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A double-blind randomized phase 2 controlled trial of intradermal hepatitis B vaccination with a topical Toll-like receptor 7 agonist imiquimod, in patients on dialysis.

在透析患者中采用局部 Toll 样受体 7 激动剂咪喹莫特进行皮内乙肝疫苗接种的双盲随机 2 期对照试验。

  • 影响因子:5.31
  • DOI:10.1093/cid/ciaa804
  • 作者列表:"Hung IF","Yap DY","Yip TP","Zhang RR","To KK","Chan KH","Tang SC","Lui SL","Levin Y","Kochba E","Lau JY","Yuen MF","Chan TM","Yuen KY
  • 发表时间:2020-06-18
Abstract

BACKGROUND:Patients on dialysis are hyporesponsive to the current hepatitis B virus vaccines (HBVv). We conducted a phase-2 trial examining four-doses of intradermal (ID) HBVv Sci-B-Vac™, with topical TLR7 agonist imiquimod pretreatment in dialysis patients. METHODS:In this double-blind, randomized-controlled trial, we enrolled and prospectively followed adult patients on dialysis between January 2016 and September 2018. Eligible patients were randomly allocated (1:1:1) into one treatment: topical imiquimod-cream followed by intradermal HBVv (IMQ_ID), and two control groups: topical aqueous-cream (placebo) followed by ID HBVv (AQ_ID) or topical aqueous-cream followed by intramuscular (IM) HBVv (AQ_IM). The primary end-point was the seroprotection rate (anti-HBs≥10mIU/mL) at 52 weeks after the first dose of HBVv. RESULTS:Ninety-four patients on dialysis were enrolled, among which 57.4% were previous non-responders. The primary outcome of seroprotection rate was significantly better at week 52 for the treatment group (IMQ_ID) with 96.9% seroprotection rate, comparing compared to 74.2% and 48.4% for the AQ_ID and AQ_IM groups, respectively (p<0.0001). The GMC was also significantly higher at week 52 for the IMQ_ID group of 1135 mIU/mL (95% CI, 579.4-2218.2 mIU/mL), compared to 86.9 mIU/mL (95% CI, 18.5-409.3 mIU/mL) and 7.2 mIU/mL (2.0-26.5mIU/mL) for the AQ_ID and AQ_IM groups, respectively (p<0.0001). IMQ_ID vaccination [OR, 3.70 (95% CI, 1.16-11.81;p=0.027) was the only factor independently associated with higher seroprotection rate at 52 weeks. Adverse reaction was infrequent. CONCLUSIONS:Pretreatment with topical imiquimod (TLR7 agonist) before ID HBVv Sci-B-Vac™ was safe with favorable seroprotection and as such potentially improved prevention against HBV infection in dialysis patients.

摘要

背景: 透析患者对目前的乙型肝炎病毒疫苗 (HBVv) 反应不足。我们进行了一项 2 期试验,检查了四剂皮内 (ID) HBVv Sci-B-Vac™,用局部 TLR7 激动剂咪喹莫特预处理透析患者。 方法: 在这项双盲、随机对照试验中,我们入组并前瞻性随访了 2016 年 1 月至 2018 年 9 月期间接受透析的成人患者。合格的患者被随机 (1:1:1) 分配到一个治疗: 外用咪喹莫特乳膏,然后皮内注射 HBVv (IMQ_ID),和两个对照组: 外用水性乳膏 (安慰剂) 其次是 ID HBVv (AQ_ID) 或局部水性乳膏,然后是肌内 (IM) HBVv (AQ_IM)。主要终点是第一剂 HBVv 后 52 周的血清保护率 (抗 hbs ≥ 10miu/mL)。 结果: 94 例透析患者,其中 57.4% 例既往无反应。治疗组 (IMQ_ID) 在第 52 周血清保护率的主要结局显著优于 96.9% 血清保护率,而 AQ_ID 和 AQ_IM 组为 74.2% 和 48.4%,分别 (p<0.0001)。IMQ_ID 组 1135 mIU/mL (95% CI,579.4-2218.2 mIU/mL) 与 86.9 mIU/mL (95% CI, 18.5-409.3 mIU/mL) 和 7.2 mIU/mL (2.0-26。5mIU/mL) 分别为 AQ_ID 和 AQ_IM 组 (p<0.0001)。IMQ_ID 疫苗接种 [OR,3.70 (95% CI,1.16-11.81;p = 0.027) 是 52 周时较高血清保护率的唯一独立相关因素。不良反应罕见。 结论: 在 ID HBVv Sci-B-Vac 之前用局部咪喹莫特 (TLR7 激动剂) 预处理™是安全的,具有良好的血清保护,因此可能改善对透析患者 HBV 感染的预防。

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作者列表:["Moon AM","Jiang Y","Rogal SS","Tapper EB","Lieber SR","Barritt AS 4th"]

METHODS:BACKGROUND:Opioids are often prescribed for pain in cirrhosis and may increase the risk of hepatic encephalopathy (HE). AIMS:To assess the association between opioids and HE in patients with well-compensated cirrhosis. METHODS:We used the IQVIA PharMetrics (Durham, NC) database to identify patients aged 18-64 years with cirrhosis. We excluded patients with any decompensation event from 1 year before cirrhosis diagnosis to 6 months after cirrhosis diagnosis. Over the 6 months after cirrhosis diagnosis, we determined the duration of continuous opioid use and classified use into short term (1-89 days) and chronic (90-180 days). We assessed whether patients developed HE over the subsequent year (ie 6-18 months after cirrhosis diagnosis). We used a landmark analysis and performed multivariable Cox proportional hazards regression to assess associations between opioid use and HE, adjusting for relevant confounders. RESULTS:The cohort included 6451 patients with compensated cirrhosis, of whom 23.3% and 4.7% had short-term and chronic opioid prescriptions respectively. Over the subsequent year, HE occurred in 6.3% patients with chronic opioid prescriptions, 5.0% with short-term opioid prescriptions and 3.3% with no opioid prescriptions. In the multivariable model, an increased risk of HE was observed with short-term (adjusted hazard ratio, HR 1.44, 95% CI 1.07-1.94) and chronic opioid prescriptions (adjusted HR 1.83, 95% CI 1.07-3.12) compared to no opioid prescriptions. CONCLUSION:In this national cohort of privately insured patients with cirrhosis, opioid prescriptions were associated with the risk of incident HE. Opioid use should be minimised in those with cirrhosis and, when required, limited to short duration.

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影响因子:3.87
发表时间:2020-02-01
DOI:10.1111/liv.14321
作者列表:["Chen VL","Chen Y","Du X","Handelman SK","Speliotes EK"]

METHODS:BACKGROUND AND AIMS:Cirrhosis is characterized by extensive fibrosis of the liver and is a major cause of liver-related mortality. Cirrhosis is partially heritable but genetic contributions to cirrhosis have not been systemically explored. Here, we carry out association analyses with cirrhosis in two large biobanks and determine the effects of cirrhosis associated variants on multiple human disease/traits. METHODS:We carried out a genome-wide association analysis of cirrhosis as a diagnosis in UK BioBank (UKBB; 1088 cases vs. 407 873 controls) and then tested top-associating loci for replication with cirrhosis in a hospital-based cohort from the Michigan Genomics Initiative (MGI; 875 cases of cirrhosis vs. 30 346 controls). For replicating variants or variants previously associated with cirrhosis that also affected cirrhosis in UKBB or MGI, we determined single nucleotide polymorphism effects on all other diagnoses in UKBB (PheWAS), common metabolic traits/diseases and serum/plasma metabolites. RESULTS:Unbiased genome-wide association study identified variants in/near PNPLA3 and HFE, and candidate variant analysis identified variants in/near TM6SF2, MBOAT7, SERPINA1, HSD17B13, STAT4 and IFNL4 that reproducibly affected cirrhosis. Most affected liver enzyme concentrations and/or aspartate transaminase-to-platelet ratio index. PheWAS, metabolic trait and serum/plasma metabolite association analyses revealed effects of these variants on lipid, inflammatory and other processes including new effects on many human diseases and traits. CONCLUSIONS:We identified eight loci that reproducibly associate with population-based cirrhosis and define their diverse effects on human diseases and traits.

翻译标题与摘要 下载文献
影响因子:2.57
发表时间:2020-02-01
DOI:10.1111/eci.13198
作者列表:["Li H","Wieser A","Zhang J","Liss I","Markwardt D","Hornung R","Neumann-Cip AC","Mayerle J","Gerbes A","Steib CJ"]

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