Short-term administration of disulfiram for reversal of latent HIV infection: a phase 2 dose-escalation study.
Short-term administration of disulfiram for reversal of latent HIV infection: a phase 2 dose-escalation study.
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二硫兰氏菌的短期施用用于潜在艾滋病毒感染的逆转：2期剂量降低研究。
DOI：
10.1016/s2352-3018(15)00226-x
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发表时间：
2015-12
期刊：
影响因子：
--
通讯作者：
Lewin SR
中科院分区：
文献类型：
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作者：
Elliott JH;McMahon JH;Chang CC;Lee SA;Hartogensis W;Bumpus N;Savic R;Roney J;Hoh R;Solomon A;Piatak M;Gorelick RJ;Lifson J;Bacchetti P;Deeks SG;Lewin SR
双硫仑在 HIV 潜伏期的原代 T 细胞模型中激活 HIV 转录，并且在一项试点临床研究中，在充分接触双硫仑的个体中，双硫仑增加了血浆 HIV RNA。我们进行了一项前瞻性剂量递增研究，以优化双硫仑暴露。 30 名接受抑制性抗逆转录病毒治疗 (ART) 的 HIV 感染者被纳入研究，按顺序分配到三个给药组之一，每天接受双硫仑治疗，持续三天，剂量为 500 毫克、1000 毫克或 2000 毫克。主要终点是 CD4+ T 细胞中的细胞相关未剪接 (CA-US) HIV RNA。该研究已在 ClinicalTrials.gov 注册，编号为 NCT01944371。每个队列在双硫仑治疗期间和之后的 CA-US HIV RNA 估计倍数增加为： 500mg：1·7（95% 置信区间 1·3 – 2·2）和 2·1（1·5 – 2·9）； 1000毫克：1·9（1·6 – 2·4）和2·5（1·9 – 3·3）；和 2000mg：分别为 1·6 (1·2 – 2·1) 和 2·1 (1·5 – 3·1)（全部 p<0·003）。所有剂量的双硫仑均具有良好的耐受性。短期服用双硫仑会导致所有剂量的 CA-US HIV RNA 增加，这与激活 HIV 潜伏期一致。双硫仑可能适合未来联合治疗和长期治疗以激活潜伏艾滋病毒的研究。
Disulfiram activates HIV transcription in a primary T-cell model of HIV latency and in a pilot clinical study increased plasma HIV RNA in individuals with adequate diulfiram exposure. We conducted a prospective dose escalation study in order to optimise disulfiram exposure. Thirty people with HIV on suppressive antiretroviral therapy (ART) were enrolled, allocated sequentially to one of three dosing cohorts and received disulfiram daily for three days at a dose of 500mg, 1000mg or 2000mg. The primary endpoint was cell-associated unspliced (CA-US) HIV RNA in CD4+ T-cells. The study is registered with ClinicalTrials.gov, number NCT01944371. The estimated fold increases in CA-US HIV RNA during and post-disulfiram for each cohort were: 500mg: 1·7 (95% confidence interval 1·3 – 2·2) and 2·1 (1·5 – 2·9); 1000mg: 1·9 (1·6 – 2·4) and 2·5 (1·9 – 3·3); and 2000mg: 1·6 (1·2 – 2·1) and 2·1 (1·5 – 3·1) respectively (p<0·003 for all). Disulfiram was well tolerated at all doses. Short-term administration of disulfiram resulted in increases in CA-US HIV RNA at all doses, consistent with activating HIV latency. Disulfiram may be suited for future studies of combination and prolonged therapy to activate latent HIV.