Alcohol use and ARV treatment outcomes in Uganda

描述（由申请方提供）：次优抗逆转录病毒暴露是临床结局的重要预测因素，可能是由于不完全依从或药代动力学变异性所致。酒精是在资源丰富的环境中不遵守的最一致的预测因素之一，是在资源有限的环境中选择的药物。酒精也可能影响抗逆转录病毒药物的暴露，通过坚持和/或抗逆转录病毒药物代谢的变化。通过依从性受损、治疗中止/配给或药代动力学改变导致的病毒抑制不充分可能导致病毒快速耐药。虽然在资源丰富的环境中，遵守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，对遵守行为的相关性知之甚少。对非洲患者的非专利抗逆转录病毒疗法的药代动力学知之甚少。没有关于酒精如何影响依从性、治疗持续时间或药代动力学以及在资源有限的环境中产生耐药性的数据。由于酒精是资源有限环境中最常滥用的物质，因此了解酒精如何影响这些重要的治疗结果非常重要。我们在乌干达坎帕拉接受艾滋病毒抗逆转录病毒治疗的患者中制定了有效和客观的依从性措施，我们计划招募174名患者，分为三个饮酒分层，以确定饮酒对Triomune（D4 T/3 TC/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。Triomune是研究依从性的理想药物，可能与酒精具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没有的依从性抗性关系。这项研究的具体目标是：1）确定酒精使用的严重程度增加是否与Triomune治疗的依从性和治疗中断/中止水平降低相关，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，和4）确定酒精使用对Triomune抗逆转录病毒药物耐药性的影响，其通过依从性、治疗持续时间和药代动力学介导。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疗法的重要第一步。

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.