抗病毒药改换用途用于治疗COVID-19——WHO Solidarity试验的期中结果
Repurposed Antiviral Drugs for Covid-19 — Interim WHO Solidarity Trial Results
背景
世界卫生组织专家组建议开展试验将4种抗病毒药（瑞德西韦、羟氯喹、洛匹那韦和干扰素β-1a）改换用途用于COVID-19住院患者，评估其对死亡率的影响。World Health Organization expert groups recommended mortality trials of four repurposed antiviral drugs — remdesivir, hydroxychloroquine, lopinavir, and interferon beta-1a — in patients hospitalized with coronavirus disease 2019 (Covid-19).方法
我们将COVID-19住院患者随机分组（均分），分别接受一种当地有的试验药物治疗和开放式对照治疗（多达5种可选方案，4种活性药物和当地标准治疗）。意向治疗主要分析在每种试验药物与其对照（有药物，但患者接受的是其他方面相同，但不包含该药物的治疗方案）的4项配对比较中研究了院内死亡率。我们根据患者年龄和进入试验时的机械通气状态分层并计算了死亡率比。We randomly assigned inpatients with Covid-19 equally between one of the trial drug regimens that was locally available and open control (up to five options, four active and the local standard of care). The intention-to-treat primary analyses examined in-hospital mortality in the four pairwise comparisons of each trial drug and its control (drug available but patient assigned to the same care without that drug). Rate ratios for death were calculated with stratification according to age and status regarding mechanical ventilation at trial entry.结果
11,330例成人患者在30个国家的405家医院接受了随机分组；2750例被分配接受瑞德西韦，954例接受羟氯喹，1411例接受洛匹那韦（不联用干扰素），2063例接受干扰素（包括接受干扰素+洛匹那韦的651例），4088例未接受试验药物治疗。期中治疗依从率为94%~96%，跨组率为2%~6%。试验共计报告了1253例死亡（死亡日的中位数，第8日；四分位距，4~14）。Kaplan-Meier 28日死亡率为11.8%（在随机分组时已接受通气治疗和未接受通气治疗的患者中，分别为39.0%和9.5%）。在接受各种治疗的患者中，死亡人数如下：接受瑞德西韦治疗的2743例患者中的301例和接受其对照治疗的2708例患者中的303例（率比，0.95；95%置信区间[CI]，0.81~1.11；P=0.50）、接受羟氯喹治疗的947例患者中的104例和接受其对照治疗的906例患者中的84例（率比，1.19；95% CI，0.89~1.59；P=0.23）、接受洛匹那韦治疗的1399例患者中的148例和接受其对照治疗的1372例患者中的146例（率比，1.00；95% CI，0.79~1.25；P=0.97）以及接受干扰素治疗的2050例患者中的243例和接受其对照治疗的2050例患者中的216例（率比，1.16；95% CI，0.96~1.39；P=0.11）。在总体患者和各亚组中，所有药物均未明确降低死亡率，也未减少通气治疗的启动或缩短住院时间。
Result
At 405 hospitals in 30 countries, 11,330 adults underwent randomization; 2750 were assigned to receive remdesivir, 954 to hydroxychloroquine, 1411 to lopinavir (without interferon), 2063 to interferon (including 651 to interferon plus lopinavir), and 4088 to no trial drug. Adherence was 94 to 96% midway through treatment, with 2 to 6% crossover. In total, 1253 deaths were reported (median day of death, day 8; interquartile range, 4 to 14). The Kaplan–Meier 28-day mortality was 11.8% (39.0% if the patient was already receiving ventilation at randomization and 9.5% otherwise). Death occurred in 301 of 2743 patients receiving remdesivir and in 303 of 2708 receiving its control (rate ratio, 0.95; 95% confidence interval [CI], 0.81 to 1.11; P=0.50), in 104 of 947 patients receiving hydroxychloroquine and in 84 of 906 receiving its control (rate ratio, 1.19; 95% CI, 0.89 to 1.59; P=0.23), in 148 of 1399 patients receiving lopinavir and in 146 of 1372 receiving its control (rate ratio, 1.00; 95% CI, 0.79 to 1.25; P=0.97), and in 243 of 2050 patients receiving interferon and in 216 of 2050 receiving its control (rate ratio, 1.16; 95% CI, 0.96 to 1.39; P=0.11). No drug definitely reduced mortality, overall or in any subgroup, or reduced initiation of ventilation or hospitalization duration.
结论
根据总死亡率、启动通气治疗的情况和住院时间，瑞德西韦、羟氯喹、洛匹那韦和干扰素治疗方案对COVID-19住院患者效应极小或无效应。（由世界卫生组织资助；在ISRCTN注册号为ISRCTN83971151；在ClinicalTrials.gov注册号为NCT04315948。）
Conclusions
These remdesivir, hydroxychloroquine, lopinavir, and interferon regimens had little or no effect on hospitalized patients with Covid-19, as indicated by overall mortality, initiation of ventilation, and duration of hospital stay. (Funded by the World Health Organization; ISRCTN Registry number, ISRCTN83971151; ClinicalTrials.gov number, NCT04315948.)
WHO Solidarity Trial Consortium. Repurposed Antiviral Drugs for Covid-19 — Interim WHO Solidarity Trial Results. DOI: 10.1056/NEJMoa2023184
NEJM医学前沿瑞德西韦治疗COVID-19的最终报告小程序
tirbanibulin软膏治疗光线性角化病的3期试验
Phase 3 Trials of Tirbanibulin Ointment for Actinic Keratosis
背景
目前正开展研究将微管蛋白聚合和Src激酶信号抑制剂tibanibulin用于光线性角化病（鳞状细胞癌的癌前病变）的外用药治疗。
The tubulin polymerization and Src kinase signaling inhibitor tirbanibulin is being investigated as a topical treatment for actinic keratosis, a precursor of squamous-cell carcinoma.方法
在两项设计相同的双盲试验中，我们以1:1的比例将面部或头皮患光线性角化病的成人患者随机分组，两组分别接受tirbanibulin或溶媒（安慰剂）软膏外用药治疗。患者将软膏涂到涵盖4~8块皮损的25 cm2相连区域，每日1次，连续用药5日。主要结局是第57日时，涂药区域内皮损数量完全（100%）减少的患者百分比。次要结局是第57日时，涂药区域内皮损数量部分（≥75%）减少的患者百分比。我们评估了1年时的复发率。并且利用4分量表（范围为0[无]至3分[重度]）对局部反应进行了评分。
In two identically designed double-blind trials, we randomly assigned, in a 1:1 ratio, adults with actinic keratoses on the face or scalp to receive either topical tirbanibulin or vehicle (placebo) ointment. The ointment was applied by the patients to a 25-cm2 contiguous area containing four to eight lesions once daily for 5 consecutive days. The primary outcome was the percentage of patients with a complete (100%) reduction in the number of lesions in the application area at day 57. The secondary outcome was the percentage of patients with a partial (≥75%) reduction in the number of lesions within the application area at day 57. The incidence of recurrence was evaluated at 1 year. Local reactions were scored with the use of 4-point scale (ranging from 0 [absent] to 3 [severe]).
结果
共计702例患者被纳入两项试验（每项试验351例患者）。在试验1中，tirbanibulin组44%的患者（77/175）和溶媒组5%的患者（8/176）实现皮损完全清除（差异，40个百分点；95%置信区间[CI]，32~47；P<0.001）；在试验2中，两组分别有54%（97/178例患者）和13%（22/173）的患者实现皮损完全清除（差异，42个百分点；95% CI，33~51；P<0.001）。tirbanibulin组中实现皮损部分清除的患者百分比高于溶媒组。1年时，在之前对tirbanibulin产生完全应答的患者中，皮损复发率为47%。tirbanibulin最常见的局部反应为红斑（91%的患者）以及脱皮或鳞屑（82%）。tirbanibulin的不良事件包括用药部位疼痛（10%的患者）和瘙痒（9%），所有这些不良事件均消退。
Result
A total of 702 patients were enrolled in the two trials (351 patients per trial). Complete clearance in trial 1 occurred in 44% of the patients (77 of 175) in the tirbanibulin group and in 5% of those (8 of 176) in the vehicle group (difference, 40 percentage points; 95% confidence interval [CI], 32 to 47; P<0.001); in trial 2, the percentages were 54% (97 of 178 patients) and 13% (22 of 173), respectively (difference, 42 percentage points; 95% CI, 33 to 51; P<0.001). The percentages of patients with partial clearance were significantly higher in the tirbanibulin groups than in the vehicle groups. At 1 year, the estimated percentage of patients with recurrent lesions was 47% among patients who had had a complete response to tirbanibulin. The most common local reactions to tirbanibulin were erythema in 91% of the patients and flaking or scaling in 82%. Adverse events with tirbanibulin were application-site pain in 10% of the patients and pruritus in 9%, all of which resolved.结论
在两项设计相同的试验中，在2个月时，tirbanibulin 1%软膏（每日1次，连续用药5日）对光线性角化病的治疗效果优于溶媒，但与一过性的局部反应和1年时的皮损复发相关。我们需要开展比较tirbanibulin和常规治疗以及随访时间较长的试验，从而确定tirbanibulin对光线性角化病的疗效。（由Athenex资助；在ClinicalTrials.gov注册号为NCT03285477和NCT03285490。）
Conclusions
In two identically designed trials, tirbanibulin 1% ointment applied once daily for 5 days was superior to vehicle for the treatment of actinic keratosis at 2 months but was associated with transient local reactions and recurrence of lesions at 1 year. Trials comparing tirbanibulin with conventional treatments and that have longer follow-up are needed to determine the effects of tirbanibulin therapy on actinic keratosis. (Funded by Athenex; ClinicalTrials.gov numbers, NCT03285477 and NCT03285490.)Andrew Blauvelt, Steven Kempers, Edward Lain, et al. Phase 3 Trials of Tirbanibulin Ointment for Actinic Keratosis. DOI: 10.1056/NEJMoa2024040
患者植入前庭植入装置后的姿势、步态、生活质量和听力
Posture, Gait, Quality of Life, and Hearing with a Vestibular Implant
背景
双耳前庭功能低下与慢性平衡障碍、姿势不稳和步态不稳相关，其原因是对眼睛、头部和身体具有稳定作用的前庭反射发生障碍。前庭植入装置可能可以有效缓解症状。
Bilateral vestibular hypofunction is associated with chronic disequilibrium, postural instability, and unsteady gait owing to failure of vestibular reflexes that stabilize the eyes, head, and body. A vestibular implant may be effective in alleviating symptoms.方法
患耳毒性（7例参与者）或特发性（1例参与者）双耳前庭功能低下2~23年的患者在单侧植入了人工前庭，该装置可对前庭神经的三个半规管分支产生电刺激。临床结局包括Bruininks-Oseretsky动作熟练度测试（Bruininks-Oseretsky Test of Motor Proficiency）平衡子测试评分（范围，0~36分，评分较高表示平衡能力较好）、改良Romberg测试失败的时间（范围，0~20秒）、动态步态指数（Dynamic Gait Index）评分（范围，0~24分，评分较高表示步态表现较好）、完成起立行走计时测试（Timed Up and Go test）所需的时间、步行速度、纯音听阈、言语识别率得分和生活质量。我们比较了基线（植入前）、6个月（8例参与者）和1年时（6例参与者）参与者的结果，装置设定为常规治疗模式（采用变化的刺激脉冲频率和幅度来代表头部转动）和安慰剂模式（脉冲频率和幅度保持恒定）。
Persons who had had ototoxic (7 participants) or idiopathic (1 participant) bilateral vestibular hypofunction for 2 to 23 years underwent unilateral implantation of a prosthesis that electrically stimulates the three semicircular canal branches of the vestibular nerve. Clinical outcomes included the score on the Bruininks–Oseretsky Test of Motor Proficiency balance subtest (range, 0 to 36, with higher scores indicating better balance), time to failure on the modified Romberg test (range, 0 to 30 seconds), score on the Dynamic Gait Index (range, 0 to 24, with higher scores indicating better gait performance), time needed to complete the Timed Up and Go test, gait speed, pure-tone auditory detection thresholds, speech discrimination scores, and quality of life. We compared participants’ results at baseline (before implantation) with those at 6 months (8 participants) and at 1 year (6 participants) with the device set in its usual treatment mode (varying stimulus pulse rate and amplitude to represent rotational head motion) and in a placebo mode (holding pulse rate and amplitude constant).结果
基线时和6个月时，Bruininks-Oseretsky测试的中位评分分别为17.5分和21.0分（中位参与者自身差异，5.5分；95%置信区间[CI]，0~10.0）；改良Romberg测试的中位时间分别为3.6秒和8.3秒（差异，5.1；95% CI，1.5~27.6）；动态步态指数的中位评分分别为12.5分和22.5分（差异，10.5分；95% CI，1.5~12.0）；起立行走计时测试的中位时间分别为11.0秒和8.7秒（差异，2.3；95% CI，-1.7~5.0）；步行速度测试的中位速度分别为1.03 m/s和1.10 m/s（差异，0.13；95% CI，-0.25~0.30）。安慰剂模式测试证实，改善是由治疗模式刺激引起。在1年时也接受了评估的6例参与者中，从基线至1年的中位参与者自身变化通常与6个月时的结果一致。装置植入引起了同侧听力损失，6个月时，5例参与者的纯音气导平均听阈提高了3~16 dB，3例参与者提高了74~104 dB。参与者报告的失能和生活质量变化情况与姿势和步态变化情况一致。
Result
The median scores at baseline and at 6 months on the Bruininks–Oseretsky test were 17.5 and 21.0, respectively (median within-participant difference, 5.5 points; 95% confidence interval [CI], 0 to 10.0); the median times on the modified Romberg test were 3.6 seconds and 8.3 seconds (difference, 5.1; 95% CI, 1.5 to 27.6); the median scores on the Dynamic Gait Index were 12.5 and 22.5 (difference, 10.5 points; 95% CI, 1.5 to 12.0); the median times on the Timed Up and Go test were 11.0 seconds and 8.7 seconds (difference, 2.3; 95% CI, −1.7 to 5.0); and the median speeds on the gait-speed test were 1.03 m per second and 1.10 m per second (difference, 0.13; 95% CI, −0.25 to 0.30). Placebo-mode testing confirmed that improvements were due to treatment-mode stimulation. Among the 6 participants who were also assessed at 1 year, the median within-participant changes from baseline to 1 year were generally consistent with results at 6 months. Implantation caused ipsilateral hearing loss, with the air-conducted pure-tone average detection threshold at 6 months increasing by 3 to 16 dB in 5 participants and by 74 to 104 dB in 3 participants. Changes in participant-reported disability and quality of life paralleled changes in posture and gait.
结论
因双耳前庭功能低下而在单侧植入人工前庭后6个月和1年时，姿势、步态和生活质量指标相对于基线一般有所改善，但除1例参与者之外，其他所有参与者植入人工前庭的一侧耳出现听力下降。（由美国国立卫生研究院等资助；在ClinicalTrials.gov注册号为NCT02725463。）
Conclusions
Six months and 1 year after unilateral implantation of a vestibular prosthesis for bilateral vestibular hypofunction, measures of posture, gait, and quality of life were generally in the direction of improvement from baseline, but hearing was reduced in the ear with the implant in all but 1 participant. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT02725463.)Margaret R. Chow, Andrianna I. Ayiotis, Desi P. Schoo, et al. Posture, Gait, Quality of Life, and Hearing with a Vestibular Implant. DOI: 10.1056/NEJMoa2020457
医护人员的SARS-CoV-2抗体状态和感染率
Antibody Status and Incidence of SARS-CoV-2 Infection in Health Care Workers
背景
SARS-CoV-2抗体阳性与之后的再次感染风险之间的关系尚不明确。
The relationship between the presence of antibodies to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the risk of subsequent reinfection remains unclear.方法
此项研究在参与英国牛津大学医院无症状和有症状工作人员检测的血清反应阳性的和血清反应阴性医护人员中评估了通过聚合酶链反应（PCR）确诊的SARS-CoV-2感染率。基线抗体状态通过抗刺突蛋白（主要分析）和抗核壳IgG检测法确定；本研究对医护人员进行了长达31周随访。针对年龄、参与者报告的性别和随时间推移的发生率变化进行校正后，我们估算了不同抗体状态下，PCR阳性检测结果和新发有症状感染的相对发生率。
We investigated the incidence of SARS-CoV-2 infection confirmed by polymerase chain reaction (PCR) in seropositive and seronegative health care workers attending testing of asymptomatic and symptomatic staff at Oxford University Hospitals in the United Kingdom. Baseline antibody status was determined by anti-spike (primary analysis) and anti-nucleocapsid IgG assays, and staff members were followed for up to 31 weeks. We estimated the relative incidence of PCR-positive test results and new symptomatic infection according to antibody status, adjusting for age, participant-reported gender, and changes in incidence over time.结果
共计12,541名医护人员参与研究并接受了抗刺突蛋白IgG测定；11,364名在抗体结果呈阳性后接受了随访，1265名在抗体结果呈阳性后接受了随访，包括在随访期间血清转阳的88人。223名抗刺突蛋白血清反应阴性的医护人员的PCR检测结果呈阳性（1.09例/10,000风险日），100名是在筛查期间无症状的情况下发现，123名是在有症状的情况下发现；2名抗刺突蛋白血清反应阳性的医护人员的PCR检测结果呈阳性（0.13例/10,000风险日），而且这两名医护人员在检测时均无症状（校正后的发生率比，0.11；95%置信区间，0.03~0.44；P=0.002）。抗刺突蛋白抗体阳性的医护人员均未发生有症状的感染。不论是单独使用抗核壳IgG检测法确定基线状态，还是结合使用抗核壳IgG检测法与抗刺突蛋白IgG检测法确定基线状态，我们获得的发生率比均相似。
Result
A total of 12,541 health care workers participated and had anti-spike IgG measured; 11,364 were followed up after negative antibody results and 1265 after positive results, including 88 in whom seroconversion occurred during follow-up. A total of 223 anti-spike–seronegative health care workers had a positive PCR test (1.09 per 10,000 days at risk), 100 during screening while they were asymptomatic and 123 while symptomatic, whereas 2 anti-spike–seropositive health care workers had a positive PCR test (0.13 per 10,000 days at risk), and both workers were asymptomatic when tested (adjusted incidence rate ratio, 0.11; 95% confidence interval, 0.03 to 0.44; P=0.002). There were no symptomatic infections in workers with anti-spike antibodies. Rate ratios were similar when the anti-nucleocapsid IgG assay was used alone or in combination with the anti-spike IgG assay to determine baseline status.
结论
抗刺突蛋白或抗核壳IgG抗体阳性与之后6个月期间SARS-CoV-2的再次感染风险显著降低相关。（由英国保健及社会服务署[U.K. Government Department of Health and Social Care]等资助。）
Conclusions
The presence of anti-spike or anti-nucleocapsid IgG antibodies was associated with a substantially reduced risk of SARS-CoV-2 reinfection in the ensuing 6 months. (Funded by the U.K. Government Department of Health and Social Care and others.)
Sheila F. Lumley, Denise O’Donnell, Nicole E. Stoesser, et al. Antibody Status and Incidence of SARS-CoV-2 Infection in Health Care Workers. DOI: 10.1056/NEJMoa2034545
预防慢性HCV感染的疫苗方案的随机试验
Randomized Trial of a Vaccine Regimen to Prevent Chronic HCV Infection
背景
可预防慢性丙型肝炎病毒（HCV）感染的安全有效疫苗是该疾病消除工作中的关键组成部分。
A safe and effective vaccine to prevent chronic hepatitis C virus (HCV) infection is a critical component of efforts to eliminate the disease.方法
在此项1-2期随机、双盲、安慰剂对照试验中，我们评估了重组黑猩猩腺病毒3载体初免和之后的重组改良型痘苗病毒安卡拉株加强，两种疫苗均编码HCV非结构蛋白。我们（以1:1的比例）将近期曾注射吸毒，因而有HCV感染风险的成人随机分组，两组分别接种疫苗或安慰剂（第0日和第56日）。与疫苗相关的严重不良事件、重度局部或全身性不良事件和实验室不良事件是主要安全性终点。主要疗效终点是慢性HCV感染（定义为持续≥6个月的病毒血症）。
In this phase 1–2 randomized, double-blind, placebo-controlled trial, we evaluated a recombinant chimpanzee adenovirus 3 vector priming vaccination followed by a recombinant modified vaccinia Ankara boost; both vaccines encode HCV nonstructural proteins. Adults who were considered to be at risk for HCV infection on the basis of a history of recent injection drug use were randomly assigned (in a 1:1 ratio) to receive vaccine or placebo on days 0 and 56. Vaccine-related serious adverse events, severe local or systemic adverse events, and laboratory adverse events were the primary safety end points. The primary efficacy end point was chronic HCV infection, defined as persistent viremia for 6 months.结果
共计548例参与者接受了随机分组，每组274例。两组的慢性HCV感染率无显著差异。在符合方案人群中，两组各有14例参与者发生了慢性HCV感染（风险比[疫苗vs.安慰剂]，1.53；95%置信区间[CI]，0.66~3.55；疫苗效力，-53%；95% CI，-255~34）。在改良意向治疗人群中，疫苗组19例参与者和安慰剂组17例参与者发生了慢性HCV感染（风险比，1.66；95% CI，0.79~3.50；疫苗效力，-66%；95% CI，-250~21）。在疫苗组和安慰剂组中，感染后的峰值HCV RNA水平的几何均值有差异（分别为152.51×103 IU/mL和1804.93×103 IU/mL）。本试验在疫苗组78%的参与者体内检测到对HCV的T细胞应答。两组发生严重不良事件的参与者百分比相似。
Result
A total of 548 participants underwent randomization, with 274 assigned to each group. There was no significant difference in the incidence of chronic HCV infection between the groups. In the per-protocol population, chronic HCV infection developed in 14 participants in each group (hazard ratio [vaccine vs. placebo], 1.53; 95% confidence interval [CI], 0.66 to 3.55; vaccine efficacy, −53%; 95% CI, −255 to 34). In the modified intention-to-treat population, chronic HCV infection developed in 19 participants in the vaccine group and 17 in placebo group (hazard ratio, 1.66; 95% CI, 0.79 to 3.50; vaccine efficacy, −66%; 95% CI, −250 to 21). The geometric mean peak HCV RNA level after infection differed between the vaccine group and the placebo group (152.51×103 IU per milliliter and 1804.93×103 IU per milliliter, respectively). T-cell responses to HCV were detected in 78% of the participants in the vaccine group. The percentages of participants with serious adverse events were similar in the two groups.
结论
在本试验中，HCV疫苗未导致严重不良事件，产生了HCV特异性T细胞应答，并且降低了峰值HCV RNA水平，但未能预防慢性HCV感染。（由美国国立过敏和传染病研究所[National Institute of Allergy and Infectious Diseases]资助；在ClinicalTrials.gov注册号为NCT01436357。）
Conclusions
In this trial, the HCV vaccine regimen did not cause serious adverse events, produced HCV-specific T-cell responses, and lowered the peak HCV RNA level, but it did not prevent chronic HCV infection. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT01436357.)Kimberly Page, Michael T. Melia, Rebecca T. Veenhuis, et al. Randomized Trial of a Vaccine Regimen to Prevent Chronic HCV Infection. DOI: 10.1056/ NEJMoa 2023345
