Margot Nicolas A, Isaacson Erica, McGowan Ian, Cheng Andrew K, Schooley Robert T, Miller Michael D
Gilead Sciences, Inc., Foster City, California 94404, USA.
AIDS. 2002 Jun 14;16(9):1227-35. doi: 10.1097/00002030-200206140-00004.
To evaluate the virologic responses and mutational profiles in antiretroviral-experienced patients adding tenofovir DF once-daily to their existing regimens.
Resistance analyses were performed for patients in a phase II placebo-controlled clinical trial of tenofovir DF.
HIV-1 reverse transcriptase and protease genes from plasma samples were analyzed genotypically and phenotypically at baseline, week 24, and week 48.
Of 184 patients, 173 (94%) had baseline HIV-1 expressing one or more nucleoside reverse transcriptase inhibitor-associated resistance mutation. Protease inhibitor and non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance mutations were observed in 57% and 32% of patients, respectively. Compared to placebo, significant reductions in HIV-1 RNA were observed for tenofovir DF-treated patients who had thymidine analog- (TAM), lamivudine- (M184V), NNRTI- or protease inhibitor-associated mutations. Patients with phenotypic susceptibility to tenofovir within 4-fold of wild-type responded durably to tenofovir DF 300 mg therapy with a decline in plasma HIV-1 RNA of > or = 0.5 log10 copies/ml; few patients had a more than 4-fold reduced susceptibility to tenofovir at baseline. Four patients (2%) developed the K65R mutation (selected by tenofovir in vitro) and showed 3- to 4-fold reductions in tenofovir susceptibility but no evidence of rebound viremia. Thirty-four percent of patients developed additional TAMs, coincident with concurrent zidovudine or stavudine therapy, but also showed durable HIV-1 reductions. There was no evidence of novel resistance to tenofovir.
Adding tenofovir DF 300 mg to an existing regimen in patients with ongoing viral replication and a wide range of genotypic resistance patterns resulted in significant and durable HIV-1 RNA reductions. In addition, there was a low incidence of genotypic or phenotypic resistance to tenofovir DF arising during 48 weeks of therapy.
评估在现有抗逆转录病毒治疗方案基础上每日一次添加替诺福韦酯（TDF）的有抗逆转录病毒治疗经验患者的病毒学应答和突变谱。
对TDF一项II期安慰剂对照临床试验中的患者进行耐药性分析。
在基线、第24周和第48周对血浆样本中的HIV-1逆转录酶和蛋白酶基因进行基因分型和表型分析。
184例患者中，173例（94%）基线时HIV-1表达一种或多种核苷类逆转录酶抑制剂相关耐药突变。分别在57%和32%的患者中观察到蛋白酶抑制剂和非核苷类逆转录酶抑制剂（NNRTI）耐药突变。与安慰剂相比，对于有胸苷类似物（TAM）、拉米夫定（M184V）、NNRTI或蛋白酶抑制剂相关突变的TDF治疗患者，HIV-1 RNA显著降低。对替诺福韦表型敏感性在野生型4倍以内的患者对300 mg TDF治疗有持久应答，血浆HIV-1 RNA下降≥0.5 log10拷贝/ml；很少有患者在基线时对替诺福韦的敏感性降低超过4倍。4例患者（2%）出现K65R突变（体外由替诺福韦选择），替诺福韦敏感性降低3至4倍，但无病毒血症反弹证据。34%的患者出现额外的TAM，与齐多夫定或司他夫定同时治疗有关，但HIV-1也出现持久降低。没有证据表明对替诺福韦有新的耐药性。
在持续病毒复制且有广泛基因型耐药模式的患者现有治疗方案中添加300 mg TDF可导致HIV-1 RNA显著且持久降低。此外，在48周治疗期间出现对TDF基因型或表型耐药的发生率较低。
