Alcohol use and ARV treatment outcomes in Uganda

描述（由申请人提供）：次优抗逆转录病毒暴露是临床结果的重要预测因子，可能是由于不完全依从性或药代动力学变异性。在资源丰富的环境中，酒精是不坚持治疗的最一致的预测因素之一，在资源有限的环境中，酒精是首选药物。酒精也可能通过依从性和/或改变抗逆转录病毒药物的CYP 3A代谢来影响抗逆转录病毒药物暴露。由于依从性受损、停止治疗/定量配给或药代动力学改变而导致的病毒抑制不足可能导致病毒迅速耐药。虽然在资源丰富的环境中，依从性的预测因素是众所周知的，但在资源有限的环境中，特别是撒哈拉以南非洲，人们对依从性行为的相关性知之甚少。对非专利抗逆转录病毒治疗在非洲患者中的药代动力学了解较少。在资源有限的情况下，没有关于酒精如何影响依从性、治疗时间、药代动力学和耐药性发展的数据。由于它是资源有限环境中最常见的滥用物质，因此了解酒精如何影响这些重要的治疗结果非常重要。我们为乌干达坎帕拉接受艾滋病毒抗逆转录病毒治疗的患者制定了有效和客观的依从性措施，我们建议招募三个酒精层的174名患者，以确定酒精使用对通用Triomune （D4T/3TC/NVP）抗逆转录病毒治疗的依从性和药代动力学的影响，观察12个月。Triomune是研究依从性的理想药物，可能与酒精有重要的药代动力学相互作用，并且具有与其他抗逆转录病毒药物未见的依从性抵抗关系。本研究的具体目的是：1)确定酒精使用严重程度的增加是否与Triomune治疗的较低依从性和治疗中断/停止有关，2)确定酒精使用对Triomune治疗的药代动力学的影响，3)确定酒精使用对通过Triomune治疗的依从性和药物动力学介导的HIV病毒抑制的影响，以及4)确定酒精使用对通过依从性介导的Triomune抗逆转录病毒耐药性的影响。治疗时间和药代动力学。这项研究将是确定酒精对在撒哈拉以南非洲扩大抗逆转录病毒治疗的治疗结果的影响的重要的第一步。

DESCRIPTION (provided by applicant): Suboptimal antiretroviral exposure is an important predictor of clinical outcome and may be due to incomplete adherence or pharmacokinetic variability. Alcohol is one of the most consistent predictors of non-adherence in resource rich-settings and is the drug of choice in resource-limited settings. Alcohol may also impact antiretroviral drug exposure through adherence and/or changes in CYP 3A metabolism of antiretroviral medications. Inadequate viral suppression through impaired adherence, treatment discontinuation/rationing, or pharmacokinetic alterations may lead to rapid viral resistance. While the predictors of adherence are well known in resource-rich settings, little is known about the correlates of adherence behavior in resource-limited settings, particularly sub-Saharan Africa. Less is known about the pharmacokinetics of generic antiretroviral therapy in African patients. There is no data on how alcohol may impact adherence, treatment duration, or pharmacokinetics and development of resistance in resource-limited settings. Since it is the most commonly abused substance in resource-limited settings, it is important to know how alcohol may impact these important treatment outcomes. We have developed valid and objective adherence measures in patients receiving HIV antiretroviral therapy in Kampala, Uganda, and we propose to recruit 174 patients in three alcohol strata to determine the impact of alcohol use on adherence and pharmacokinetics of generic Triomune (D4T/3TC/NVP) antiretroviral therapy over 12 months of observation. Triomune is an ideal medication to study adherence, may have important pharmacokinetic interactions with alcohol, and possesses an adherence resistance relationship not seen with other antiretrovirals. The specific aims of this study are to: 1) determine whether increased severity of alcohol use is associated with lower levels of adherence to and treatment interruptions/discontinuations of Triomune therapy, 2) determine the effect of alcohol use on pharmacokinetics of Triomune therapy, 3) determine the impact of alcohol use on HIV viral suppression mediated through adherence to and pharmac0kinetics of Triomune therapy, and 4) determine the impact of alcohol use on Triomune antiretroviral drug resistance mediated through adherence, treatment duration, and pharmacokinetics. This research will be an essential first step to determine the impact of alcohol on treatment outcomes to expanding antiretroviral therapy in sub-Saharan Africa.