HIV脂肪萎缩中的线粒体功能、炎症、脂肪与骨骼：补充尿苷或换用替诺福韦的随机研究
Mitochondrial function, inflammation, fat and bone in HIV lipoatrophy: randomized study of uridine supplementation or switch to tenofovir.
作者信息
McComsey Grace A, O'Riordan MaryAnn, Choi Julia, Libutti Daniel, Rowe David, Storer Norma, Harrill Danielle, Gerschenson Mariana
机构信息
University Hospitals Case Medical Center, Case Western Reserve University, Cleveland, OH, USA.
出版信息
Antivir Ther. 2012;17(2):347-53. doi: 10.3851/IMP1928. Epub 2011 Oct 13.
BACKGROUND
Lipoatrophy modestly improves when the thymidine analogue nucleoside reverse transcriptase inhibitor (tNRTI) is removed. In vitro, uridine (NucleomaxX(®); Pharma Nord, Vojens, Denmark) reversed tNRTI mitochondrial toxicity.
METHODS
All patients had lipoatrophy on a tNRTI-containing regimen with HIV RNA<400 copies/ml. A randomized 48-week study switched patients from tNRTI to tenofovir (TDF) or added uridine (continuing tNRTI). End points were changes in limb fat (DEXA), subcutaneous abdominal fat mitochondrial DNA (mtDNA) and mitochondrial RNA (mtRNA), inflammation markers (soluble tumour necrosis factor receptors, high-sensitivity C reactive protein [hsCRP], interleukin-6 [IL-6], soluble vascular cell adhesion molecule 1), bone mineral density (BMD) of the hip and spine, HIV-1 RNA, CD4(+) T-cells and fasting metabolic parameters.
RESULTS
Fifty patients were enrolled (n=24 TDF switch; n=26 uridine); median age 48 years; 54% white; 86% male; limb fat 4,494 g. Baseline characteristics were similar between groups. In the NucleomaxX(®) arm, mtRNA increased (all P<0.001), hsCRP and IL-6 increased (both P=0.02), whereas fat mtDNA decreased without changes in limb fat. In the TDF-switch arm, fat mtDNA and inflammation markers did not change; however, significant increases in mtRNAs (P<0.001), limb fat (409 g; IQR -59-1,155) and CD4(+) T-cell count (P=0.03), and decreases in total and hip BMD (median -3.3%; IQR -5.1-0; P=0.005) were observed. Between-group changes were significant for fat mtDNA, hsCRP, IL-6, limb fat and hip BMD. No correlation was found between changes in limb fat and those of fat mtRNA, inflammation markers or protease inhibitor duration.
CONCLUSIONS: In HIV lipoatrophy, NucleomaxX(®) improved mtRNA, but worsened inflammation markers and fat mtDNA without changes in limb fat. Switching from a tNRTI to TDF for 48 weeks increased limb fat and fat mtRNA. Large decreases in total and hip BMD were seen after TDF switch. ClinicalTrials.gov identifier: NCT00119379.
背景
去除胸苷类似物核苷逆转录酶抑制剂（tNRTI）后，脂肪萎缩有一定程度改善。在体外实验中，尿苷（NucleomaxX(®)；丹麦沃耶恩的法玛诺德公司）可逆转tNRTI的线粒体毒性。
方法
所有患者在接受含tNRTI方案治疗且HIV RNA<400拷贝/ml时出现脂肪萎缩。一项为期48周的随机研究将患者从tNRTI转换为替诺福韦（TDF）或添加尿苷（继续使用tNRTI）。终点指标包括肢体脂肪（双能X线吸收法）、腹部皮下脂肪线粒体DNA（mtDNA）和线粒体RNA（mtRNA）的变化、炎症标志物（可溶性肿瘤坏死因子受体、高敏C反应蛋白[hsCRP]、白细胞介素-6[IL-6]、可溶性血管细胞黏附分子1）、髋部和脊柱的骨密度（BMD）、HIV-1 RNA、CD4(+) T细胞以及空腹代谢参数。
结果
共纳入50例患者（n = 24例转换为TDF；n = 26例添加尿苷）；中位年龄48岁；54%为白人；86%为男性；肢体脂肪4494克。两组间基线特征相似。在添加NucleomaxX(®)的组中，mtRNA增加（所有P<0.001），hsCRP和IL-6升高（均P = 0.02），而脂肪mtDNA减少，肢体脂肪无变化。在转换为TDF的组中，脂肪mtDNA和炎症标志物无变化；然而，观察到mtRNAs显著增加（P<0.001）、肢体脂肪增加（409克；四分位间距-59 - 1155）和CD4(+) T细胞计数增加（P = 0.03），以及总骨密度和髋部骨密度降低（中位值-3.3%；四分位间距-5.1 - 0；P = 0.005）。两组间脂肪mtDNA、hsCRP、IL-6、肢体脂肪和髋部骨密度的变化具有显著性差异。未发现肢体脂肪变化与脂肪mtRNA、炎症标志物或蛋白酶抑制剂使用时长的变化之间存在相关性。
结论
在HIV相关性脂肪萎缩中，NucleomaxX(®)可改善mtRNA，但会使炎症标志物和脂肪mtDNA恶化，肢体脂肪无变化。从tNRTI转换为TDF持续48周可增加肢体脂肪和脂肪mtRNA。转换为TDF后，总骨密度和髋部骨密度大幅下降。
临床试验注册号
NCT00119379
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