Inserm CIC 007, APHP, Hôpital Bichat, Paris, France.
PLoS Med. 2010 Nov 2;7(11):e1000362. doi: 10.1371/journal.pmed.1000362.
Neuraminidase inhibitors are thought to be efficacious in reducing the time to alleviation of symptoms in outpatients with seasonal influenza. The objective of this study was to compare the short-term virological efficacy of oseltamivir-zanamivir combination versus each monotherapy plus placebo.
We conducted a randomized placebo-controlled trial with 145 general practitioners throughout France during the 2008-2009 seasonal influenza epidemic. Patients, general practitioners, and outcome assessors were all blinded to treatment assignment. Adult outpatients presenting influenza-like illness for less than 36 hours and a positive influenza A rapid test diagnosis were randomized to oseltamivir 75 mg orally twice daily plus zanamivir 10 mg by inhalation twice daily (OZ), oseltamivir plus inhaled placebo (O), or zanamivir plus oral placebo (Z). Treatment efficacy was assessed virologically according to the proportion of patients with nasal influenza reverse transcription (RT)-PCR below 200 copies genome equivalent (cgeq)/µl at day 2 (primary outcome), and clinically to the time to alleviation of symptoms until day 14. Overall 541 patients (of the 900 planned) were included (OZ, =192; O, n=176; Z, n=173), 49% male, mean age 39 years. In the intention-to-treat analysis conducted in the 447 patients with RT-PCR-confirmed influenza A, 46%, 59%, and 34% in OZ (n=157), O (n=141), and Z (n=149) arms had RT-PCR<200 cgeq/µl (-13.0%, 95% confidence interval [CI] -23.1 to -2.9, p=0.025; +12.3%, 95% CI 2.39-22.2, p=0.028 for OZ/O and OZ/Z comparisons). Mean day 0 to day 2 viral load decrease was 2.14, 2.49, and 1.68 log(10) cgeq/µl (p=0.060, p=0.016 for OZ/O and OZ/Z). Median time to alleviation of symptoms was 4.0, 3.0, and 4.0 days (+1.0, 95% CI 0.0-4.0, p=0.018; +0.0, 95% CI -3.0 to 3.0, p=0.960 for OZ/O and OZ/Z). Four severe adverse events were observed. Nausea and/or vomiting tended to be more frequent in the combination arm (OZ, n=13; O, n=4; and Z, n=5 patients, respectively).
In adults with seasonal influenza A mainly H3N2 virus infection, the oseltamivir-zanamivir combination appeared less effective than oseltamivir monotherapy, and not significantly more effective than zanamivir monotherapy. Despite the theoretical potential for the reduction of the emergence of antiviral resistance, the lower effectiveness of this combination calls for caution in its use in clinical practice.
神经氨酸酶抑制剂被认为可以有效缩短季节性流感患者症状缓解的时间。本研究旨在比较奥司他韦-扎那米韦联合治疗与单药治疗加安慰剂的短期病毒学疗效。
我们在法国各地的 145 位全科医生中进行了一项随机、安慰剂对照试验，在 2008-2009 年季节性流感流行期间进行。患者、全科医生和结果评估者均对治疗分配情况不知情。出现症状不足 36 小时且流感 A 快速检测呈阳性的成年门诊患者随机接受奥司他韦 75 mg 口服，每日 2 次，联合扎那米韦 10 mg 吸入，每日 2 次（OZ）、奥司他韦加吸入安慰剂（O）或扎那米韦加口服安慰剂（Z）。根据第 2 天鼻内流感逆转录（RT）-PCR 低于 200 个基因组当量（cgeq）/µl 的患者比例评估治疗效果（主要终点），并在第 14 天之前评估临床症状缓解时间。共有 541 名患者（计划 900 名中的）入选（OZ，n=192；O，n=176；Z，n=173），其中 49%为男性，平均年龄 39 岁。在对 RT-PCR 确诊的甲型流感患者（n=447）进行的意向治疗分析中，OZ（n=157）、O（n=141）和 Z（n=149）组分别有 46%、59%和 34%的患者 RT-PCR<200 cgeq/µl（-13.0%，95%置信区间[CI] -23.1 至 -2.9，p=0.025；+12.3%，95% CI 2.39-22.2，p=0.028，OZ/O 和 OZ/Z 比较）。第 0 天至第 2 天的平均病毒载量下降分别为 2.14、2.49 和 1.68 log(10) cgeq/µl（p=0.060，p=0.016，OZ/O 和 OZ/Z 比较）。症状缓解的中位时间分别为 4.0、3.0 和 4.0 天（+1.0，95% CI 0.0-4.0，p=0.018；+0.0，95% CI -3.0 至 3.0，p=0.960，OZ/O 和 OZ/Z 比较）。共观察到 4 例严重不良事件。联合组（OZ，n=13；O，n=4；和 Z，n=5 名患者）中恶心和/或呕吐的发生率较高。
在甲型季节性流感 A 病毒感染的成年患者中，奥司他韦-扎那米韦联合治疗的效果不如奥司他韦单药治疗，也不比扎那米韦单药治疗更有效。尽管这种联合治疗在减少抗病毒耐药性出现方面具有理论上的潜力，但这种联合治疗效果较低，因此在临床实践中使用时需要谨慎。
