STRATEGIC MANAGEMENT OF ANTIRETROVIRALS IN HIV INFECTION

在过去的两年中，艾滋病毒感染的治疗取得了巨大的进步。蛋白水解酶抑制剂和非核苷类逆转录酶抑制剂的问世使抗逆转录病毒药物(HAART)的开发成为可能，可以完全阻断HIV病毒的复制。高效抗逆转录病毒疗法的使用极大地改变了艾滋病毒感染和艾滋病的发病率和死亡率。这一进展并非没有问题。蛋白水解酶抑制剂具有主要的毒性，目前对其了解还不完全。它们很难服用，需要严格的时间表和饮食限制，而且它们很贵。需要在使用这些药物方面采取更好的策略，以最大限度地发挥临床效益，提高患者的生活质量。鉴于对许多不同组合进行大规模战略试验是不可行的，因此必须确定是否可以制定替代战略办法。两种可能的选择构成了这笔赠款中拟议的研究：a)使用决策分析等统计方法来指导治疗决定，以及b)使用小型先导性研究来为支持或拒绝可以指导战略决策的假设提供基础。为了实现这些目标，研究人员将：1)使用决策分析技术以及马尔可夫模型，对艾滋病毒感染患者抗逆转录病毒治疗的不同策略进行计算建模；2)评估包含蛋白酶抑制剂的完全抑制抗逆转录病毒方案是否可以简化，用非核苷类逆转录酶抑制剂(NNRTI)取代蛋白酶抑制剂。他还将确定这一简化策略是否具有额外的病理生理效应，如纠正与蛋白酶抑制剂治疗相关的代谢异常、改变通过双能X射线吸收法(DEXA)扫描测量的患者的身体成分，或改变CD4/CD8 T记忆和NA Ve细胞的分布和绝对数量。

Over the last 2 years there have been dramatic advances in the treatment of HIV infection. The availability of protease inhibitors and non-nucleoside reverse transcriptase inhibitors allowed the development of combinations of antiretroviral drugs (HAART) that can completely block HIV viral replication. The use of highly active antiretroviral therapy has dramatically changed the morbidity and mortality rates of HIV infection and AIDS. This progress is not without problems. Protease inhibitors have major toxicities that are only partially understood. They are difficult to take requiring tight schedules and dietary restrictions and they are expensive. Better strategies in the use of these drugs are needed in order to maximize clinical benefits and improve the quality of life of patients. Given the fact that large strategic trials of many different combinations are not feasible, it is essential to determine if alternative strategic approaches can be developed. Two possible options constitute the proposed research in this grant: a)the use of statistical methods such as decision analysis to guide treatment decisions, and b) use of small pilot studies to provide basis for supporting or rejecting hypothesis that can guide strategic decisions. To accomplish these aims the investigator will: 1) Perfrom computing modeling of different strategies in the management of antiretroviral therapy in HIV infected patients using decision analysis techniques as well as Markov models; 2) Evaluate whether a fully suppressive antiretroviral regimen containing a protease inhibitor can be simplified substituting the protease inhibitor with a non-nucleoside reverse transcriptase inhibitor (NNRTI). He will also determine whether this simplification strategy has additional pathophysiologic effects correcting the metabolic abnormalities associated with protease inhibitor therapy, changing the body composition of the patients as measured by DEXA (dual energy x-ray absorptiometry) scans, or changing the distribution and absolute numbers of CD4/CD8 T memory and nave cells.