Harrigan P R, Miller M D, McKenna P, Brumme Z L, Larder B A
BC Centre for Excellence in HIV/AIDS, St. Paul's Hospital, Vancouver, British Columbia, Canada.
Antimicrob Agents Chemother. 2002 Apr;46(4):1067-72. doi: 10.1128/AAC.46.4.1067-1072.2002.
Tenofovir is a nucleotide analogue human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) inhibitor, and its oral prodrug, tenofovir disoproxil fumarate, has recently been approved for the treatment of HIV-1 infection in the United States. The objective of this study was to characterize the in vitro susceptibility profiles of a large panel of clinically derived HIV-1 isolates for tenofovir. The distribution of tenofovir susceptibilities in over 1,000 antiretroviral-naive, HIV-1-infected individuals worldwide was determined using the Virco Antivirogram assay. In addition, phenotypic susceptibilities to tenofovir and other RT inhibitors were determined in a panel of nearly 5,000 recombinant HIV-1 clinical isolates from predominantly treatment-experienced patients analyzed as a part of routine drug resistance testing. Greater than 97.5% of isolates from treatment-naive patients had tenofovir susceptibilities <3-fold above those of the wild-type controls by the Antivirogram. The clinically derived panel of 5,000 samples exhibited a broad range of antiretroviral drug susceptibilities, including 69, 43, and 16% having >10-fold-decreased susceptibilities to at least one, two, and three antiretroviral drug classes, respectively. Greater than 88% of these 5,000 clinical isolates were within the threefold susceptibility range for tenofovir, and >99% exhibited <10-fold-reduced susceptibilities to tenofovir. Decreased susceptibility to tenofovir was not directly associated with resistance to other RT inhibitors; r(2) values of log-log linear regression plots of susceptibility to tenofovir versus susceptibility to other RT inhibitors were <0.4. The results suggest that the majority of treatment-naive and treatment-experienced individuals harbor HIV that remains within the normal range of tenofovir susceptibilities and may be susceptible to tenofovir disoproxil fumarate therapy.
替诺福韦是一种核苷酸类似物，为人类免疫缺陷病毒1型（HIV-1）逆转录酶（RT）抑制剂，其口服前体药物富马酸替诺福韦二吡呋酯最近在美国已被批准用于治疗HIV-1感染。本研究的目的是描述一大组临床分离的HIV-1毒株对替诺福韦的体外敏感性谱。使用Virco抗病毒谱检测法确定了全球1000多名未接受过抗逆转录病毒治疗的HIV-1感染者中替诺福韦敏感性的分布情况。此外，作为常规耐药性检测的一部分，对一组近5000株主要来自有治疗经验患者的重组HIV-1临床分离株进行了替诺福韦及其他RT抑制剂的表型敏感性测定。抗病毒谱检测显示，超过97.5%的未接受过治疗患者的分离株对替诺福韦的敏感性比野生型对照高不到3倍。这组5000份临床样本表现出广泛的抗逆转录病毒药物敏感性，其中分别有69%、43%和16%的样本对至少一类、两类和三类抗逆转录病毒药物的敏感性降低了10倍以上。这5000株临床分离株中，超过88%对替诺福韦的敏感性在3倍范围内，超过99%对替诺福韦的敏感性降低不到10倍。对替诺福韦敏感性降低与对其他RT抑制剂耐药无直接关联；替诺福韦敏感性与其他RT抑制剂敏感性的对数-对数线性回归图的r(2)值<0.4。结果表明，大多数未接受过治疗和有治疗经验的个体所携带的HIV对替诺福韦的敏感性仍在正常范围内，可能对富马酸替诺福韦二吡呋酯治疗敏感。
