Innovative methods for measuring antiretroviral exposure

测量抗逆转录病毒暴露的创新方法

• 批准号: 7615657
• 负责人: RUTH Martha GREENBLATT
• 金额: $ 49.41万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-05 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7615657
• 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; Research; Resistance; Sampling; Sampling Studies; Series; Site; Specimen; Testing; Therapeutic; Time; Transcriptase; Treatment Protocols; 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）：尽管高效抗逆转录病毒治疗（HAART）方案在降低人群水平上的艾滋病毒发病率和死亡率方面取得了成功，但个体反应和不良反应却存在差异。许多因素影响 HAART 的结果，包括到达活动部位的药物量（治疗暴露）。行为因素和药理学参数（生物利用度、清除率、分布）影响暴露。由于抗逆转录病毒药物必须以足够的量长期存在才能发挥作用，因此需要采取长期暴露措施。 受头发中茚地那韦（一种 HIV 蛋白酶抑制剂）水平与病毒载量反应和耐药性高度相关这一发现的刺激，我们开始开展初步工作，开发定量小样本中抗逆转录病毒蛋白酶抑制剂和非核苷逆转录酶抑制剂含量的方法的头发。我们发现头发中的洛匹那韦水平与基于洛匹那韦的治疗的初始病毒学反应之间存在很强的相关性。应答者头发中的洛匹那韦浓度显着高于无应答者（Mann-Whitney 精确检验，p < 0.0001）。与单一血液水平相比，头发中的抗逆转录病毒药物水平可能与长期结果更密切相关。 我们使用另一种慢性疾病——糖尿病，来比较短期和长期疾病控制措施（分别是血糖和血红蛋白艾尔）的价值，作为比较血液和头发中抗逆转录病毒水平的类比。拟议研究的总体目标是开发和评估确定头发样本中抗逆转录病毒药物长期暴露的方法，并测试头发测量对病毒学和免疫学反应的预测价值，以及不良反应和副作用的发生率。抗性突变。 我们还建议通过真黑色素含量（药物结合能力的衡量标准）来评估校正头发中药物水平的价值。测量头发中的药物水平已成功应用于确定各种治疗和娱乐药物的暴露情况。这项工作可能提供一种廉价、非侵入性、现场友好的方法来确定抗逆转录病毒暴露水平，可应用于国内和国际艾滋病治疗和研究环境。因此，我们提出了一系列基于女性机构间艾滋病毒研究 (WIHS) 队列（美国最大的女性艾滋病毒感染纵向队列研究）中使用头发样本进行抗逆转录病毒药物测量价值的研究。