首页 > 最新文献

Antiviral Therapy最新文献

英文 中文
Repurposing FDA-approved drugs for COVID-19: targeting the main protease through multi-phase in silico approach. 重新利用fda批准的COVID-19药物:通过多阶段芯片方法靶向主要蛋白酶。
IF 1.3 4区 医学 Q4 INFECTIOUS DISEASES Pub Date : 2024-12-01 DOI: 10.1177/13596535241305536
Ahmed M Metwaly, Eslam B Elkaeed, Aisha A Alsfouk, Ibrahim M Ibrahim, Hazem Elkady, Ibrahim H Eissa

Background: The COVID-19 pandemic has created an urgent need for effective therapeutic agents. The SARS-CoV-2 Main Protease (Mpro) plays a crucial role in viral replication and immune evasion, making it a key target for drug development. While several studies have explored Mpro inhibition, identifying FDA-approved drugs with potential efficacy remains a critical research focus.

Purpose: This study aims to identify FDA-approved drugs that could inhibit SARS-CoV-2 Mpro. Using computational screening, we seek compounds that share structural similarities with a known co-crystallized ligand (PRD_002214) and exhibit strong binding affinity to the enzyme, providing viable candidates for COVID-19 treatment.

Research design: A systematic in silico approach was used, screening 3009 FDA-approved drugs. The initial screening focused on structural similarity to PRD_002214 (PDB ID: 6LU7), followed by molecular docking studies to predict binding affinity. Promising compounds were further analyzed through molecular dynamics (MD) simulations to evaluate their stability and interactions with Mpro over 100 ns.

Study sample: Of the 3009 FDA-approved drugs screened, 74 were selected for initial evaluation. After refinement, 28 compounds underwent docking analysis, with eight showing strong binding potential to Mpro.

Analysis: Molecular docking assessed the binding affinity and interaction of the selected compounds with Mpro. MD simulations were conducted on the top compound, Atazanavir, to study its dynamic interactions. MM-GBSA, PLIP, and PCAT analyses were used to validate binding affinity and interactions.

Results: Eight compounds, including Carfilzomib, Atazanavir, Darunavir, and others, exhibited promising binding affinities. Among them, Atazanavir showed the highest binding strength and was selected for further MD simulation studies. These simulations revealed that Atazanavir forms stable interactions with Mpro, demonstrating favorable binding and dynamic stability. The binding affinity was further confirmed through MM-GBSA, PLIP, and PCAT analyses, supporting Atazanavir's potential as an effective Mpro inhibitor.

Conclusions: In silico results suggest that Atazanavir is a promising candidate for targeting SARS-CoV-2 Mpro, with strong binding affinity and dynamic stability. These findings support its potential as a lead compound for further preclinical and clinical testing, though in vitro and in vivo validation are needed to confirm its therapeutic efficacy against COVID-19.

背景:COVID-19大流行迫切需要有效的治疗药物。SARS-CoV-2主蛋白酶(Mpro)在病毒复制和免疫逃避中起着至关重要的作用,使其成为药物开发的关键靶点。虽然有几项研究探索了Mpro的抑制作用,但确定fda批准的具有潜在功效的药物仍然是一个关键的研究重点。目的:本研究旨在鉴定fda批准的抑制SARS-CoV-2 Mpro的药物。通过计算筛选,我们寻找与已知共结晶配体(PRD_002214)具有结构相似性并与酶具有强结合亲和力的化合物,为COVID-19治疗提供可行的候选药物。研究设计:采用系统的计算机方法,筛选3009种fda批准的药物。最初的筛选重点是与PRD_002214 (PDB ID: 6LU7)的结构相似性,然后进行分子对接研究以预测结合亲和力。通过分子动力学(MD)模拟进一步分析了有希望的化合物,以评估它们在100 ns内的稳定性和与Mpro的相互作用。研究样本:在筛选的3009种fda批准的药物中,74种被选中进行初步评估。精化后,28个化合物进行对接分析,其中8个化合物与Mpro具有较强的结合潜力。分析:分子对接评估了所选化合物与Mpro的结合亲和力和相互作用。对顶层化合物Atazanavir进行了MD模拟,研究其动态相互作用。MM-GBSA、PLIP和PCAT分析用于验证结合亲和力和相互作用。结果:Carfilzomib、Atazanavir、Darunavir等8个化合物具有良好的结合亲和力。其中,Atazanavir的结合强度最高,被选中进行进一步的MD模拟研究。这些模拟结果表明,Atazanavir与Mpro形成稳定的相互作用,表现出良好的结合和动态稳定性。通过MM-GBSA, PLIP和PCAT分析进一步证实了结合亲和力,支持Atazanavir作为有效Mpro抑制剂的潜力。结论:Atazanavir具有较强的结合亲和力和动态稳定性,是靶向SARS-CoV-2 Mpro的候选药物。这些发现支持其作为进一步临床前和临床试验的先导化合物的潜力,尽管需要进行体外和体内验证以确认其对COVID-19的治疗效果。
{"title":"Repurposing FDA-approved drugs for COVID-19: targeting the main protease through multi-phase <i>in silico</i> approach.","authors":"Ahmed M Metwaly, Eslam B Elkaeed, Aisha A Alsfouk, Ibrahim M Ibrahim, Hazem Elkady, Ibrahim H Eissa","doi":"10.1177/13596535241305536","DOIUrl":"https://doi.org/10.1177/13596535241305536","url":null,"abstract":"<p><strong>Background: </strong>The COVID-19 pandemic has created an urgent need for effective therapeutic agents. The SARS-CoV-2 Main Protease (M<sup>pro</sup>) plays a crucial role in viral replication and immune evasion, making it a key target for drug development. While several studies have explored M<sup>pro</sup> inhibition, identifying FDA-approved drugs with potential efficacy remains a critical research focus.</p><p><strong>Purpose: </strong>This study aims to identify FDA-approved drugs that could inhibit SARS-CoV-2 M<sup>pro</sup>. Using computational screening, we seek compounds that share structural similarities with a known co-crystallized ligand (PRD_002214) and exhibit strong binding affinity to the enzyme, providing viable candidates for COVID-19 treatment.</p><p><strong>Research design: </strong>A systematic <i>in silico</i> approach was used, screening 3009 FDA-approved drugs. The initial screening focused on structural similarity to PRD_002214 (PDB ID: 6LU7), followed by molecular docking studies to predict binding affinity. Promising compounds were further analyzed through molecular dynamics (MD) simulations to evaluate their stability and interactions with M<sup>pro</sup> over 100 ns.</p><p><strong>Study sample: </strong>Of the 3009 FDA-approved drugs screened, 74 were selected for initial evaluation. After refinement, 28 compounds underwent docking analysis, with eight showing strong binding potential to M<sup>pro</sup>.</p><p><strong>Analysis: </strong>Molecular docking assessed the binding affinity and interaction of the selected compounds with M<sup>pro</sup>. MD simulations were conducted on the top compound, Atazanavir, to study its dynamic interactions. MM-GBSA, PLIP, and PCAT analyses were used to validate binding affinity and interactions.</p><p><strong>Results: </strong>Eight compounds, including Carfilzomib, Atazanavir, Darunavir, and others, exhibited promising binding affinities. Among them, Atazanavir showed the highest binding strength and was selected for further MD simulation studies. These simulations revealed that Atazanavir forms stable interactions with M<sup>pro</sup>, demonstrating favorable binding and dynamic stability. The binding affinity was further confirmed through MM-GBSA, PLIP, and PCAT analyses, supporting Atazanavir's potential as an effective M<sup>pro</sup> inhibitor.</p><p><strong>Conclusions: </strong><i>In silico</i> results suggest that Atazanavir is a promising candidate for targeting SARS-CoV-2 M<sup>pro</sup>, with strong binding affinity and dynamic stability. These findings support its potential as a lead compound for further preclinical and clinical testing, though in vitro and in vivo validation are needed to confirm its therapeutic efficacy against COVID-19.</p>","PeriodicalId":8364,"journal":{"name":"Antiviral Therapy","volume":"29 6","pages":"13596535241305536"},"PeriodicalIF":1.3,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142784041","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Effectiveness of bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) as switch strategy in virologically-suppressed patients: real world data from a monocentric cohort. bictegravir/emtricitabine/替诺福韦alafenamide (BIC/FTC/TAF)作为病毒学抑制患者切换策略的有效性:来自单中心队列的真实世界数据
IF 1.3 4区 医学 Q4 INFECTIOUS DISEASES Pub Date : 2024-12-01 DOI: 10.1177/13596535241306467
R A Passerotto, F Lamanna, P F Salvo, V Iannone, R J Steiner, A Carbone, D Farinacci, A D'Angelillo, G Baldin, A Ciccullo, S Di Giambenedetto, C Torti, A Borghetti

Introduction: BIC/FTC/TAF showed efficacy and tolerability in randomized trials as a switch strategy in virologically-suppressed people living with HIV. We evaluated its effectiveness in a real-life setting.

Methods: A retrospective monocentric cohort including 431 virologically-suppressed (HIV-RNA <50 copies/ml) people switching to BIC/FTC/TAF in the period 2018-2022 was evaluated. Probabilities of virological failure (VF, i.e.2 consecutive HIV-RNA ≥50 copies/ml or a single HIV-RNA ≥200 copies/ml) and of treatment discontinuation (TD) were estimated by Kaplan-Meier, and predictors of both outcomes were identified through multivariable Cox regression. Analysis-of-variance for repeated measures was used to examine changes in CD4 count and CD4-to-CD8 ratio.

Results: Overall, 16 VF occurred during 22 months of median follow-up time. Estimated probabilities of VF at 1, 2 and 3 years were 2.0% (95% CI 1.04.2%), 2.9% (95% CI 1.5%-5.6%) and 5.5% (95% CI 3.2%-9.2%), respectively. Caucasian ethnicity and a history of previous VF independently predicted VF. TD occurred in 42 cases, predominantly for simplification. One discontinuation due to VF was reported. No predictors of discontinuation were identified. An increase in CD4-to-CD8 ratio over 3 years was evidenced (p < 0.001). Total cholesterol decreased over 3 years (p < 0.001). Triglycerides did not significantly change (p = 0.465).

Conclusions: BIC/FTC/TAF demonstrated high effectiveness, tolerability and safety.

在随机试验中,BIC/FTC/TAF作为一种切换策略在病毒学抑制的HIV感染者中显示出疗效和耐受性。我们在现实生活中评估了它的有效性。方法:一项包括431例病毒学抑制(HIV-RNA)患者的回顾性单中心队列研究结果:总体而言,在22个月的中位随访时间内发生了16例VF。估计1、2和3年发生VF的概率分别为2.0% (95% CI 1.04.2%)、2.9% (95% CI 1.5%-5.6%)和5.5% (95% CI 3.2%-9.2%)。高加索人种和既往VF病史独立预测VF。42例发生TD,主要是简化。据报道,有一例因VF而中止。没有发现停药的预测因素。cd4 / cd8比值在3年内增加(p < 0.001)。总胆固醇在3年内下降(p < 0.001)。甘油三酯无显著变化(p = 0.465)。结论:BIC/FTC/TAF具有良好的疗效、耐受性和安全性。
{"title":"Effectiveness of bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) as switch strategy in virologically-suppressed patients: real world data from a monocentric cohort.","authors":"R A Passerotto, F Lamanna, P F Salvo, V Iannone, R J Steiner, A Carbone, D Farinacci, A D'Angelillo, G Baldin, A Ciccullo, S Di Giambenedetto, C Torti, A Borghetti","doi":"10.1177/13596535241306467","DOIUrl":"https://doi.org/10.1177/13596535241306467","url":null,"abstract":"<p><strong>Introduction: </strong>BIC/FTC/TAF showed efficacy and tolerability in randomized trials as a switch strategy in virologically-suppressed people living with HIV. We evaluated its effectiveness in a real-life setting.</p><p><strong>Methods: </strong>A retrospective monocentric cohort including 431 virologically-suppressed (HIV-RNA <50 copies/ml) people switching to BIC/FTC/TAF in the period 2018-2022 was evaluated. Probabilities of virological failure (VF, i.e.2 consecutive HIV-RNA ≥50 copies/ml or a single HIV-RNA ≥200 copies/ml) and of treatment discontinuation (TD) were estimated by Kaplan-Meier, and predictors of both outcomes were identified through multivariable Cox regression. Analysis-of-variance for repeated measures was used to examine changes in CD4 count and CD4-to-CD8 ratio.</p><p><strong>Results: </strong>Overall, 16 VF occurred during 22 months of median follow-up time. Estimated probabilities of VF at 1, 2 and 3 years were 2.0% (95% CI 1.04.2%), 2.9% (95% CI 1.5%-5.6%) and 5.5% (95% CI 3.2%-9.2%), respectively. Caucasian ethnicity and a history of previous VF independently predicted VF. TD occurred in 42 cases, predominantly for simplification. One discontinuation due to VF was reported. No predictors of discontinuation were identified. An increase in CD4-to-CD8 ratio over 3 years was evidenced (<i>p</i> < 0.001). Total cholesterol decreased over 3 years (<i>p</i> < 0.001). Triglycerides did not significantly change (<i>p</i> = 0.465).</p><p><strong>Conclusions: </strong>BIC/FTC/TAF demonstrated high effectiveness, tolerability and safety.</p>","PeriodicalId":8364,"journal":{"name":"Antiviral Therapy","volume":"29 6","pages":"13596535241306467"},"PeriodicalIF":1.3,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142852306","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Comparative efficacy and safety of tenofovir amibufenamide vs tenofovir alafenamide in the initial 48-week treatment of high viral load chronic hepatitis B: A single-centre retrospective study. 替诺福韦-阿米布非那胺与替诺福韦-阿拉非那胺在高病毒载量慢性乙型肝炎初始 48 周治疗中的疗效和安全性比较:单中心回顾性研究。
IF 1.2 4区 医学 Q4 INFECTIOUS DISEASES Pub Date : 2024-10-01 DOI: 10.1177/13596535241284226
Qing Zhang,Jianhua Xu,Dan Liu,Lilin Wang,Shan Ren,Sujun Zheng,Xinyue Chen,Li Qi,Junfeng Lu
BACKGROUND/AIMTenofovir amibufenamide (TMF) employs innovative ProTide technology and a methylation strategy to enhance the lipid solubility and plasma stability of the amide bond, providing advantages over tenofovir alafenamide (TAF). Despite promising Phase III clinical trial results demonstrating its antiviral efficacy, real-world data on TMF remains scarce. This study evaluates the antiviral efficacy and safety of TMF compared to TAF as the initial treatment in patients with high viral loads of chronic hepatitis B (CHB).METHODSWe retrospectively collected clinical data from March 1 2022 to June 30 2022 for highly viremic CHB patients who received either TMF (n = 58) or TAF (n = 32) as their initial monotherapy at Beijing YouAn Hospital. To understand the efficacy and safety of TMF over 48 weeks, we compared the virological response rates and HBeAg/HBsAg serological clearance rates between TMF and TAF groups. Also, the changes in serum creatinine, eGFR and serum lipid levels were assessed.RESULTSBaseline median HBV DNA levels were 7.85 (6.89, 8.36) IgIU/ml for TMF and 7.44 (6.89, 8.03) IgIU/ml for TAF. Median ALT levels were 102.0 (56.0, 210.0) U/L for TMF and 195.0 (73.5, 371.0) U/L for TAF, with HBeAg positivity rates of 70.7% and 75.0%, respectively. At 48 weeks, virological response rates (HBV DNA <10 IU/ml) were 43.5% (20/46) for TMF and 42.9% (12/28) for TAF (p = 1.000). ALT normalization rates were 87.9% for TMF and 90.6% for TAF (p = .969), and HBeAg serological clearance rates were 21.1% and 18.2%, respectively (p = 1.000). No patients achieved HBsAg clearance. Compared with the baseline, LDL-C levels increased, while eGFR decreased, with no significant differences in serum creatinine, triglycerides and total cholesterol levels noted at week 48 for both TMF and TAF groups.CONCLUSIONTMF demonstrates comparable antiviral efficacy to TAF when used as initial therapy in highly viremic CHB patients, with similar impacts on renal function and lipid profiles.
背景/目的替诺福韦-阿米布非那胺(TMF)采用创新的 ProTide 技术和甲基化策略来提高酰胺键的脂溶性和血浆稳定性,与替诺福韦-阿拉非那胺(TAF)相比更具优势。尽管 III 期临床试验结果表明 TMF 具有良好的抗病毒疗效,但有关 TMF 的实际数据仍然很少。方法 我们回顾性地收集了2022年3月1日至2022年6月30日期间北京佑安医院接受TMF(58例)或TAF(32例)作为初始单药治疗的高病毒载量CHB患者的临床数据。为了解 48 周内 TMF 的疗效和安全性,我们比较了 TMF 组和 TAF 组的病毒学应答率和 HBeAg/HBsAg 血清学清除率。结果 TMF 和 TAF 的基线 HBV DNA 中位水平分别为 7.85 (6.89, 8.36) IgIU/ml和 7.44 (6.89, 8.03) IgIU/ml。TMF和TAF的ALT水平中位数分别为102.0(56.0,210.0)U/L和195.0(73.5,371.0)U/L,HBeAg阳性率分别为70.7%和75.0%。48周时,TMF的病毒学应答率(HBV DNA <10 IU/ml)为43.5%(20/46),TAF为42.9%(12/28)(p = 1.000)。TMF和TAF的ALT正常化率分别为87.9%和90.6%(p = .969),HBeAg血清学清除率分别为21.1%和18.2%(p = 1.000)。没有患者达到 HBsAg 清除率。与基线相比,TMF 组和 TAF 组的低密度脂蛋白胆固醇(LDL-C)水平升高,而 eGFR 下降,但在第 48 周时,血清肌酐、甘油三酯和总胆固醇水平无显著差异。
{"title":"Comparative efficacy and safety of tenofovir amibufenamide vs tenofovir alafenamide in the initial 48-week treatment of high viral load chronic hepatitis B: A single-centre retrospective study.","authors":"Qing Zhang,Jianhua Xu,Dan Liu,Lilin Wang,Shan Ren,Sujun Zheng,Xinyue Chen,Li Qi,Junfeng Lu","doi":"10.1177/13596535241284226","DOIUrl":"https://doi.org/10.1177/13596535241284226","url":null,"abstract":"BACKGROUND/AIMTenofovir amibufenamide (TMF) employs innovative ProTide technology and a methylation strategy to enhance the lipid solubility and plasma stability of the amide bond, providing advantages over tenofovir alafenamide (TAF). Despite promising Phase III clinical trial results demonstrating its antiviral efficacy, real-world data on TMF remains scarce. This study evaluates the antiviral efficacy and safety of TMF compared to TAF as the initial treatment in patients with high viral loads of chronic hepatitis B (CHB).METHODSWe retrospectively collected clinical data from March 1 2022 to June 30 2022 for highly viremic CHB patients who received either TMF (n = 58) or TAF (n = 32) as their initial monotherapy at Beijing YouAn Hospital. To understand the efficacy and safety of TMF over 48 weeks, we compared the virological response rates and HBeAg/HBsAg serological clearance rates between TMF and TAF groups. Also, the changes in serum creatinine, eGFR and serum lipid levels were assessed.RESULTSBaseline median HBV DNA levels were 7.85 (6.89, 8.36) IgIU/ml for TMF and 7.44 (6.89, 8.03) IgIU/ml for TAF. Median ALT levels were 102.0 (56.0, 210.0) U/L for TMF and 195.0 (73.5, 371.0) U/L for TAF, with HBeAg positivity rates of 70.7% and 75.0%, respectively. At 48 weeks, virological response rates (HBV DNA <10 IU/ml) were 43.5% (20/46) for TMF and 42.9% (12/28) for TAF (p = 1.000). ALT normalization rates were 87.9% for TMF and 90.6% for TAF (p = .969), and HBeAg serological clearance rates were 21.1% and 18.2%, respectively (p = 1.000). No patients achieved HBsAg clearance. Compared with the baseline, LDL-C levels increased, while eGFR decreased, with no significant differences in serum creatinine, triglycerides and total cholesterol levels noted at week 48 for both TMF and TAF groups.CONCLUSIONTMF demonstrates comparable antiviral efficacy to TAF when used as initial therapy in highly viremic CHB patients, with similar impacts on renal function and lipid profiles.","PeriodicalId":8364,"journal":{"name":"Antiviral Therapy","volume":"79 3 1","pages":"13596535241284226"},"PeriodicalIF":1.2,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142216269","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Analysis of risk factors and prediction model construction for varicella encephalitis in children: A retrospective cohort study. 儿童水痘脑炎的风险因素分析和预测模型构建:回顾性队列研究。
IF 1.3 4区 医学 Q4 INFECTIOUS DISEASES Pub Date : 2024-10-01 DOI: 10.1177/13596535241291132
Ce Wang, Li Tang, Dandan Guo

Introduction: This study aimed to analyze the risk factors for varicella encephalitis in children and establish a predictive model.

Methods: This retrospective cohort study included a varicella encephalitis group (n = 75) and a varicella-non-encephalitis group (n = 135). Logistic regression analysis was employed to find risk factors for varicella encephalitis and create a predictive model.

Results: Older age, vomiting, poor mental status, and prolonged rash duration were independent risk factors for varicella encephalitis (p < .05). The predictive model for varicella encephalitis combined above four factors. The ROC curve of the predictive model showed an area under the curve of 0.955 (95% CI 0.925-0.986) for varicella encephalitis in children with a sensitivity of 94.7%, and a specificity of 86.0%.

Conclusion: Children with varicella who are older, experience vomiting, exhibit poor mental status, or have a prolonged rash duration should be closely monitored clinically. The predictive model combining these four factors demonstrates good predictive efficiency.

简介:本研究旨在分析儿童水痘脑炎的风险因素,并建立预测模型:本研究旨在分析儿童水痘脑炎的风险因素,并建立一个预测模型:这项回顾性队列研究包括水痘脑炎组(75 人)和水痘非脑炎组(135 人)。研究采用逻辑回归分析找出水痘脑炎的风险因素,并建立预测模型:结果:年龄大、呕吐、精神状态差和皮疹持续时间长是水痘脑炎的独立危险因素(p < .05)。水痘脑炎预测模型综合了上述四个因素。预测模型的 ROC 曲线显示,儿童水痘脑炎的曲线下面积为 0.955(95% CI 0.925-0.986),敏感性为 94.7%,特异性为 86.0%:结论:对于年龄较大、出现呕吐、精神状态不佳或皮疹持续时间较长的水痘患儿,临床上应密切监测。结合这四个因素的预测模型具有良好的预测效果。
{"title":"Analysis of risk factors and prediction model construction for varicella encephalitis in children: A retrospective cohort study.","authors":"Ce Wang, Li Tang, Dandan Guo","doi":"10.1177/13596535241291132","DOIUrl":"https://doi.org/10.1177/13596535241291132","url":null,"abstract":"<p><strong>Introduction: </strong>This study aimed to analyze the risk factors for varicella encephalitis in children and establish a predictive model.</p><p><strong>Methods: </strong>This retrospective cohort study included a varicella encephalitis group (<i>n</i> = 75) and a varicella-non-encephalitis group (<i>n</i> = 135). Logistic regression analysis was employed to find risk factors for varicella encephalitis and create a predictive model.</p><p><strong>Results: </strong>Older age, vomiting, poor mental status, and prolonged rash duration were independent risk factors for varicella encephalitis (<i>p</i> < .05). The predictive model for varicella encephalitis combined above four factors. The ROC curve of the predictive model showed an area under the curve of 0.955 (95% CI 0.925-0.986) for varicella encephalitis in children with a sensitivity of 94.7%, and a specificity of 86.0%.</p><p><strong>Conclusion: </strong>Children with varicella who are older, experience vomiting, exhibit poor mental status, or have a prolonged rash duration should be closely monitored clinically. The predictive model combining these four factors demonstrates good predictive efficiency.</p>","PeriodicalId":8364,"journal":{"name":"Antiviral Therapy","volume":"29 5","pages":"13596535241291132"},"PeriodicalIF":1.3,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142456853","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Andrographolide suppresses SARS-CoV-2 infection by downregulating ACE2 expression: A mechanistic study. 穿心莲内酯通过下调 ACE2 表达抑制 SARS-CoV-2 感染:机理研究
IF 1.3 4区 医学 Q4 INFECTIOUS DISEASES Pub Date : 2024-06-01 DOI: 10.1177/13596535241259952
Qing Li, Hongmei Lu, Yongdui Ruan, Yuxuan Geng, Zuguo Zhao, Ying Liu, Long Feng, Wentao Guo

Angiotensin-converting enzyme 2 (ACE2) is the receptor that enables SARS-CoV-2 to invade host cells. Previous studies have reported that reducing ACE2 expression may have an anti-SARS-CoV-2 effect. In this study, we constructed a pGL4.10-F2-ACE2 vector with double luciferase genes (firefly and Renilla luciferase) under the control of the ACE2 promoter and used it to screen compounds from Chinese traditional medicinal herbs (CTMHs) that can inhibit ACE2 transcription in human cells. We transfected HEK293T cells with pGL4.10-F2-ACE2 and treated them with CTMH compounds and then measured fluorescence to evaluate the indirect inhibition of ACE2 transcription. Out of 37 compounds tested, andrographolide demonstrated a dose-dependent inhibition of ACE2 transcription. We further confirmed by RT-qPCR and Western blot assays that andrographolide also reduced ACE2 expression in BEAS-2B cells in a dose-dependent manner. Moreover, pseudovirus infection assays in BEAS-2B cells demonstrated that andrographolide can inhibit SARS-CoV-2 infection in a dose-dependent manner. These results suggest that andrographolide has potential anti-SARS-CoV-2 activity and could be a candidate drug for COVID-19 prevention and treatment.

血管紧张素转换酶 2(ACE2)是使 SARS-CoV-2 侵入宿主细胞的受体。以前的研究报道,减少 ACE2 的表达可能具有抗 SARS-CoV-2 的作用。在本研究中,我们构建了一个pGL4.10-F2-ACE2载体,该载体含有双荧光素酶基因(萤火虫荧光素酶和雷尼拉荧光素酶),受ACE2启动子控制。我们用pGL4.10-F2-ACE2转染了HEK293T细胞,并用CTMH化合物处理它们,然后测量荧光来评估对ACE2转录的间接抑制作用。在测试的 37 种化合物中,穿心莲内酯对 ACE2 转录具有剂量依赖性抑制作用。我们还通过 RT-qPCR 和 Western 印迹检测进一步证实,穿心莲内酯也能以剂量依赖的方式降低 BEAS-2B 细胞中 ACE2 的表达。此外,在 BEAS-2B 细胞中进行的假病毒感染实验表明,穿心莲内酯能以剂量依赖性方式抑制 SARS-CoV-2 感染。这些结果表明穿心莲内酯具有潜在的抗 SARS-CoV-2 活性,可作为 COVID-19 预防和治疗的候选药物。
{"title":"Andrographolide suppresses SARS-CoV-2 infection by downregulating ACE2 expression: A mechanistic study.","authors":"Qing Li, Hongmei Lu, Yongdui Ruan, Yuxuan Geng, Zuguo Zhao, Ying Liu, Long Feng, Wentao Guo","doi":"10.1177/13596535241259952","DOIUrl":"10.1177/13596535241259952","url":null,"abstract":"<p><p>Angiotensin-converting enzyme 2 (ACE2) is the receptor that enables SARS-CoV-2 to invade host cells. Previous studies have reported that reducing ACE2 expression may have an anti-SARS-CoV-2 effect. In this study, we constructed a pGL4.10-F2-ACE2 vector with double luciferase genes (firefly and Renilla luciferase) under the control of the ACE2 promoter and used it to screen compounds from Chinese traditional medicinal herbs (CTMHs) that can inhibit ACE2 transcription in human cells. We transfected HEK293T cells with pGL4.10-F2-ACE2 and treated them with CTMH compounds and then measured fluorescence to evaluate the indirect inhibition of ACE2 transcription. Out of 37 compounds tested, andrographolide demonstrated a dose-dependent inhibition of ACE2 transcription. We further confirmed by RT-qPCR and Western blot assays that andrographolide also reduced ACE2 expression in BEAS-2B cells in a dose-dependent manner. Moreover, pseudovirus infection assays in BEAS-2B cells demonstrated that andrographolide can inhibit SARS-CoV-2 infection in a dose-dependent manner. These results suggest that andrographolide has potential anti-SARS-CoV-2 activity and could be a candidate drug for COVID-19 prevention and treatment.</p>","PeriodicalId":8364,"journal":{"name":"Antiviral Therapy","volume":"29 3","pages":"13596535241259952"},"PeriodicalIF":1.3,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141316681","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
In-silico approach to characterize the structure and function of a hypothetical protein of Monkeypox virus exploring Chordopox-A20R domain-containing protein activity. 通过实验室方法确定猴痘病毒假定蛋白的结构和功能,探索含 Chordopox-A20R 结构域蛋白的活性。
IF 1.2 4区 医学 Q4 INFECTIOUS DISEASES Pub Date : 2024-06-01 DOI: 10.1177/13596535241255199
Md Iqbal Hosen, Md Easin Mia, Md Nur Islam, Most Ummay Salma Khatun, Tanvir Hossain Emon, Md Anwar Hossain, Farzana Akter, Md Abdul Kader, Sadia Hossain Jeba, Asm Faisal, Md Abunasar Miah

Background: Monkeypox has emerged as a noteworthy worldwide issue due to its daily escalating case count. This illness presents diverse symptoms, including skin manifestations, which have the potential to spread through contact. The transmission of this infectious agent is intricate and readily transfers between individuals.Methods: The hypothetical protein MPXV-SI-2022V502225_00135 strain of monkeypox underwent structural and functional analysis using NCBI-CD Search, Pfam, and InterProScan. Quality assessment utilized PROCHECK, QMEAN, Verify3D, and ERRAT, followed by protein-ligand docking, visualization, and a 100-nanosecond simulation on Schrodinger Maestro.Results: Different physicochemical properties were estimated, indicating a stable molecular weight (49147.14) and theoretical pI (5.62) with functional annotation tools predicting the target protein to contain the domain of Chordopox_A20R domain. In secondary structure analysis, the helix coil was found to be predominant. The three-dimensional (3D) structure of the protein was obtained using a template protein (PDB ID: 6zyc.1), which became more stable after YASARA energy minimization and was validated by quality assessment tools like PROCHECK, QMEAN, Verify3D, and ERRAT. Protein-ligand docking was conducted using PyRx 9.0 software to examine the binding and interactions between a ligand and a hypothetical protein, focusing on various amino acids. The model structure, active site, and binding site were visualized using the CASTp server, FTsite, and PyMOL. A 100 nanosecond simulation was performed with ligand CID_16124688 to evaluate the efficiency of this protein.Conclusion: The analysis revealed significant binding interactions and enhanced stability, aiding in drug or vaccine design for effective antiviral treatment and patient management.

背景:猴痘的病例数与日俱增,已成为一个值得注意的世界性问题。这种疾病表现出多种症状,包括皮肤表现,有可能通过接触传播。这种传染病的传播方式错综复杂,很容易在人与人之间传播:方法:使用 NCBI-CD Search、Pfam 和 InterProScan 对猴痘的假定蛋白 MPXV-SI-2022V502225_00135 株进行了结构和功能分析。利用 PROCHECK、QMEAN、Verify3D 和 ERRAT 进行质量评估,然后在 Schrodinger Maestro 上进行蛋白质配体对接、可视化和 100 纳秒模拟:对不同的理化性质进行了估计,结果表明目标蛋白质的分子量(49147.14)和理论pI(5.62)比较稳定,功能注释工具预测目标蛋白质含有Chordopox_A20R结构域。二级结构分析发现,螺旋线圈占主导地位。利用模板蛋白(PDB ID:6zyc.1)获得了该蛋白质的三维(3D)结构,经过 YASARA 能量最小化后,该结构变得更加稳定,并通过 PROCHECK、QMEAN、Verify3D 和 ERRAT 等质量评估工具进行了验证。使用 PyRx 9.0 软件进行了蛋白质-配体对接,研究了配体与假定蛋白质之间的结合和相互作用,重点研究了各种氨基酸。使用 CASTp 服务器、FTsite 和 PyMOL 对模型结构、活性位点和结合位点进行了可视化。对配体 CID_16124688 进行了 100 纳秒模拟,以评估该蛋白质的效率:分析结果表明,该蛋白具有明显的结合相互作用和更高的稳定性,有助于设计药物或疫苗,从而实现有效的抗病毒治疗和患者管理。
{"title":"<i>In-silico</i> approach to characterize the structure and function of a hypothetical protein of Monkeypox virus exploring Chordopox-A20R domain-containing protein activity.","authors":"Md Iqbal Hosen, Md Easin Mia, Md Nur Islam, Most Ummay Salma Khatun, Tanvir Hossain Emon, Md Anwar Hossain, Farzana Akter, Md Abdul Kader, Sadia Hossain Jeba, Asm Faisal, Md Abunasar Miah","doi":"10.1177/13596535241255199","DOIUrl":"10.1177/13596535241255199","url":null,"abstract":"<p><p><b>Background:</b> Monkeypox has emerged as a noteworthy worldwide issue due to its daily escalating case count. This illness presents diverse symptoms, including skin manifestations, which have the potential to spread through contact. The transmission of this infectious agent is intricate and readily transfers between individuals.<b>Methods:</b> The hypothetical protein MPXV-SI-2022V502225_00135 strain of monkeypox underwent structural and functional analysis using NCBI-CD Search, Pfam, and InterProScan. Quality assessment utilized PROCHECK, QMEAN, Verify3D, and ERRAT, followed by protein-ligand docking, visualization, and a 100-nanosecond simulation on Schrodinger Maestro.<b>Results:</b> Different physicochemical properties were estimated, indicating a stable molecular weight (49147.14) and theoretical pI (5.62) with functional annotation tools predicting the target protein to contain the domain of Chordopox_A20R domain. In secondary structure analysis, the helix coil was found to be predominant. The three-dimensional (3D) structure of the protein was obtained using a template protein (PDB ID: <i>6zyc.1</i>), which became more stable after YASARA energy minimization and was validated by quality assessment tools like PROCHECK, QMEAN, Verify3D, and ERRAT. Protein-ligand docking was conducted using PyRx 9.0 software to examine the binding and interactions between a ligand and a hypothetical protein, focusing on various amino acids. The model structure, active site, and binding site were visualized using the CASTp server, FTsite, and PyMOL. A 100 nanosecond simulation was performed with ligand CID_16124688 to evaluate the efficiency of this protein.<b>Conclusion:</b> The analysis revealed significant binding interactions and enhanced stability, aiding in drug or vaccine design for effective antiviral treatment and patient management.</p>","PeriodicalId":8364,"journal":{"name":"Antiviral Therapy","volume":"29 3","pages":"13596535241255199"},"PeriodicalIF":1.2,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141157246","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Assessment of swallowability and acceptability of scored darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) fixed-dose combination (FDC) tablets in HIV-1-infected children aged ≥6 to <12 years, using matching placebo tablets: A randomized study. 使用匹配的安慰剂片剂,评估达芦那韦/考比司他/恩曲他滨/替诺福韦-阿拉非那胺(D/C/F/TAF)固定剂量复方片剂(FDC)在年龄≥6至<12岁的HIV-1感染儿童中的吞咽性和可接受性:随机研究。
IF 1.2 4区 医学 Q4 INFECTIOUS DISEASES Pub Date : 2024-04-01 DOI: 10.1177/13596535241248282
Sandy Van Hemelryck, Erika Van Landuyt, Veerle Hufkens, Simon Vanveggel

Background: Darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) fixed-dose combination (FDC) was developed as a once-daily, complete antiretroviral (ARV) regimen therapy to address the need for simplified protease inhibitor-based ARV regimens. This study assessed the swallowability and acceptability for long-term use of scored placebo tablets matching the D/C/F/TAF FDC tablets in children living with HIV-1.

Methods: This study (NCT04006704) was a Phase 1, open-label, randomized, single-dose, 2-period, 2-sequence crossover study in children living with HIV-1, aged ≥6 to <12 years and weighing ≥25 to <40 kg, on a stable ARV regimen for ≥3 months. Participants were asked to swallow whole (size, 21 × 11 × 7 mm) and split matching placebo D/C/F/TAF tablets. Swallowability of the matching placebo D/C/F/TAF tablets (primary endpoint) was assessed by observers. Acceptability of taking matching placebo D/C/F/TAF tablets and current ARVs was evaluated by participants using a 3-point questionnaire. Participants rated the acceptability for long-term daily use of the placebo D/C/F/TAF tablets, and observers assessed how easily caregivers could split a scored tablet by hand, using 3-point questionnaires.

Results: Among the 24 participants who enrolled and completed the study, 95.8% (23/24) were able to swallow the whole and split matching placebo D/C/F/TAF tablets after 1 or 2 attempts. Most participants (>70%) rated the acceptability of tablets for long-term daily use as acceptable or good to take. Breaking the tablets was considered easy or OK by 79.2% (19/24) of caregivers.

Conclusion: Scored D/C/F/TAF FDC tablets are swallowable - with whole favoured over split - and considered at least acceptable for long-term daily intake in children living with HIV-1 aged ≥6 to <12 years.

Trial registration: ClinicalTrials.gov Identifier: NCT04006704.

背景:达芦那韦/可比司他/恩曲他滨/替诺福韦-阿拉非那胺(D/C/F/TAF)固定剂量复合制剂(FDC)被开发为每日一次的全套抗逆转录病毒(ARV)疗法,以满足简化蛋白酶抑制剂型抗逆转录病毒疗法的需求。本研究评估了与D/C/F/TAF FDC片剂相匹配的已评分安慰剂片剂在HIV-1感染儿童中的吞咽性和长期使用的可接受性:本研究(NCT04006704)是一项第 1 期、开放标签、随机、单剂量、2 期、2 顺序交叉研究,研究对象为年龄≥6 岁的 HIV-1 儿童:在 24 名注册并完成研究的参与者中,95.8%(23/24)的人在尝试 1 或 2 次后就能吞下整片和分装的对等安慰剂 D/C/F/TAF 药片。大多数参与者(>70%)认为长期每天服用药片的可接受性是可以接受或可以服用的。79.2%(19/24)的护理人员认为掰药片很容易或没问题:结论:经评分的D/C/F/TAF FDC片剂可吞咽(整片比掰开的片剂更受欢迎),对于年龄≥6岁至12岁的HIV-1感染儿童来说,至少可以接受长期每日服用:试验注册:ClinicalTrials.gov Identifier:NCT04006704。
{"title":"Assessment of swallowability and acceptability of scored darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) fixed-dose combination (FDC) tablets in HIV-1-infected children aged ≥6 to <12 years, using matching placebo tablets: A randomized study.","authors":"Sandy Van Hemelryck, Erika Van Landuyt, Veerle Hufkens, Simon Vanveggel","doi":"10.1177/13596535241248282","DOIUrl":"10.1177/13596535241248282","url":null,"abstract":"<p><strong>Background: </strong>Darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) fixed-dose combination (FDC) was developed as a once-daily, complete antiretroviral (ARV) regimen therapy to address the need for simplified protease inhibitor-based ARV regimens. This study assessed the swallowability and acceptability for long-term use of scored placebo tablets matching the D/C/F/TAF FDC tablets in children living with HIV-1.</p><p><strong>Methods: </strong>This study (NCT04006704) was a Phase 1, open-label, randomized, single-dose, 2-period, 2-sequence crossover study in children living with HIV-1, aged ≥6 to <12 years and weighing ≥25 to <40 kg, on a stable ARV regimen for ≥3 months. Participants were asked to swallow whole (size, 21 × 11 × 7 mm) and split matching placebo D/C/F/TAF tablets. Swallowability of the matching placebo D/C/F/TAF tablets (primary endpoint) was assessed by observers. Acceptability of taking matching placebo D/C/F/TAF tablets and current ARVs was evaluated by participants using a 3-point questionnaire. Participants rated the acceptability for long-term daily use of the placebo D/C/F/TAF tablets, and observers assessed how easily caregivers could split a scored tablet by hand, using 3-point questionnaires.</p><p><strong>Results: </strong>Among the 24 participants who enrolled and completed the study, 95.8% (23/24) were able to swallow the whole and split matching placebo D/C/F/TAF tablets after 1 or 2 attempts. Most participants (>70%) rated the acceptability of tablets for long-term daily use as acceptable or good to take. Breaking the tablets was considered easy or OK by 79.2% (19/24) of caregivers.</p><p><strong>Conclusion: </strong>Scored D/C/F/TAF FDC tablets are swallowable - with whole favoured over split - and considered at least acceptable for long-term daily intake in children living with HIV-1 aged ≥6 to <12 years.</p><p><strong>Trial registration: </strong>ClinicalTrials.gov Identifier: NCT04006704.</p>","PeriodicalId":8364,"journal":{"name":"Antiviral Therapy","volume":"29 2","pages":"13596535241248282"},"PeriodicalIF":1.2,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140897130","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Adverse drug reactions attributed to generic substitution of antiretroviral medications among HIV treatment and pre-exposure prophylaxis clients in British Columbia, Canada. 加拿大不列颠哥伦比亚省艾滋病治疗和暴露前预防客户中因抗逆病毒药物非专利替代品引起的药物不良反应。
IF 1.2 4区 医学 Q4 INFECTIOUS DISEASES Pub Date : 2024-02-01 DOI: 10.1177/13596535241233128
Katherine J Lepik, Olivia L Hunt, Nic Bacani, Lu Wang, Marianne Harris, Junine Toy, Taylor McLinden, Paul Sereda, Linda J Akagi, Erin Ready, Julio Sg Montaner, Rolando Barrios

Background: In British Columbia, antiretrovirals (ARVs) for HIV treatment (HIV-Tx) and pre-exposure prophylaxis (PrEP) are free-of-charge through publicly-funded Drug Treatment Programs (DTPs). When available, less costly generics are substituted for brand-name ARVs. We describe the incidence and type of product substitution issue (PSI) adverse drug reactions (ADRs) attributed to generic ARVs.

Methods: Cohorts included DTP clients ≥19 years who received generic ARVs for HIV-Tx (abacavir-lamivudine, emtricitabine-tenofovir DF, efavirenz-emtricitabine-tenofovir DF, atazanavir or darunavir between 01 Jun 2017 and 30 Jun 2022) or PrEP (emtricitabine-tenofovir DF, 01 Apr 2018 to 30 Jun 2022). Demographic, ARV and ADR data were extracted from DTP databases and summarized by descriptive statistics. PSI incidence was calculated for each product during the year following brand-to-generic and generic-to-generic transitions (first-year-post-rollout), and compared between generic versions using generalized estimating equations. For context, incidence of any ARV product-related ADR was calculated in the same 1-year periods.

Results: During first-year-post-rollout periods, 5339 HIV-Tx (83% male, median age 52 years) and 8095 PrEP (99% male, median 33 years) clients received generic ARVs, and reported 78 and 23 generic PSIs, respectively. PSI incidence was <1% for most generic ARVs, with mild-moderate symptoms including gastrointestinal upset, headache, dizziness, fatigue/malaise and skin rash. In HIV-Tx clients, the efavirenz-containing product had higher PSI incidence than other ARVs (2.2%, p = .004), due to more neuropsychiatric adverse reactions. Any ADR incidence was stable across measurement periods, and generic PSIs represented less than one third of all product-related ADRs.

Conclusions: Generic substitution of antiretrovirals for HIV-Tx and PrEP was well tolerated, with ≤2% incidence of mild-moderate PSI ADRs.

背景:在不列颠哥伦比亚省,用于艾滋病毒治疗(HIV-Tx)和暴露前预防(PrEP)的抗逆转录病毒药物(ARVs)通过公共资助的药物治疗计划(DTPs)免费提供。如果有价格较低的非专利药,则用其替代品牌抗逆转录病毒药物。我们描述了由非专利抗逆转录病毒药物引起的产品替代问题(PSI)药物不良反应(ADR)的发生率和类型:队列包括接受非专利ARV治疗HIV-Tx(阿巴卡韦-拉米夫定、恩曲他滨-替诺福韦DF、依非韦伦-恩曲他滨-替诺福韦DF、阿扎那韦或达鲁那韦,2017年6月1日至2022年6月30日)或PrEP(恩曲他滨-替诺福韦DF,2018年4月1日至2022年6月30日)的≥19岁的DTP患者。从 DTP 数据库中提取了人口统计学、ARV 和 ADR 数据,并通过描述性统计进行了总结。在品牌向非专利药过渡和非专利药向普通药过渡(推出后第一年)后的一年中,计算每种产品的 PSI 发生率,并使用广义估计方程比较不同非专利药之间的发生率。为便于理解,在相同的 1 年时间内,还计算了与任何抗逆转录病毒药物相关的 ADR 发生率:结果:在推广后的第一年期间,5339 名 HIV-Tx 客户(83% 为男性,中位年龄为 52 岁)和 8095 名 PrEP 客户(99% 为男性,中位年龄为 33 岁)接受了非专利抗逆转录病毒药物治疗,并分别报告了 78 例和 23 例非专利 PSI。由于神经精神不良反应较多,PSI 发生率为 p = .004。任何 ADR 的发生率在各测量期间均保持稳定,非专利 PSI 占所有产品相关 ADR 的比例不到三分之一:结论:HIV-Tx 和 PrEP 抗逆转录病毒药物的非专利替代品耐受性良好,轻度-中度 PSI ADR 发生率低于 2%。
{"title":"Adverse drug reactions attributed to generic substitution of antiretroviral medications among HIV treatment and pre-exposure prophylaxis clients in British Columbia, Canada.","authors":"Katherine J Lepik, Olivia L Hunt, Nic Bacani, Lu Wang, Marianne Harris, Junine Toy, Taylor McLinden, Paul Sereda, Linda J Akagi, Erin Ready, Julio Sg Montaner, Rolando Barrios","doi":"10.1177/13596535241233128","DOIUrl":"10.1177/13596535241233128","url":null,"abstract":"<p><strong>Background: </strong>In British Columbia, antiretrovirals (ARVs) for HIV treatment (HIV-Tx) and pre-exposure prophylaxis (PrEP) are free-of-charge through publicly-funded Drug Treatment Programs (DTPs). When available, less costly generics are substituted for brand-name ARVs. We describe the incidence and type of product substitution issue (PSI) adverse drug reactions (ADRs) attributed to generic ARVs.</p><p><strong>Methods: </strong>Cohorts included DTP clients ≥19 years who received generic ARVs for HIV-Tx (abacavir-lamivudine, emtricitabine-tenofovir DF, efavirenz-emtricitabine-tenofovir DF, atazanavir or darunavir between 01 Jun 2017 and 30 Jun 2022) or PrEP (emtricitabine-tenofovir DF, 01 Apr 2018 to 30 Jun 2022). Demographic, ARV and ADR data were extracted from DTP databases and summarized by descriptive statistics. PSI incidence was calculated for each product during the year following brand-to-generic and generic-to-generic transitions (first-year-post-rollout), and compared between generic versions using generalized estimating equations. For context, incidence of any ARV product-related ADR was calculated in the same 1-year periods.</p><p><strong>Results: </strong>During first-year-post-rollout periods, 5339 HIV-Tx (83% male, median age 52 years) and 8095 PrEP (99% male, median 33 years) clients received generic ARVs, and reported 78 and 23 generic PSIs, respectively. PSI incidence was <1% for most generic ARVs, with mild-moderate symptoms including gastrointestinal upset, headache, dizziness, fatigue/malaise and skin rash. In HIV-Tx clients, the efavirenz-containing product had higher PSI incidence than other ARVs (2.2%, <i>p</i> = .004), due to more neuropsychiatric adverse reactions. Any ADR incidence was stable across measurement periods, and generic PSIs represented less than one third of all product-related ADRs.</p><p><strong>Conclusions: </strong>Generic substitution of antiretrovirals for HIV-Tx and PrEP was well tolerated, with ≤2% incidence of mild-moderate PSI ADRs.</p>","PeriodicalId":8364,"journal":{"name":"Antiviral Therapy","volume":"29 1","pages":"13596535241233128"},"PeriodicalIF":1.2,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139904878","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Failure of bamlanivimab with selection of E484K mutation in an allogeneic stem cell transplant recipient with nosocomial SARS-CoV-2 infection. 在一名感染 SARS-CoV-2 的同种异体干细胞移植受者中,选择 E484K 突变的巴马伊单抗治疗失败。
IF 1.2 4区 医学 Q4 INFECTIOUS DISEASES Pub Date : 2024-02-01 DOI: 10.1177/13596535221097495
Inès Boussen, Maud Salmona, Flore Sicre De Fontbrune, Aliénor Xhaard, Nathalie De Castro, Constance Delaugerre, Marie-Laure Chaix, Jean-Michel Molina

We report the case of an allogeneic stem cell transplant recipient with nosocomial acquisition of SARS-CoV-2 infection who received antispike neutralizing monoclonal antibody bamlanivimab 2 days after diagnosis of SARS-CoV-2 infection but progressed to severe COVID-19 pneumonia and died with the selection of E484K/Q resistance mutations to bamlanivimab.

我们报告了一例异体干细胞移植受者的病例,该受者在确诊感染 SARS-CoV-2 2 天后接受了抗梭形病毒中和单克隆抗体巴马替尼,但病情恶化为严重的 COVID-19 肺炎,并因对巴马替尼产生 E484K/Q 抗性突变而死亡。
{"title":"Failure of bamlanivimab with selection of E484K mutation in an allogeneic stem cell transplant recipient with nosocomial SARS-CoV-2 infection.","authors":"Inès Boussen, Maud Salmona, Flore Sicre De Fontbrune, Aliénor Xhaard, Nathalie De Castro, Constance Delaugerre, Marie-Laure Chaix, Jean-Michel Molina","doi":"10.1177/13596535221097495","DOIUrl":"10.1177/13596535221097495","url":null,"abstract":"<p><p>We report the case of an allogeneic stem cell transplant recipient with nosocomial acquisition of SARS-CoV-2 infection who received antispike neutralizing monoclonal antibody bamlanivimab 2 days after diagnosis of SARS-CoV-2 infection but progressed to severe COVID-19 pneumonia and died with the selection of E484K/Q resistance mutations to bamlanivimab.</p>","PeriodicalId":8364,"journal":{"name":"Antiviral Therapy","volume":"29 1","pages":"13596535221097495"},"PeriodicalIF":1.2,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139728864","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Cross-resistance to entry inhibitors and lenacapavir resistance through Week 52 in study CAPELLA. CAPELLA 研究第 52 周的入口抑制剂交叉耐药性和来那卡韦耐药性。
IF 1.2 4区 医学 Q4 INFECTIOUS DISEASES Pub Date : 2023-12-01 DOI: 10.1177/13596535231220754
Nicolas Margot, Nina Pennetzdorfer, Vidula Naik, Martin Rhee, Christian Callebaut

Background: Lenacapavir (LEN) is a first-in-class inhibitor of human immunodeficiency virus type 1 (HIV-1) capsid function for the treatment of heavily treatment-experienced people with HIV (PWH) harbouring multidrug resistance in combination with an optimized background regimen (OBR). Here, we describe in vitro analysis of the interplay between entry inhibitors (EI; enfuvirtide, fostemsavir, ibalizumab, and maraviroc) susceptibility and LEN susceptibility in samples from 72 participants in the phase 2/3 CAPELLA study, as well as the emergence of resistance in CAPELLA through 52 weeks.

Methods: The phenotypic susceptibility to EIs of screening samples from participants was analysed using entry assays, and susceptibility to LEN was generated. Genotypic and phenotypic resistance to LEN was evaluated for subjects with virological failure through Week 52.

Results: Overall, viruses with resistance to EIs showed no cross-resistance to LEN, with a mean fold change from wild type close to 1.0. Of the 22 participants analysed for resistance through Week 52, 9 participants (13%) had emergence of capsid resistance mutation(s) while the remaining 13 participants (18%) had no change in the capsid sequence.

Conclusion: The gag sequence from EI-resistant isolates did not affect LEN susceptibility. The lack of cross-resistance to LEN across ARV-resistant isolates supports the use of LEN in PWH regardless of their treatment history. During the second half-year period of the CAPELLA Study, development of LEN resistance was rare and was overall associated with functional LEN monotherapy due to either nonadherence or resistance-driven non-susceptibility to OBR.

背景:来那卡韦(LEN)是第一类人类免疫缺陷病毒1型(HIV-1)衣壳功能抑制剂,用于治疗存在多药耐药性的重度治疗经验HIV感染者(PWH),并与优化背景方案(OBR)联合使用。在此,我们描述了在体外分析2/3期CAPELLA研究中72名参与者样本中入口抑制剂(EI;恩夫韦地、福斯替沙韦、伊巴利珠单抗和马拉韦罗)敏感性和LEN敏感性之间的相互作用,以及CAPELLA在52周内出现耐药性的情况:方法:使用入口检测法分析了参与者筛选样本对 EIs 的表型药敏性,并生成了对 LEN 的药敏性。对第 52 周之前出现病毒学失败的受试者的基因型和表型对 LEN 的耐药性进行了评估:总体而言,对 EIs 产生耐药性的病毒对 LEN 没有交叉耐药性,与野生型相比的平均折叠变化接近 1.0。在第 52 周耐药性分析的 22 名参与者中,9 名参与者(13%)出现了囊膜耐药性突变,其余 13 名参与者(18%)的囊膜序列没有变化:结论:耐 EI 分离物的 gag 序列不会影响 LEN 的敏感性。耐抗逆转录病毒药物的分离株对 LEN 没有交叉耐药性,这支持了在 PWH 中使用 LEN,无论其治疗史如何。在CAPELLA研究的后半年期间,LEN耐药性的产生非常罕见,总体上与功能性LEN单药治疗有关,原因是不坚持治疗或对OBR产生耐药性。
{"title":"Cross-resistance to entry inhibitors and lenacapavir resistance through Week 52 in study CAPELLA.","authors":"Nicolas Margot, Nina Pennetzdorfer, Vidula Naik, Martin Rhee, Christian Callebaut","doi":"10.1177/13596535231220754","DOIUrl":"10.1177/13596535231220754","url":null,"abstract":"<p><strong>Background: </strong>Lenacapavir (LEN) is a first-in-class inhibitor of human immunodeficiency virus type 1 (HIV-1) capsid function for the treatment of heavily treatment-experienced people with HIV (PWH) harbouring multidrug resistance in combination with an optimized background regimen (OBR). Here, we describe in vitro analysis of the interplay between entry inhibitors (EI; enfuvirtide, fostemsavir, ibalizumab, and maraviroc) susceptibility and LEN susceptibility in samples from 72 participants in the phase 2/3 CAPELLA study, as well as the emergence of resistance in CAPELLA through 52 weeks.</p><p><strong>Methods: </strong>The phenotypic susceptibility to EIs of screening samples from participants was analysed using entry assays, and susceptibility to LEN was generated. Genotypic and phenotypic resistance to LEN was evaluated for subjects with virological failure through Week 52.</p><p><strong>Results: </strong>Overall, viruses with resistance to EIs showed no cross-resistance to LEN, with a mean fold change from wild type close to 1.0. Of the 22 participants analysed for resistance through Week 52, 9 participants (13%) had emergence of capsid resistance mutation(s) while the remaining 13 participants (18%) had no change in the capsid sequence.</p><p><strong>Conclusion: </strong>The <i>gag</i> sequence from EI-resistant isolates did not affect LEN susceptibility. The lack of cross-resistance to LEN across ARV-resistant isolates supports the use of LEN in PWH regardless of their treatment history. During the second half-year period of the CAPELLA Study, development of LEN resistance was rare and was overall associated with functional LEN monotherapy due to either nonadherence or resistance-driven non-susceptibility to OBR.</p>","PeriodicalId":8364,"journal":{"name":"Antiviral Therapy","volume":"28 6","pages":"13596535231220754"},"PeriodicalIF":1.2,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138794829","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
期刊
Antiviral Therapy
全部 Acc. Chem. Res. ACS Applied Bio Materials ACS Appl. Electron. Mater. ACS Appl. Energy Mater. ACS Appl. Mater. Interfaces ACS Appl. Nano Mater. ACS Appl. Polym. Mater. ACS BIOMATER-SCI ENG ACS Catal. ACS Cent. Sci. ACS Chem. Biol. ACS Chemical Health & Safety ACS Chem. Neurosci. ACS Comb. Sci. ACS Earth Space Chem. ACS Energy Lett. ACS Infect. Dis. ACS Macro Lett. ACS Mater. Lett. ACS Med. Chem. Lett. ACS Nano ACS Omega ACS Photonics ACS Sens. ACS Sustainable Chem. Eng. ACS Synth. Biol. Anal. Chem. BIOCHEMISTRY-US Bioconjugate Chem. BIOMACROMOLECULES Chem. Res. Toxicol. Chem. Rev. Chem. Mater. CRYST GROWTH DES ENERG FUEL Environ. Sci. Technol. Environ. Sci. Technol. Lett. Eur. J. Inorg. Chem. IND ENG CHEM RES Inorg. Chem. J. Agric. Food. Chem. J. Chem. Eng. Data J. Chem. Educ. J. Chem. Inf. Model. J. Chem. Theory Comput. J. Med. Chem. J. Nat. Prod. J PROTEOME RES J. Am. Chem. Soc. LANGMUIR MACROMOLECULES Mol. Pharmaceutics Nano Lett. Org. Lett. ORG PROCESS RES DEV ORGANOMETALLICS J. Org. Chem. J. Phys. Chem. J. Phys. Chem. A J. Phys. Chem. B J. Phys. Chem. C J. Phys. Chem. Lett. Analyst Anal. Methods Biomater. Sci. Catal. Sci. Technol. Chem. Commun. Chem. Soc. Rev. CHEM EDUC RES PRACT CRYSTENGCOMM Dalton Trans. Energy Environ. Sci. ENVIRON SCI-NANO ENVIRON SCI-PROC IMP ENVIRON SCI-WAT RES Faraday Discuss. Food Funct. Green Chem. Inorg. Chem. Front. Integr. Biol. J. Anal. At. Spectrom. J. Mater. Chem. A J. Mater. Chem. B J. Mater. Chem. C Lab Chip Mater. Chem. Front. Mater. Horiz. MEDCHEMCOMM Metallomics Mol. Biosyst. Mol. Syst. Des. Eng. Nanoscale Nanoscale Horiz. Nat. Prod. Rep. New J. Chem. Org. Biomol. Chem. Org. Chem. Front. PHOTOCH PHOTOBIO SCI PCCP Polym. Chem.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1