺福韦(TDF)相比，具有更好的效力和药物释放特性。TAF目前正处于与其他抗逆转录病毒药物联合治疗HIV-1感染的第三阶段临床研究。1期和2期研究表明，与TDF治疗相比，TAF与外周血单核细胞(PBMC)药物负荷增加和HIV-1复制抑制增加有关。在这项研究中，对TAF和亲本化合物TFV的体外抗性选择导致了RT中K65R氨基酸替代的HIV-1的出现，其对TAF的敏感性降低了6.5倍。尽管TAF在体外比TFV更有效，但一大组核苷/核苷酸逆转录酶抑制剂(NRTI)抗性突变体对TAF和TFV的敏感性高度相关(R-2=0.97)，表明这两种化合物在评估为野生型的倍增变化时具有几乎相同的抗药性。Taf对具有蛋白酶抑制剂、非核苷类逆转录酶抑制剂(NNRTI)或整合酶链转移抑制剂抗性的HIV-1原代分离株显示出完全的抗病毒活性，但对具有广泛NRTI抗性氨基酸替换的分离株显示出较低的抗病毒活性。然而，体内观察到，携带TAF的TFV与TDF相比，细胞载量增加，这表明TAF可能保持了对TDF耐药突变病毒的活性。
Tenofovir alafenamide (TAF) is an investigational prodrug of the HIV-1 nucleotide reverse transcriptase (RT) inhibitor (NtRTI) tenofovir (TFV), with improved potency and drug delivery properties over the current prodrug, tenofovir disoproxil fumarate (TDF). TAF is currently in phase 3 clinical studies for the treatment of HIV-1 infection, in combination with other antiretroviral agents. Phase 1 and 2 studies have shown that TAF was associated with increased peripheral blood mononuclear cell (PBMC) drug loading and increased suppression of HIV-1 replication compared to treatment with TDF. In this study, selection of in vitro resistance to both TAF and the parent compound, TFV, led to the emergence of HIV-1 with the K65R amino acid substitution in RT with 6.5-fold-reduced susceptibility to TAF. Although TAF is more potent than TFV in vitro, the antiviral susceptibilities to TAF and TFV of a large panel of nucleoside/nucleotide RT inhibitor (NRTI)-resistant mutants were highly correlated (R-2 = 0.97), indicating that the two compounds have virtually the same resistance profile when assessed as fold change from the wild type. TAF showed full antiviral activity in PBMCs against primary HIV-1 isolates with protease inhibitor, nonnucleoside RT inhibitor (NNRTI), or integrase strand transfer inhibitor resistance but reduced activity against isolates with extensive NRTI resistance amino acid substitutions. However, the increased cell loading of TFV with TAF versus TDF observed in vivo suggests that TAF may retain activity against TDF-resistant mutant viruses.