近日，美国布朗大学Edward D. Huey团队研究了伐昔洛韦治疗早期症状性阿尔茨海默病的疗效与安全性。2025年12月17日，《美国医学会杂志》发表了这一成果。

神经科学、流行病学和电子健康记录研究表明单纯疱疹病毒（HSV）是阿尔茨海默病（AD）的潜在病因。

为了比较缬昔洛韦与安慰剂在早期症状性AD和HSV血清阳性（HSV-1或HSV-2）患者中的疗效和不良反应，研究组进行了一项随机临床试验，纳入了临床诊断可能为阿尔茨海默病或临床诊断为轻度认知障碍、阿尔茨海默病生物标志物阳性、HSV-1或HSV-2血清抗体检测（IgG或IgM）阳性、迷你精神状态检查得分在18至28分之间的成年人。该试验在美国3家专门研究记忆障碍的门诊诊所进行。招募时间为2018年1月至2022年5月；最后一次随访发生在2024年9月。将120例患者随机分为两组，分别接受4克/天的伐昔洛韦（n = 60) 或匹配安慰剂（n = 60)。

主要结局是阿尔茨海默病评估量表认知（ADAS认知）子量表11项评分（范围为0-70；评分越高表示损伤越大）在78周时的最小二乘平均值（LSM）变化。次要结局是阿尔茨海默病合作研究-日常生活活动量表（ADCS-ADL）评分中的LSM变化；6个脑区（内侧眶额叶、前扣带、顶叶、后扣带、颞叶和楔前叶）¹⁸F-florbetapir淀粉样蛋白正电子发射断层扫描（PET）标准化摄取值比（SUVR；得分越高表示淀粉样蛋白水平越高）的LSM变化；以及4个脑区（杏仁核、海马、内嗅和海马旁）18F-MK-6240 tau PET内侧颞侧SUVR的LSM变化（得分越高表示tau水平越高）。不良事件的频率是安全性结果。

在120名参与者（平均年龄71.4 [SD， 8.6]岁，55%为女性）中，93名（77.5%）完成了试验。78周时，伐昔洛韦组11项ADAS-Cognitive Subscale评分的LSM变化为10.86 (95% CI, 8.80 - 12.91)，而安慰剂组为6.92 (95% CI, 4.88 - 8.97)，表明伐昔洛韦组的认知恶化程度大于安慰剂组（组间差异为3.93;P = 0.01）。78周时，伐昔洛韦组ADCS-ADL量表评分的LSM变化为13.78 (95% CI, 17.00 - 10.56)，安慰剂组为10.16 (95% CI, 13.37 - 6.96)（组间差异为3.62）。78周时，伐昔洛韦组¹⁸F-florbetapir淀粉样PET SUVR的LSM变化为0.03 (95% CI， 0.04至0.10)，安慰剂组为0.01 (95% CI， 0.06至0.08)（组间差异为0.02）。78周时，伐昔洛韦组¹⁸F-MK-6240 tau PET内侧颞叶SUVR的LSM变化为0.07 (95% CI, - 0.06至0.19)，安慰剂组为0.04 (95% CI, - 0.15至0.07)（组间差异为0.11）。最常见的不良事件是血清肌酐水平升高（valacyclovir组5例[8.3%]vs安慰剂组2例[3.3%]）和COVID-19感染（分别为3例[5%]vs 2例[3.3%]）。

研究结果表明，伐昔洛韦对认知恶化的主要结果无效，不推荐用于治疗早期症状性AD和HSV血清阳性的个体。

附：英文原文

Title: Valacyclovir Treatment of Early Symptomatic Alzheimer Disease: The VALAD Randomized Clinical Trial

Author: D. P. Devanand, Thomas Wisniewski, Qolamreza Razlighi, Min Qian, Renjie Wei, Howard F. Andrews, Edward P. Acosta, Karen L. Bell, Gregory H. Pelton, Deborah Deliyannides, Allison C. Perrin, Elise Caccappolo, Anne A. Gershon, K. M. Prasad, William C. Kreisl, Akiva Mintz, Edward D. Huey

Issue&Volume: 2025-12-17

Abstract:

Importance  Neuroscientific, epidemiological, and electronic health record studies implicate herpes simplex virus (HSV) as potentially etiological for Alzheimer disease (AD).

Objective  To compare the efficacy and adverse effects of valacyclovir vs placebo in participants with early symptomatic AD and HSV seropositivity (HSV-1 or HSV-2).

Design, Setting, and Participants  This randomized clinical trial included adults with a clinical diagnosis of probable AD or a clinical diagnosis of mild cognitive impairment with positive biomarkers for AD, a positive serum antibody test (IgG or IgM) for HSV-1 or HSV-2, and a Mini-Mental State Examination score of 18 to 28. The trial was conducted at 3 US outpatient clinics specializing in memory disorders. Recruitment occurred from January 2018 to May 2022; the last follow-up occurred in September 2024.

Intervention  Either 4 g/d of valacyclovir (n=60) or matching placebo (n=60).

Main Outcomes and Measures  The primary outcome was least-squares mean (LSM) change at 78 weeks in the 11-item Alzheimer’s Disease Assessment Scale Cognitive (ADAS-Cognitive) Subscale score (range, 0-70; higher scores indicate greater impairment). The secondary outcomes were LSM change in the Alzheimer’s Disease Cooperative Study–Activities of Daily Living (ADCS-ADL) Scale score; LSM change in the 18F-florbetapir amyloid positron emission tomography (PET) standardized uptake value ratio (SUVR; higher scores indicate higher amyloid levels) for 6 brain regions (medial orbitofrontal, anterior cingulate, parietal lobe, posterior cingulate, temporal lobe, and precuneus); and LSM change in 18F-MK-6240 tau PET medial temporal SUVR (higher scores indicate higher tau levels) for 4 brain regions (amygdala, hippocampus, entorhinal, and parahippocampus). The frequency of adverse events was the safety outcome.

Results  Of the 120 participants (mean age, 71.4 [SD, 8.6] years; 55% were female), 93 (77.5%) completed the trial. At 78 weeks, the LSM change in the 11-item ADAS-Cognitive Subscale score was 10.86 (95% CI, 8.80 to 12.91) in the valacyclovir group vs 6.92 (95% CI, 4.88 to 8.97) in the placebo group, indicating greater cognitive worsening with valacyclovir than placebo (between-group difference, 3.93 [95% CI, 1.03 to 6.83]; P=.01). The LSM change in the ADCS-ADL Scale score at 78 weeks was 13.78 (95% CI, 17.00 to 10.56) in the valacyclovir group vs 10.16 (95% CI, 13.37 to 6.96) in the placebo group (between-group difference, 3.62 [95% CI, 8.16 to 0.93]). At 78 weeks, the LSM change in the 18F-florbetapir amyloid PET SUVR was 0.03 (95% CI, 0.04 to 0.10) in the valacyclovir group vs 0.01 (95% CI, 0.06 to 0.08) in the placebo group (between-group difference, 0.02 [95% CI, 0.08 to 0.12]). The LSM change in the 18F-MK-6240 tau PET medial temporal SUVR at 78 weeks was 0.07 (95% CI, 0.06 to 0.19) in the valacyclovir group vs 0.04 (95% CI, 0.15 to 0.07) in the placebo group (between-group difference, 0.11 [95% CI, 0.06 to 0.28]). The most common adverse events were elevated serum creatinine level (5 participants [8.3%] in the valacyclovir group vs 2 participants [3.3%] in the placebo group) and COVID-19 infection (3 [5%] vs 2 [3.3%], respectively).

Conclusions and Relevance  Valacyclovir was not efficacious with cognitive worsening for the primary outcome and it is not recommended to treat individuals with early symptomatic AD and HSV seropositivity.

DOI: 10.1001/jama.2025.21738

Source: https://jamanetwork.com/journals/jama/fullarticle/2842964