依非韦伦在柬埔寨接受结核病治疗的HIV感染成人中的血浆浓度、疗效及安全性（ANRS 1295-CIPRA KH001 CAMELIA试验）
Plasma concentrations, efficacy and safety of efavirenz in HIV-infected adults treated for tuberculosis in Cambodia (ANRS 1295-CIPRA KH001 CAMELIA trial).
作者信息
Borand Laurence, Madec Yoann, Laureillard Didier, Chou Monidarin, Marcy Olivier, Pheng Phearavin, Prak Narom, Kim Chindamony, Lak Khemarin Kim, Hak Chanroeun, Dim Bunnet, Nerrienet Eric, Fontanet Arnaud, Sok Thim, Goldfeld Anne E, Blanc François-Xavier, Taburet Anne-Marie
机构信息
Institut Pasteur du Cambodge, Epidemiology and Public Health Unit, Phnom Penh, Cambodia.
Institut Pasteur, Unité de Recherche et d'Expertise Epidémiologie des Maladies Emergentes, Paris, France.
出版信息
PLoS One. 2014 Mar 7;9(3):e90350. doi: 10.1371/journal.pone.0090350. eCollection 2014.
OBJECTIVE
To assess efavirenz plasma concentrations and their association with treatment efficacy and tolerance of efavirenz 600 mg daily in HIV-tuberculosis co-infected patients.
METHODS
HIV-infected adults with CD4+ T cell count ≤ 200/mm(3) received standard 6-month tuberculosis treatment and antiretroviral therapy including a daily-dose of 600 mg of efavirenz, irrespective of their body weight. Mid-dose blood samples were drawn both on tuberculosis treatment (week +2 and week +6 after antiretroviral therapy initiation, and week 22 of follow-up) and off tuberculosis treatment (week 50 of follow-up). Considered therapeutic range was 1,000 to 4,000 ng/mL. Multivariate analysis was performed to evaluate the association between efavirenz concentration below 1,000 ng/mL and virological failure. Linear regression was used to test the association between efavirenz exposure and CD4+ T cell gain. Severe side effects potentially related to efavirenz were described and their association with efavirenz exposure was tested by multivariate analysis.
RESULTS
Efavirenz plasma concentrations were available in 540 patients. Median [interquartile range] efavirenz concentrations were 2,674 ng/mL [1,690-4,533], 2,667 ng/mL [1,753-4,494] and 2,799 ng/mL [1,804-4,744] at week +2, week +6, week 22, respectively, and 2,766 ng/mL [1,941-3,976] at week 50. Efavirenz concentrations were lower at week 50 (off rifampicin) compared to week 22 (on rifampicin) (p<0.001). Late attendance to study visit and low hemoglobinemia were the only factors associated with an increased risk of efavirenz concentration below 1,000 ng/mL. Efavirenz concentration below 1,000 ng/mL was not associated with treatment failure. Efavirenz concentration above 4,000 ng/mL was associated with higher risk of central nervous system side effects (p<0.001) and of hepatotoxicity (p<0.001).
CONCLUSION
Body weight and tuberculosis treatment were not associated with low efavirenz concentrations or treatment failure, supporting the 600 mg daily-dose of efavirenz in HIV-tuberculosis co-infected patients. High efavirenz concentrations were related to a higher risk of central nervous system side effects and hepatotoxicity.
TRIAL REGISTRATION
ClinicalTrials.gov NCT01300481.
目的
评估依法韦仑的血浆浓度及其与HIV-结核合并感染患者每日服用600mg依法韦仑的治疗效果和耐受性之间的关系。
方法
CD4+T细胞计数≤200/mm³的HIV感染成人接受标准的6个月抗结核治疗和抗逆转录病毒治疗，包括每日剂量600mg依法韦仑，不论其体重如何。在抗结核治疗期间（抗逆转录病毒治疗开始后第2周和第6周以及随访第22周）和停止抗结核治疗后（随访第50周）采集血样。治疗有效范围为1000至4000ng/mL。进行多变量分析以评估依法韦仑浓度低于1000ng/mL与病毒学失败之间的关联。使用线性回归测试依法韦仑暴露量与CD4+T细胞增加之间的关联。描述了可能与依法韦仑相关的严重副作用，并通过多变量分析测试其与依法韦仑暴露量的关联。
结果
540例患者有依法韦仑血浆浓度数据。第2周、第6周、第22周的依法韦仑浓度中位数[四分位间距]分别为2674ng/mL[1690 - 4533]、2667ng/mL[1753 - 4494]和2799ng/mL[1804 - 4744]，第50周为2766ng/mL[1941 - 3976]。与第22周（服用利福平）相比，第50周（未服用利福平）时依法韦仑浓度较低（p<0.001）。研究访视迟到和低血红蛋白血症是与依法韦仑浓度低于1000ng/mL风险增加相关的唯一因素。依法韦仑浓度低于1000ng/mL与治疗失败无关。依法韦仑浓度高于4000ng/mL与中枢神经系统副作用（p<0.001）和肝毒性（p<0.001）风险较高相关。
结论
体重和抗结核治疗与依法韦仑低浓度或治疗失败无关，支持HIV-结核合并感染患者每日服用600mg依法韦仑。依法韦仑高浓度与中枢神经系统副作用和肝毒性风险较高相关。
试验注册
ClinicalTrials.gov NCT01300481
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