Bednasz Cindy J, Venuto Charles S, Ma Qing, Daar Eric S, Sax Paul E, Fischl Margaret A, Collier Ann C, Smith Kimberly Y, Tierney Camlin, Yang Yang, Wilding Gregory E, Morse Gene D
*AIDS Clinical Trials Group Pharmacology Specialty Laboratory, New York State Center of Excellence in Bioinformatics and Life Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, New York; †Center for Human Experimental Therapeutics, University of Rochester, Rochester, New York; ‡Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center and the University of California, Los Angeles, California; §Division of Infectious Diseases and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; ¶University of Miami School of Medicine, Miami, Florida; ‖University of Washington School of Medicine and Harborview Medical Center, Seattle, Washington; **ViiV Healthcare, Research Triangle Park, North Carolina; ††Statistical Data Analysis Center, Harvard T. H. Chan School of Public Health, Boston, Massachusetts; and ‡‡Department of Biostatistics, University at Buffalo, Buffalo, New York.
Ther Drug Monit. 2017 Dec;39(6):596-603. doi: 10.1097/FTD.0000000000000443.
Efavirenz is currently suggested as an alternative to recommended antiretroviral (ARV) regimens by the Department of Health and Human Services for the treatment of HIV-1 in ARV-naive patients. A mid-dosing interval therapeutic range between 1000 and 4000 ng/mL for efavirenz has been proposed in the literature, with patients more likely to experience virologic failure below this range and adverse effects above. The current study reports an analysis of virologic outcome between those above, below, or within the reported efavirenz therapeutic range (1000-4000 ng/mL) and within subgroups.
This analysis examined efavirenz plasma concentrations obtained from participants enrolled in AIDS Clinical Trials Group Study A5202. This investigation divided subjects into those who experienced virologic failure and those who did not. These subjects were further separated to investigate those who had "high," "within," or "low" plasma concentrations, based on the therapeutic range. The association between virologic failure and plasma concentration was statistically examined in addition to the variables: race/ethnicity, sex, assigned nucleos(t)ide reverse transcriptase inhibitor backbone, age at study entry, history of intravenous drug use, weight, and screening HIV-1 RNA stratification level.
In univariate analyses, a statistically significant difference was found when comparing the efavirenz concentration groups, (22 failures among the "low" concentration group [19%], 65 failures among the "within" concentration group [12%], and 11 failures among the "high" concentration group [9%]) when evaluating virologic failure as an outcome (P = 0.04). In addition, the proportion of participants with virologic failure differed across race/ethnicity groups (P = 0.03) with black non-Hispanic participants observed to have the highest rate (17%). Efavirenz concentration group, race/ethnicity, age, weight, and the interaction between efavirenz concentration group and weight were found to be significantly associated with virologic failure in multivariable logistic regression analysis.
The proposed efavirenz therapeutic range, combined with the impact of a patient's weight, is associated with virologic failure in HIV-infected ARV-naive individuals in the United States. Additional analysis is recommended to determine the most appropriate concentration value that defines the lower limit of the efavirenz therapeutic range.
美国卫生与公众服务部目前建议，依非韦伦可作为推荐的抗逆转录病毒（ARV）治疗方案的替代药物，用于初治HIV-1患者。文献中提出依非韦伦的给药间隔中期治疗范围为1000至4000 ng/mL，低于该范围的患者更易出现病毒学失败，高于该范围则更易出现不良反应。本研究报告了对依非韦伦治疗范围（1000 - 4000 ng/mL）以上、以下或范围内以及亚组间病毒学结果的分析。
本分析检测了参与艾滋病临床试验组A5202研究的受试者的依非韦伦血浆浓度。该研究将受试者分为发生病毒学失败和未发生病毒学失败两组。根据治疗范围，进一步将这些受试者分为血浆浓度“高”、“在范围内”或“低”三组进行研究。除了种族/民族、性别、指定的核苷（酸）逆转录酶抑制剂主干、研究入组时的年龄、静脉吸毒史、体重和筛查时的HIV-1 RNA分层水平等变量外，还对病毒学失败与血浆浓度之间的关联进行了统计学检验。
在单因素分析中，以病毒学失败作为观察指标时，比较依非韦伦浓度组发现存在统计学显著差异（“低”浓度组22例失败[19%]，“在范围内”浓度组65例失败[12%]，“高”浓度组11例失败[9%]）（P = 0.04）。此外，不同种族/民族组的病毒学失败参与者比例存在差异（P = 0.03），其中非西班牙裔黑人参与者的发生率最高（17%）。在多变量逻辑回归分析中，发现依非韦伦浓度组、种族/民族、年龄、体重以及依非韦伦浓度组与体重之间的相互作用与病毒学失败显著相关。
在美国，初治的HIV感染者中，依非韦伦建议的治疗范围以及患者体重的影响与病毒学失败相关。建议进行进一步分析，以确定定义依非韦伦治疗范围下限的最合适浓度值。
