Antiretroviral intensification and valproic acid lack sustained effect on residual HIV-1 viremia or resting CD4+ cell infection.
Antiretroviral intensification and valproic acid lack sustained effect on residual HIV-1 viremia or resting CD4+ cell infection.
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DOI：
10.1371/journal.pone.0009390
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发表时间：
2010-02-23
期刊：
影响因子：
3.7
通讯作者：
Margolis DM
中科院分区：
文献类型：
--
作者：
Archin NM;Cheema M;Parker D;Wiegand A;Bosch RJ;Coffin JM;Eron J;Cohen M;Margolis DM
尽管进行了抗逆转录病毒治疗（ART），但人类免疫缺陷病毒（HIV）感染仍然存在，这是一个令人生畏的问题。考虑到静息CD 4 + T细胞感染（RCI）受组蛋白脱乙酰酶（HDAC）抑制剂丙戊酸（VPA）影响的证据有限，我们测量了在添加VPA+或不添加雷特格韦（RAL）或恩夫韦肽（ENF）+或不添加VPA的患者中RCI和残留病毒血症的稳定性，血浆HIV RNA<50 c/mL的患者每天两次添加缓释VPA（Depakote ER®）、RAL 400 mg每天两次或ENF 90 mcg每天两次。RCI的变化通过生长测定来测量。通过单拷贝血浆HIV RNA测定（SCA）定量低水平病毒血症。在接受标准ART治疗的3例患者中，在VPA治疗16周后观察到RCI耗竭，但这种效应在进一步VPA治疗96周后减弱。在两名患者中，ENF加稳定的ART对RCI没有影响。在一名患者中，同时强化ENF和添加VPA对RCI频率没有影响，并导致第二名患者的RCI频率下降46%。在加入RAL和VPA后，在6名志愿者中未观察到RCI的显著消耗（>50%）。在6例患者中，4例患者的疗效缺乏可能归因于间歇性病毒血症、低VPA水平或间歇性研究治疗依从性。总体而言，添加RAL或ENF对SCA测量的低水平病毒血症没有影响。前瞻性添加VPA和RAL、VPA和ENF或ENF未能逐渐降低RCI的频率，或消除间歇性和低水平病毒血症。新的方法，如更有效的HDAC抑制，单独或与强化ART或其他可能破坏前病毒潜伏期的药物联合使用，必须加以追求。
Human immunodeficiency virus (HIV) infection that persists despite antiretroviral therapy (ART) is a daunting problem. Given the limited evidence that resting CD4+ T cell infection (RCI) is affected by the histone deacetylase (HDAC) inhibitor valproic acid (VPA), we measured the stability of RCI and residual viremia in patients who added VPA with or without raltegravir (RAL), or enfuvirtide (ENF) with or without VPA, to standard ART. Patients with plasma HIV RNA<50 c/mL added sustained-release VPA (Depakote ER®) twice daily, RAL 400 mg twice daily, or ENF 90 mcg twice daily. Change in RCI was measured by outgrowth assays. Low-level viremia was quantitated by single-copy plasma HIV RNA assay (SCA). In three patients on standard ART a depletion of RCI was observed after 16 weeks of VPA, but this effect waned over up to 96 weeks of further VPA. In two patients ENF added to stable ART had no effect on RCI. Simultaneous intensification with ENF and addition of VPA had no effect on RCI frequency in one patient, and resulted in a 46% decline in a second. No significant depletion of RCI (>50%) was seen in six volunteers after the addition of RAL and VPA. In 4 of the 6 patients this lack of effect might be attributed to intermittent viremia, low VPA levels, or intermittent study therapy adherence. Overall, there was no effect of the addition of RAL or ENF on low-level viremia measured by SCA. The prospective addition of VPA and RAL, VPA and ENF, or ENF failed to progressively reduce the frequency of RCI, or ablate intermittent and low-level viremia. New approaches such as more potent HDAC inhibition, alone or in combination with intensified ART or other agents that may disrupt proviral latency must be pursued.
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DOI：
10.1097/qad.0b013e32832ec1dc
发表时间：
2009-09-10
期刊：
AIDS (London, England)
影响因子：
--
作者：
Archin NM;Keedy KS;Espeseth A;Dang H;Hazuda DJ;Margolis DM
通讯作者：
Margolis DM
影响因子：
3.3
作者：
Colin L;Van Lint C
通讯作者：
Van Lint C
影响因子：
6.2
作者：
Bowman, Mary-Catherine;Archin, Nancie M.;Margolis, David M.
通讯作者：
Margolis, David M.
影响因子：
1.5
作者：
Archin, Nancie M.;Espeseth, Amy;Margolis, David M.
通讯作者：
Margolis, David M.
影响因子：
3.8
作者：
Sagot-Lerolle, Nathalie;Lamine, Aurelia;Lambotte, Olivier
通讯作者：
Lambotte, Olivier