贝达喹啉-普托马尼德-利奈唑胺方案治疗耐药结核病。
Bedaquiline-Pretomanid-Linezolid Regimens for Drug-Resistant Tuberculosis.
机构信息
From the Clinical HIV Research Unit (F.C., P.H.) and Klerksdorp-Tshepong Hospital Complex, Department of Internal Medicine (E.V.), Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, the Clinical HIV Research Unit, King DinuZulu Hospital, Durban (N.N.), and the TB Alliance, Pretoria (M.O.) - all in South Africa; the Central TB Research Institute of the Federal Agency of Scientific Organizations Moscow (T.R.B.), Moscow City Research and Practice Tuberculosis Treatment Center (S.B.), and National Medical Research Center of Phthisiopulmonology and Infectious Diseases (A.S.), Moscow, Ural Research Institute of Phthisiopulmonology, Yekaterinburg (S.S.), and St. Petersburg Research Institute of Phthisiopulmonology, St. Petersburg (P.Y.) - all in Russia; the National Center for Tuberculosis and Lung Disease, Tbilisi, Georgia (L.M.); the Chiril Draganiuc Institute of Phthisiopneumology, Chisinau, Moldova (E.T.); the TB Alliance, New York (D.E., E.S., E.E., M.L., A.H., J.T., S.F., C.M.M., M.S.); and the Medical Research Council Clinical Trials Unit at University College London (G.H.W., A.M.C., S.M.F., C.D.T.) and the University College London Centre for Clinical Microbiology (A.B., R.H., T.D.M.), University College London, London.
出版信息
N Engl J Med. 2022 Sep 1;387(9):810-823. doi: 10.1056/NEJMoa2119430.
BACKGROUND
The bedaquiline-pretomanid-linezolid regimen has been reported to have 90% efficacy against highly drug-resistant tuberculosis, but the incidence of adverse events with 1200 mg of linezolid daily has been high. The appropriate dose of linezolid and duration of treatment with this agent to minimize toxic effects while maintaining efficacy against highly drug-resistant tuberculosis are unclear.
METHODS
We enrolled participants with extensively drug-resistant (XDR) tuberculosis (i.e., resistant to rifampin, a fluoroquinolone, and an aminoglycoside), pre-XDR tuberculosis (i.e., resistant to rifampin and to either a fluoroquinolone or an aminoglycoside), or rifampin-resistant tuberculosis that was not responsive to treatment or for which a second-line regimen had been discontinued because of side effects. We randomly assigned the participants to receive bedaquiline for 26 weeks (200 mg daily for 8 weeks, then 100 mg daily for 18 weeks), pretomanid (200 mg daily for 26 weeks), and daily linezolid at a dose of 1200 mg for 26 weeks or 9 weeks or 600 mg for 26 weeks or 9 weeks. The primary end point in the modified intention-to-treat population was the incidence of an unfavorable outcome, defined as treatment failure or disease relapse (clinical or bacteriologic) at 26 weeks after completion of treatment. Safety was also evaluated.
RESULTS
A total of 181 participants were enrolled, 88% of whom had XDR or pre-XDR tuberculosis. Among participants who received bedaquiline-pretomanid-linezolid with linezolid at a dose of 1200 mg for 26 weeks or 9 weeks or 600 mg for 26 weeks or 9 weeks, 93%, 89%, 91%, and 84%, respectively, had a favorable outcome; peripheral neuropathy occurred in 38%, 24%, 24%, and 13%, respectively; myelosuppression occurred in 22%, 15%, 2%, and 7%, respectively; and the linezolid dose was modified (i.e., interrupted, reduced, or discontinued) in 51%, 30%, 13%, and 13%, respectively. Optic neuropathy developed in 4 participants (9%) who had received linezolid at a dose of 1200 mg for 26 weeks; all the cases resolved. Six of the seven unfavorable microbiologic outcomes through 78 weeks of follow-up occurred in participants assigned to the 9-week linezolid groups.
CONCLUSIONS
A total of 84 to 93% of the participants across all four bedaquiline-pretomanid-linezolid treatment groups had a favorable outcome. The overall risk-benefit ratio favored the group that received the three-drug regimen with linezolid at a dose of 600 mg for 26 weeks, with a lower incidence of adverse events reported and fewer linezolid dose modifications. (Funded by the TB Alliance and others; ZeNix ClinicalTrials.gov number, NCT03086486.).
背景
贝达喹啉-普托马尼德-利奈唑胺方案已被报道对高度耐药性结核病有 90%的疗效，但每天使用 1200 毫克利奈唑胺的不良反应发生率较高。为了在保持对高度耐药性结核病的疗效的同时，将该药物的毒性作用最小化，利奈唑胺的适当剂量和治疗持续时间尚不清楚。
方法
我们招募了广泛耐药性（XDR）结核病（即对利福平、氟喹诺酮类和氨基糖苷类药物耐药）、预广泛耐药性（即对利福平以及氟喹诺酮类或氨基糖苷类药物耐药）或对治疗无反应或因不良反应而停用二线方案的耐利福平的结核病患者。我们将参与者随机分配接受贝达喹啉治疗 26 周（8 周每天 200mg，然后 18 周每天 100mg）、普托马尼德（26 周每天 200mg）和每天 1200mg 利奈唑胺治疗 26 周或 9 周或 600mg 利奈唑胺治疗 26 周或 9 周。改良意向治疗人群的主要终点是不良结局的发生率，定义为治疗结束后 26 周时治疗失败或疾病复发（临床或细菌学）。安全性也进行了评估。
结果
共有 181 名参与者入组，其中 88%患有 XDR 或预 XDR 结核病。在接受贝达喹啉-普托马尼德-利奈唑胺联合利奈唑胺治疗的参与者中，每天 1200mg 治疗 26 周或 9 周、每天 600mg 治疗 26 周或 9 周的参与者中，分别有 93%、89%、91%和 84%的人有良好的结局；周围神经病变分别发生在 38%、24%、24%和 13%的参与者中；骨髓抑制分别发生在 22%、15%、2%和 7%的参与者中；分别有 51%、30%、13%和 13%的人调整了利奈唑胺剂量（即中断、减少或停止）；视神经病变在接受 1200mg 利奈唑胺治疗 26 周的 4 名（9%）参与者中发生；所有病例均已解决。在接受 9 周利奈唑胺治疗的参与者中，有 6 例（7%）的 78 周随访期间的不良微生物学结局。
结论
在所有四个贝达喹啉-普托马尼德-利奈唑胺治疗组中，有 84%至 93%的参与者有良好的结局。总的来说，风险效益比倾向于接受利奈唑胺剂量为 600mg 治疗 26 周的三联方案的组，不良反应发生率较低，利奈唑胺剂量调整较少。（由 TB 联盟和其他机构资助；ZeNix ClinicalTrials.gov 编号，NCT03086486。）
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