基于雷特格韦的高效抗逆转录病毒治疗期间，雷特格韦对HIV前病毒DNA总量及未整合前病毒的影响。

Effect of raltegravir on the total and unintegrated proviral HIV DNA during raltegravir-based HAART.

作者信息

Nicastri Emanuele, Tommasi Chiara, Abbate Isabella, Bonora Stefano, Tempestilli Massimo, Bellagamba Rita, Viscione Magdalena, Rozera Gabriella, Gallo Anna L, Ivanovic Jelena, Amendola Alessandra, Pucillo Leopoldo, Di Perri Giovanni, Capobianchi Maria R, Narciso Pasquale

机构信息

National Institute for Infectious Diseases, IRCCS Lazzaro Spallanzani, Rome, Italy.

出版信息

Antivir Ther. 2011;16(6):797-803. doi: 10.3851/IMP1833.

DOI:10.3851/IMP1833

PMID:21900711

Abstract

BACKGROUND

Raltegravir is the first approved antiretroviral able to prevent HIV genome integration into the host chromosomes. The aim of the study is to test if raltegravir plasma concentrations can be associated with proviral DNA decline during raltegravir-based salvage therapy.

METHODS

A total of 33 multidrug-resistant HIV-infected patients were enrolled in a longitudinal open-label pilot study and completed a 24-week follow-up. The CD4(+) T-cell count, plasma viral load, proviral HIV DNA and two-long-terminal repeat (2-LTR) circular forms were assessed at baseline, day 14, 30, 60, 90 and 180. The raltegravir trough concentration (C (trough)) was measured by HPLC-ultraviolet and patients were divided into two groups according to the median raltegravir C (trough).

RESULTS

The mean±SD values of baseline HIV RNA, CD4(+) T-cell count and HIV DNA were 4.4±0.82 log copies/ml, 256±177 cells/mm(3) , and 2,668±4,721 copies/10(6) peripheral blood mononuclear cells, respectively. Despite a transient increase of total DNA at week 2, a marked proviral DNA decay (P=0.01) with an increase of the 2-LTR unintegrated/total DNA ratio (P=0.06) over time was observed. At univariate analysis, no correlation between raltegravir C(trough) and classical virological parameters was observed. Nevertheless, the decay of proviral HIV DNA was more pronounced in patients displaying C(trough)<158 ng/ml with respect to those with C(trough)>158 ng/ml (P=0.046).

CONCLUSIONS

Successful raltegravir-based therapy produces a significant decline in proviral DNA and is associated with an increase of the unintegrated/total DNA ratio. Further studies are necessary to define the possible role of pharmacokinetic raltegravir monitoring and the biological meaning of unintegrated proviral DNA.

摘要

背景

雷特格韦是首个被批准的能够防止HIV基因组整合到宿主染色体中的抗逆转录病毒药物。本研究的目的是测试在基于雷特格韦的挽救治疗期间，雷特格韦血浆浓度是否与前病毒DNA下降相关。

方法

共有33例多重耐药HIV感染患者参加了一项纵向开放标签的试点研究，并完成了24周的随访。在基线、第14天、30天、60天、90天和180天评估CD4(+) T细胞计数、血浆病毒载量、前病毒HIV DNA和双长末端重复序列（2-LTR）环状形式。通过高效液相色谱-紫外法测量雷特格韦谷浓度（C（谷）），并根据雷特格韦C（谷）的中位数将患者分为两组。

结果

基线时HIV RNA、CD4(+) T细胞计数和HIV DNA的平均值±标准差分别为4.4±0.82 log拷贝/ml、256±177个细胞/mm(3)和2,668±4,721拷贝/10(6)外周血单个核细胞。尽管在第2周时总DNA有短暂增加，但随着时间的推移，观察到明显的前病毒DNA衰减（P = 0.01），2-LTR未整合/总DNA比值增加（P = 0.06）。在单变量分析中，未观察到雷特格韦C（谷）与经典病毒学参数之间的相关性。然而，与C（谷）>158 ng/ml的患者相比，C（谷）<158 ng/ml的患者中前病毒HIV DNA的衰减更为明显（P = 0.046）。