Effects of Antiretroviral Drugs on Metabolism

描述(申请人提供)：为了确定抗逆转录病毒药物(ARV)的直接毒性，并将这些变化与它们对HIV感染的影响分开，我们给健康志愿者提供了单一的ARV，并将结果与对HIV感染患者进行的研究进行了比较。我们现在建议解决目前使用的抗逆转录病毒药物的争议。1)利托那韦增加甘油三酯的机制(S)尚不清楚，但对动脉粥样硬化有重要意义。假设1：利托那韦方案通过增加极低密度脂蛋白的产生和减少极低密度脂蛋白的清除来增加甘油三酯和极低密度脂蛋白。具体目标1A：利用稳定的同位素周转和其他清除方法，量化利托那韦对极低密度脂蛋白的产生和清除的影响。特定目的2B：确定富含甘油三酯的颗粒的组成2)NNRTI升高高密度脂蛋白胆固醇，但机制尚不清楚，NNRTI可能不会产生具有较强抗动脉粥样硬化作用的高密度脂蛋白颗粒。假设2：NNRTI药物并不是通过增加载脂蛋白AI的产生来增加高密度脂蛋白，而是通过减少载脂蛋白AI的清除，延长循环中的时间，并产生有限的抗动脉粥样硬化特性的颗粒来提高高密度脂蛋白。具体目标2a：测定NNRTI前后高密度脂蛋白的组成并评价其功能。具体目标2B：使用稳定同位素定量NNRTI对载脂蛋白AI产生和清除的影响。具体目的2C：确定Eefavirenz诱导的高密度脂蛋白升高是否伴随着血流介导的血管扩张和循环内皮功能标志物的改善3)PI对糖代谢的影响不能仅仅用它们对胰岛素抵抗的影响来解释。PIS可能会损害胰岛素的分泌，这对设计更安全的PIS具有重要意义。假设3：基于利托那韦的PI会损害胰岛素的分泌。具体目标3：确定哪些利托那韦PI方案会改变胰岛素的分泌。这些研究的结果将确定ARV的直接毒性，为合理评估治疗策略和咨询患者提供必要的信息。

DESCRIPTION (provided by applicant): To define the direct toxicities of antiretroviral drugs (ARV) and separate those changes from their effects on HIV infection, we gave single ARV to healthy volunteers and compared results to studies in HIV infected patients on those ARV. We now propose to resolve controversies with currently used ARV. 1) The mechanism(s) by which ritonavir increases triglycerides is unknown, but have significant implications for atherosclerosis. Hypothesis 1: Ritonavir-based regimens increase triglycerides and VLDL by both increasing VLDL production and decreasing VLDL clearance. Specific Aim 1A: To quantify the effect of ritonavir on VLDL production and clearance using stable isotope turnover and other clearance methods. Specific Aim 2B: To determine the composition of the triglyceride rich particles 2) NNRTI increase HDL cholesterol, but the mechanism is unknown and NNRTI may not generate HDL particles that have strong anti-atherogenic effects. Hypothesis 2: NNRTI drugs do not increase HDL by increasing apo AI production, but by decreasing apo AI clearance, prolonging time in circulation and producing particles with limited anti-atherogenic properties. Specific Aim 2A: To determine the composition of HDL before and after NNRTI and assess its function. Specific Aim 2B: To quantify the effect of NNRTI on apo AI production & clearance using stable isotopes. Specific Aim 2C: To determine if the efavirenz induced increase in HDL is accompanied by improvement in flow mediated vasodilation and circulating markers of endothelial function 3) The effects of PI on glucose metabolism cannot be solely explained by their effects on insulin resistance. PIs may impair insulin secretion, which has important implications for design of safer PI. Hypothesis 3: Ritonavir-based PIs impair insulin secretion. Specific Aim 3: To determine which ritonavir-based PI regimens alter insulin secretion. The results from these studies will define the direct toxicities of ARV, which provide essential information for rationally evaluating treatment strategies and counseling patients.Carl Grunfeld, MD, PhD.