Innovative methods for measuring antiretroviral exposure

测量抗逆转录病毒暴露的创新方法

• 批准号: 8102620
• 负责人: RUTH Martha GREENBLATT
• 金额: $ 22.53万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-12 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8102620
• 关键词: AIDS Treatment Research; Adherence; Adverse effects; Anti-Retroviral Agents; Atazanavir; Behavioral; Binding; Biological Assay; Biological Availability; Blood; Blood Glucose; Blood specimen; Chronic Disease; Clinical; Cohort Studies; Data; Data Set; Diabetes Mellitus; Diet; Dose; Drug Exposure; Drug Kinetics; Drug Monitoring; Event; Exposure to; Funding; Genes; Genotype; Goals; HIV; HIV Infections; HIV Protease Inhibitors; Hair; Hemoglobin; Highly Active Antiretroviral Therapy; Immunologics; Incidence; Indinavir; Individual; International AIDS; Life; Lopinavir; Maintenance; Measurement; Measures; Methods; Modeling; Morbidity - disease rate; Mutation; Nelfinavir; Nevirapine; Outcome; Participant; Patient Self-Report; Pattern; Peptide Hydrolases; Pharmaceutical Preparations; Pigments; Plasma; Population; Predictive Value of Tests; Principal Investigator; Protease Inhibitor; RNA-Directed DNA Polymerase; Recovery; Recreational Drugs; Regimen; Research; Resistance; Sampling; Sampling Studies; Series; Site; Specimen; Testing; Therapeutic; Time; Transcriptase; Treatment outcome; Viral; Viral Load result; Virus; Visit; Woman; Work; antiretroviral therapy; base; cohort; disorder control; efavirenz; eumelanin; experience; inhibitor/antagonist; innovation; member; mortality; non-nucleoside reverse transcriptase inhibitors; pharmacokinetic model; pressure; programs; resistance mutation; response; success; therapy outcome

DESCRIPTION (provided by applicant): Despite the success of highly active antiretroviral therapy (HAART) regimens in reducing HIV morbidity and mortality on the population level, individual responses and adverse effects are variable. Many factors influence the outcome of HAART, including the amount of drug that reaches the site of activity (treatment exposure). Behavioral factors and pharmacological parameters (bioavailability, clearance, distribution) influence exposure. Since antiretroviral drugs must be present in adequate quantities for long periods to be effective, measures of long-term exposure are needed. Stimulated by the finding that indinavir (an HIV protease inhibitor) levels in hair were highly correlated with viral load responses and resistance, we initiated preliminary work to develop methods for quantifying the amount of antiretroviral protease inhibitors and non-nucleoside reverse transcriptase inhibitors in small samples of hair. We found a strong correlation between lopinavir levels in hair and initial virologic response to lopinavir-based therapy; lopinavir concentrations in hair were significantly higher in responders versus nonresponders (Mann-Whitney exact test, p < 0.0001). Hair levels of antiretrovirals may correlate more closely with long-term outcomes than single blood levels. We use another chronic illness, diabetes mellitus, to compare the value of short term and longer-term measures of disease control (blood glucose and hemoglobin Ale, respectively) as an analogy for the comparison of antiretroviral levels in blood and in hair. The overarching goals of the proposed research are to develop and evaluate methods for determining long-term exposure to antiretroviral drugs in hair samples and to test the predictive value of the hair measures for virologic and immunologic responses, as well as the incidence of adverse effects and resistance mutations. We also propose to assess the value of correcting drug levels in hair by eumelanin content (a measure of the binding capacity for drug). Measuring drug levels in hair has been successfully applied to determination of exposure to a broad array of therapeutic and recreational drugs. This work may provide an inexpensive, noninvasive, field-friendly method for determination of the level of antiretroviral exposure, which could be applied in domestic and international AIDS treatment and research settings. We therefore propose a series of studies of the value of antiretroviral drug measurement using hair specimens based in the Women's Interagency HIV Study (WIHS) cohort, the largest longitudinal cohort study of HIV infection in women in the U.S.

描述（由申请人提供）：尽管高度活跃的抗逆转录病毒疗法（HAART）方案在降低人群水平上的HIV发病率和死亡率方面取得了成功，但个体反应和不良影响是可变的。许多因素会影响HAART的结果，包括达到活动部位的药物量（治疗暴露）。行为因素和药理学参数（生物利用度，清除率，分布）会影响暴露。由于必须以足够的量为有效的抗逆转录病毒药物，因此需要长期暴露的措施。 由于头发中的吲哚奈韦（HIV蛋白酶抑制剂）水平与病毒载荷反应和耐药性高度相关的发现，我们开始了初步工作，以开发用于量化小毛样品样品中抗逆转录病毒蛋白酶抑制剂和非核苷蛋白酶抑制剂的量和非核糖苷反向转录酶抑制剂的方法。我们发现头发中的洛匹那韦水平与基于lopinavir的治疗的初始病毒学反应之间存在很强的相关性。反应者与无反应者的头发中的lopinavir浓度明显更高（Mann-Whitney精确测试，p <0.0001）。抗逆转录病毒的头发水平可能比单血液水平更与长期结局更紧密地相关。 我们使用另一种慢性疾病，即糖尿病，比较短期和长期疾病控制（分别是血糖和血红蛋白啤酒）的价值，以比较血液和头发中抗逆转录病毒水平的比较。拟议的研究的总体目标是开发和评估头发样本中长期暴露于抗逆转录病毒药物的方法，并测试针对病毒学和免疫学反应的头发测量的预测价值，以及不良反应和抵抗突变的发生率。 我们还建议评估eumelanin含量纠正头发中的药物水平的价值（对药物的结合能力的量度）。测量头发的药物水平已成功地用于确定暴露于广泛的治疗和休闲药物中。这项工作可能会提供廉价，无创，现场友好的方法来确定抗逆转录病毒暴露水平，可用于国内和国际艾滋病治疗和研究环境中。因此，我们提出了一系列研究抗逆转录病毒药物测量的价值，使用基于妇女妇女间HIV研究（WIHS）队列中的头发标本，这是美国妇女艾滋病毒感染最大的纵向队列研究。

项目成果

Sensitive analysis of anti-HIV drugs, efavirenz, lopinavir and ritonavir, in human hair by liquid chromatography coupled with tandem mass spectrometry.

• DOI: 10.1002/rcm.3750
• 发表时间: 2008-11
• 期刊: RAPID COMMUNICATIONS IN MASS SPECTROMETRY
• 影响因子: 2
• 作者: Huang, Yong;Gandhi, Monica;Greenblatt, Ruth M.;Gee, Winnie;Lin, Emil T.;Messenkoff, Nicholas
• 通讯作者: Messenkoff, Nicholas