A Pilot Study Assessing the Safety and Latency-Reversing Activity of Disulfiram in HIV-1-Infected Adults on Antiretroviral Therapy
A Pilot Study Assessing the Safety and Latency-Reversing Activity of Disulfiram in HIV-1-Infected Adults on Antiretroviral Therapy
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DOI：
10.1093/cid/cit813
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发表时间：
2014-03-15
影响因子：
11.8
通讯作者：
Deeks, Steven G.
中科院分区：
文献类型：
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作者：
Spivak, Adam M.;Andrade, Adriana;Deeks, Steven G.
背景尽管抗逆转录病毒治疗，转录沉默的人类免疫缺陷病毒1型（HIV-1）DNA仍然存在于静息记忆CD 4（+）T细胞中。在原代细胞模型中，抗酒精中毒药物双硫仑在体内达到一定浓度时，可诱导潜伏感染的静息记忆CD 4（+）T细胞中HIV-1的转录。我们进行了一项单臂初步研究，以评估接受稳定抑制性抗逆转录病毒治疗的HIV-1感染者每天给予500 mg双硫仑持续14天是否会逆转HIV-1潜伏期，同时伴随残留病毒血症的短暂增加或静息记忆CD 4（+）T细胞中潜伏库的耗竭。双硫仑安全且耐受性良好。受试者间血浆双硫仑水平变异性较高。潜在储库没有显著变化（1.16倍变化; 95%置信区间[CI]，0.70 - 1.92倍; P = 0.56）。双硫仑给药期间，残留病毒血症与基线相比无显著变化（1.53倍; 95% CI，88- 2.69倍; P = 0.13），尽管估计残留病毒血症在给药后期间与基线相比增加了1.88倍（95% CI，1.03- 3.43倍; P = 0.04）。在一项事后分析中，在给药后立即采样的一个个体亚组（n = 6）中观察到病毒血症的快速和短暂增加（HIV-1 RNA增加，2.96倍; 95%CI，1.29- 6.81倍; P = 0.01）。对接受抗逆转录病毒治疗的患者给予双硫仑并不能减少潜伏性储库的大小。对残留病毒血症的可能剂量相关效应支持未来评估更高剂量对HIV-1产生影响的研究。双硫仑影响相关信号通路，可以安全给药，支持该药物的未来研究。
Background. Transcriptionally silent human immunodeficiency virus type 1 (HIV-1) DNA persists in resting memory CD4(+) T cells despite antiretroviral therapy. In a primary cell model, the antialcoholism drug disulfiram has been shown to induce HIV-1 transcription in latently infected resting memory CD4(+) T cells at concentrations achieved in vivo.Methods. We conducted a single-arm pilot study to evaluate whether 500 mg of disulfiram administered daily for 14 days to HIV-1-infected individuals on stable suppressive antiretroviral therapy would result in reversal of HIV-1 latency with a concomitant transient increase in residual viremia or depletion of the latent reservoir in resting memory CD4(+) T cells.Results. Disulfiram was safe and well tolerated. There was a high level of subject-to-subject variability in plasma disulfiram levels. The latent reservoir did not change significantly (1.16-fold change; 95% confidence interval [CI], .70- to 1.92-fold; P = .56). During disulfiram administration, residual viremia did not change significantly compared to baseline (1.53-fold; 95% CI, 88- to 2.69-fold; P = .13), although residual viremia was estimated to increase by 1.88-fold compared to baseline during the postdosing period (95% CI, 1.03- to 3.43-fold; P = .04). In a post hoc analysis, a rapid and transient increase in viremia was noted in a subset of individuals (n = 6) with immediate postdose sampling (HIV-1 RNA increase, 2.96-fold; 95% CI, 1.29- to 6.81-fold; P = .01).Conclusions. Administration of disulfiram to patients on antiretroviral therapy does not reduce the size of the latent reservoir. A possible dose-related effect on residual viremia supports future studies assessing the impact of higher doses on HIV-1 production. Disulfiram affects relevant signaling pathways and can be safely administered, supporting future studies of this drug.