Alcohol use and ARV treatment outcomes in Uganda

描述(由申请人提供)：次佳的抗逆转录病毒暴露是临床结果的重要预测因素，可能是由于不完全依从性或药代动力学变化所致。在资源丰富的环境中，酒精是不遵守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。酒精还可能通过对抗逆转录病毒药物的细胞色素PYP3A代谢的坚持和/或改变来影响抗逆转录病毒药物的暴露。由于粘附性受损、停止/配给治疗或药代动力学改变而导致的病毒抑制不足，可能会导致病毒的快速抗药性。虽然在资源丰富的情况下，遵守的预测因素是众所周知的，但在资源有限的情况下，特别是撒哈拉以南非洲，人们对遵守行为的相关性知之甚少。对非洲患者非专利抗逆转录病毒疗法的药代动力学知之甚少。在资源有限的情况下，没有数据表明酒精可能会如何影响依从性、治疗持续时间或药代动力学和耐药性的发展。由于它是在资源有限的环境中最常见的滥用物质，了解酒精可能如何影响这些重要的治疗结果是很重要的。我们在乌干达坎帕拉为接受HIV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，并建议招募三个酒精水平的174名患者，以确定酒精使用对仿制药Triomune(d4T/3TC/NVP)抗逆转录病毒治疗依从性和药代动力学的影响，为期12个月的观察。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，并具有与其他抗逆转录病毒药物所未见的依从性耐药关系。这项研究的具体目的是：1)确定酒精使用的严重性是否与Triomune疗法的坚持和治疗中断/中断的水平降低有关；2)确定酒精使用对Triomune疗法的药代动力学的影响；3)确定酒精使用对Triomune疗法的坚持和药代动力学介导的艾滋病毒抑制的影响；以及4)确定酒精使用对Triomune抗逆转录病毒耐药性的影响，这些影响是通过坚持、治疗时间和药代动力学来调节的。这项研究将是确定酒精对治疗结果的影响，以扩大撒哈拉以南非洲抗逆转录病毒治疗的重要第一步。

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.