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Impact of new cyclooxygenase 2 inhibitors on human cytomegalovirus replication in vitro 新型环氧合酶2抑制剂对人巨细胞病毒体外复制的影响
IF 1.2 4区 医学 Q4 INFECTIOUS DISEASES Pub Date : 2021-11-01 DOI: 10.1177/13596535211064078
D. Andouard, R. Guèye, S. Hantz, C. Fagnère, B. Liagre, L. Bernardaud, C. Pouget, JL Duroux, S. Alain
Background Human cytomegalovirus (HCMV) is involved in complications on immunocompromised patients. Current therapeutics are associated with several drawbacks, such as nephrotoxicity. Purpose: As HCMV infection affects inflammation pathways, especially prostaglandin E2 (PGE2) production via cyclooxygenase 2 enzyme (COX-2), we designed 2'-hydroxychalcone compounds to inhibit human cytomegalovirus. Study design We first selected the most efficient new synthetic chalcones for their effect against COX-2-catalyzed PGE2. Study sample Among the selected compounds, we assessed the antiviral efficacy against different HCMV strains, such as the laboratory strain AD169 and clinical strains (naïve or multi-resistant to conventional drugs) and toxicity on human cells. Results The most efficient and less toxic compound (chalcone 7) was tested against HCMV in combination with other antiviral molecules: artesunate (ART), baicalein (BAI), maribavir (MBV), ganciclovir (GCV), and quercetin (QUER) using Compusyn software. Association of chalcone 7 with MBV and BAI is synergistic, antagonistic with QUER, and additive with GCV and ART. Conclusion These results provide a promising search path for potential bitherapies against HCMV.
背景人巨细胞病毒(HCMV)与免疫功能低下患者的并发症有关。目前的治疗方法有几个缺点,例如肾毒性。目的:由于HCMV感染影响炎症途径,特别是通过环氧合酶2(COX-2)产生前列腺素E2(PGE2),我们设计了2'-羟基查尔酮化合物来抑制人巨细胞病毒。研究设计我们首先选择了最有效的新合成查尔酮,以对抗COX-2催化的PGE2。研究样本在选定的化合物中,我们评估了对不同HCMV菌株的抗病毒效果,如实验室菌株AD169和临床菌株(对常规药物具有幼稚或多重耐药性),以及对人体细胞的毒性。结果用Compusyn软件检测了最有效、毒性最小的化合物查尔酮7与其他抗病毒分子青蒿琥酯(ART)、黄芩苷(BAI)、马里巴韦(MBV)、更昔洛韦(GCV)和槲皮素(QUER)联合对抗HCMV。查尔酮7与MBV和BAI具有协同作用,与QUER具有拮抗作用,与GCV和ART具有加性作用。
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引用次数: 4
Topical cidofovir for benign human papillomavirus–associated skin lesions 局部西多福韦治疗良性人乳头瘤病毒相关皮肤病变
IF 1.2 4区 医学 Q4 INFECTIOUS DISEASES Pub Date : 2021-11-01 DOI: 10.1177/13596535211059889
L. Napolitano, Liesl Schroedl, Alexander Kerman, C. Shea
Cidofovir is a broad-spectrum antiviral agent that has shown efficacy against skin lesions caused by human papillomavirus (HPV). We present a case of extensive verruca vulgaris lesions refractory to imiquimod that was responsive to topical cidofovir therapy, and analyze other case series in the literature of successful treatment of benign HPV-associated skin lesions with topical cidofovir. Topical cidofovir’s favorable response rate and tolerability make it a useful treatment option for patients of differing ages and immune status who have nonmalignant HPV-associated skin lesions and desire topical therapy.
西多福韦是一种广谱抗病毒药物,对人乳头瘤病毒(HPV)引起的皮肤损伤具有疗效。我们报告了一例咪喹莫特难治的广泛寻常疣病变,该病变对局部西多福韦治疗有反应,并分析了文献中用局部西多福韦成功治疗良性HPV相关皮肤病变的其他病例系列。局部西多福韦良好的反应率和耐受性使其成为不同年龄和免疫状态的患者的有用治疗选择,这些患者患有非恶性HPV相关皮肤病变并希望进行局部治疗。
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引用次数: 1
Markers of immune activation and inflammation in individuals with post-acute sequelae of SARS-CoV-2 infection SARS-CoV-2感染急性后后遗症患者的免疫激活和炎症标志物
IF 1.2 4区 医学 Q4 INFECTIOUS DISEASES Pub Date : 2021-07-11 DOI: 10.1101/2021.07.09.21260287
M. Peluso, S. Lu, A. Tang, M. Durstenfeld, Hsi-en Ho, S. Goldberg, C. Forman, S. Munter, R. Hoh, V. Tai, A. Chenna, B. C. Yee, J. W. Winslow, C. Petropoulos, B. Greenhouse, P. Hunt, P. Hsue, J. N. Martin, J. D. Kelly, D. Glidden, S. Deeks, T. Henrich
BACKGROUND: The biological processes associated with post-acute sequelae of SARS-CoV-2 infection (PASC) are unknown. METHODS: We measured soluble markers of inflammation in a SARS-CoV-2 recovery cohort at early (<90 days) and late (>90 days) timepoints. We defined PASC as the presence of one or more COVID-19-attributed symptoms beyond 90 days. We compared fold-changes in marker values between those with and without PASC using mixed effects models with terms for PASC and early and late recovery time periods. RESULTS: During early recovery, those who went on to develop PASC generally had higher levels of cytokine biomarkers including TNF-alpha (1.14-fold higher mean ratio, 95%CI 1.01-1.28, p=0.028) and IP-10 (1.28-fold higher mean ratio, 95%CI 1.01-1.62, p=0.038). Among those with PASC, there was a trend toward higher IL-6 levels during early recovery (1.28-fold higher mean ratio, 95%CI 0.98-1.70, p=0.07) which became more pronounced in late recovery (1.44-fold higher mean ratio, 95%CI: 1.11-1.86, p<0.001). These differences were more pronounced among those with a greater number of PASC symptoms. CONCLUSIONS: Persistent immune activation may be associated with ongoing symptoms following COVID-19. Further characterization of these processes might identify therapeutic targets for those experiencing PASC.
背景:与SARS-CoV-2感染急性后后遗症(PASC)相关的生物学过程尚不清楚。方法:我们在SARS-CoV-2康复队列的早期(90天)时间点测量了可溶性炎症标志物。我们将PASC定义为超过90天存在一种或多种与covid -19相关的症状。我们使用带有PASC术语和早期和晚期恢复时间的混合效应模型,比较了有PASC和没有PASC的标记值的倍数变化。结果:在早期恢复期间,继续发展为PASC的患者通常具有更高水平的细胞因子生物标志物,包括tnf - α(平均比值高1.14倍,95%CI 1.01-1.28, p=0.028)和IP-10(平均比值高1.28倍,95%CI 1.01-1.62, p=0.038)。在PASC患者中,IL-6水平在恢复早期有升高的趋势(平均比值高1.28倍,95%CI: 0.98 ~ 1.70, p=0.07),在恢复晚期更为明显(平均比值高1.44倍,95%CI: 1.11 ~ 1.86, p<0.001)。这些差异在PASC症状较多的人群中更为明显。结论:持续的免疫激活可能与COVID-19后持续的症状有关。对这些过程的进一步表征可能会确定PASC患者的治疗靶点。
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引用次数: 8
Safety, tolerability, pharmacokinetics, and pharmacodynamics of oral JNJ-64794964, a TLR-7 agonist, in healthy adults. 健康成人口服TLR-7激动剂JNJ-64794964的安全性、耐受性、药代动力学和药效学
IF 1.2 4区 医学 Q4 INFECTIOUS DISEASES Pub Date : 2021-05-01 DOI: 10.1177/13596535211056581
E. Gane, M. Pastagia, U. Schwertschlag, A. de Creus, C. Schwabe, J. Vandenbossche, L. Slaets, B. Fevery, Ilham Smyej, L. Wu, Rui Li, S. Siddiqui, A. Oey, C. Musto, P. van Remoortere
BACKGROUNDThis Phase I, two-part, first-in-human study assessed safety/tolerability and pharmacokinetics/pharmacodynamics of single-ascending doses (SAD) and multiple doses (MD) of the oral toll-like receptor-7 agonist, JNJ-64794964 (JNJ-4964) in healthy adults.METHODSIn the SAD phase, participants received JNJ-4964 0.2 (N = 6), 0.6 (N = 6), 1.25 (N = 8) or 1.8 mg (N = 6) or placebo (N = 2/dose cohort) in a fasted state. Food effect was evaluated for the 1.25 mg cohort following ≥6 weeks washout. In the MD phase, participants received JNJ-4964 1.25 mg (N = 6) or placebo (N = 2) weekly (fasted) for 4 weeks. Participants were followed-up for 4 weeks.RESULTSNo serious adverse events (AEs) occurred. 10/34 (SAD) and 5/8 (MD) participants reported mild-to-moderate (≤Grade 2), transient, reversible AEs possibly related to JNJ-4964. Five (SAD) participants had fever/flu-like AEs, coinciding with interferon-α serum levels ≥100 pg/mL and lymphopenia (<1 × 109/L), between 24-48 h after dosing and resolving approximately 96 h after dosing. One participant (MD) had an asymptomatic Grade 1 AE of retinal exudates (cotton wool spots) during follow-up, resolving 6 weeks after observation. JNJ-4964 exhibited dose-proportional pharmacokinetics, with rapid absorption (tmax 0.5-0.75 h) and distribution, and a long terminal half-life (150-591 h). Overall, no significant differences in JNJ-4964 pharmacokinetic parameters were observed in the fed versus fasted state. JNJ-4964 dose-dependently and transiently induced cytokines with potential anti-HBV activity, including interferon-α, IP-10, IL-1 RA, and/or MCP-1, and interferon-stimulated genes (ISG15, MX1, and OAS1) in serum.CONCLUSIONSIn healthy adults, JNJ-4964 was generally well-tolerated, exhibited dose-proportional pharmacokinetics and induced cytokines/ISGs, with possible anti-HBV activity.
这项I期、两部分、首次人体研究评估了健康成人口服toll样受体-7激动剂JNJ-64794964 (JNJ-4964)单次递增剂量(SAD)和多剂量(MD)的安全性/耐受性和药代动力学/药效学。方法在SAD期,受试者在禁食状态下接受JNJ-4964 0.2 (N = 6)、0.6 (N = 6)、1.25 (N = 8)或1.8 mg (N = 6)或安慰剂(N = 2/剂量队列)。在≥6周洗脱期后,评估1.25 mg组的食物效应。在MD阶段,参与者每周(禁食)接受JNJ-4964 1.25 mg (N = 6)或安慰剂(N = 2),持续4周。参与者随访4周。结果无严重不良事件发生。10/34 (SAD)和5/8 (MD)参与者报告了可能与JNJ-4964相关的轻度至中度(≤2级)、短暂、可逆的ae。5名(SAD)参与者在给药后24-48小时出现发烧/流感样不良反应,与血清干扰素α水平≥100 pg/mL和淋巴细胞减少(<1 × 109/L)一致,并在给药后约96小时消退。1名参与者(MD)在随访期间出现无症状的1级AE视网膜渗出物(棉絮斑),观察6周后消退。JNJ-4964表现出剂量比例药代动力学,吸收快(最长0.5-0.75 h),分布快,终末半衰期长(150-591 h)。总体而言,JNJ-4964药代动力学参数在喂养状态和禁食状态下无显著差异。JNJ-4964具有潜在抗hbv活性的剂量依赖性和瞬时诱导细胞因子,包括血清中的干扰素-α、IP-10、IL-1 RA和/或MCP-1,以及干扰素刺激基因(ISG15、MX1和OAS1)。结论在健康成人中,JNJ-4964总体耐受良好,表现出剂量比例药代动力学和诱导的细胞因子/ isg,可能具有抗hbv活性。
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引用次数: 5
Real-life findings on the impact of the COVID-19 pandemic on HIV care 关于新冠肺炎大流行对艾滋病毒护理影响的现实调查结果
IF 1.2 4区 医学 Q4 INFECTIOUS DISEASES Pub Date : 2021-05-01 DOI: 10.1177/13596535211052215
A. Ciccullo, G. Baldin, A. Borghetti, S. Di Giambenedetto
The ongoing COVID-19 pandemic is rapidly reshaping the organization of healthcare systems worldwide, prompting the creation of COVID-19–dedicated wards and services at the expense of pre-existing structures. European countries are now facing the “second wave” of the COVID-19 epidemic, with increasing numbers of cases and deaths; hence, people with chronic conditions, including those living with HIV (PLWHIV), are struggling to maintain their routine disease management, resulting in missed medical visits and the risk of lower adherence to treatment. In our clinical center in Rome, Italy, we conducted a retrospective study aimed at observing how PLWHIV were followed-up during the “first wave” of the COVID-19 epidemic in the country and during the national lockdown from March 9 to May 28, 2020. We analyzed all treatment-experienced, virologically suppressed PLWHIV who had had at least one visit between March 10 and June 1, 2020, and collected viroimmunological parameters. We compared this group of PLWHIV with the patients observed over the same period in 2019. Our primary aim was to assess the rate of virological failures (VF, defined as two consecutive HIVRNA ≥ 50 copies/mL or a single HIV-RNA ≥ 1000 copies/mL). Predictors of VF were assessed using Cox regression analysis. Regarding the 2020 group, data from 341 patients were analyzed: 235 (68.9%) were males, with a median age of 54 years (Interquartile range = 46–60), a median time from HIV diagnosis of 16.1 years (IQR = 7.6–23.8), and a median time of virological suppression of 82.4 months (IQR = 31.1–142.9). With regard to antiretroviral therapy, 149 patients (43.7%) were on a 2NRTI+INI regimen, 74 (21.7%) were on 2NRTI+NNRTI, 70 (20.5%) were on a dual regimen with DTG+3 TC, 22 (6.5%) were on a regimen with 2NRTI+bPI, and 26 (7.6%) were on other regimens. Regarding the 2019 group, data from 1066 patients were available. All patients’ characteristics and differences between groups are shown in Table 1. During 184.3 Patient-Years of Follow-Up (PYFU) of the 2020 group, we observed 23 VF, a rate of 12.5 per 100 PYFU. In patients experiencing VF, we performed a genotypic test to investigate acquired mutations: among the 23 analyzed individuals, two of them, both on a 2NRTI+raltegravir (RAL) strategy, presented newly discovered mutations (one had both the 138K and the 148R mutations and the other had the 155H mutation) conferring resistance to RAL. Interestingly, patients on a dual regimen had significantly less probability of showing VF compared to patients on 3+ drug regimens: 6-month probability of remaining virologically suppressed was 98.8% vs 90.5%, respectively (log-rank p = 0.031). In the calendar period of 2019, we observed 50 VF during 675 PYFU, a rate of 7.4 per 100 PYFU. Time of virological suppression (aHR = 0.96 per month longer, 95%CI 0.95–0.98, p < 0.001) emerged as the only
持续的新冠肺炎疫情正在迅速重塑全球医疗系统的组织,促使新冠肺炎——以牺牲原有结构为代价,建立专门的病房和服务。欧洲国家目前正面临新冠肺炎“第二波”疫情,病例和死亡人数不断增加;因此,慢性病患者,包括艾滋病毒感染者,正在努力维持他们的常规疾病管理,导致错过医疗就诊,并有降低治疗依从性的风险。在我们位于意大利罗马的临床中心,我们进行了一项回顾性研究,旨在观察PLWHIV在该国新冠肺炎“第一波”疫情期间以及2020年3月9日至5月28日全国封锁期间的随访情况。我们分析了所有在2020年3月10日至6月1日期间至少接受过一次治疗的病毒抑制PLWHIV,并收集了病毒免疫学参数。我们将这组PLWHIV与2019年同期观察到的患者进行了比较。我们的主要目的是评估病毒学失败率(VF,定义为两个连续的HIVRNA≥50拷贝/mL或单个HIVRNA≥1000拷贝/mL)。使用Cox回归分析评估VF的预测因素。关于2020组,对341名患者的数据进行了分析:235名(68.9%)为男性,中位年龄为54岁(四分位间距=46-30),从HIV诊断起的中位时间为16.1年(IQR=7.6–23.8),病毒学抑制的中位时间为82.4个月(IQR=31.1–142.9)。在抗逆转录病毒治疗方面,149名患者(43.7%)接受了2NRTI+INI方案,74例(21.7%)接受2NRTI+NNRTI治疗,70例(20.5%)接受DTG+3TC双重方案治疗,22例(6.5%)接受2NRI+bPI方案治疗,26例(7.6%)接受其他方案治疗。关于2019年组,有1066名患者的数据可用。所有患者的特征和组间差异如表1所示。在2020组的184.3患者随访年(PYFU)中,我们观察到23例VF,比率为每100例PYFU 12.5例。在经历VF的患者中,我们进行了基因型测试,以研究获得性突变:在23个分析的个体中,其中两个都采用2NRTI+拉替拉韦(RAL)策略,出现了新发现的对RAL具有耐药性的突变(一个同时具有138K和148R突变,另一个具有155H突变)。有趣的是,与3+药物方案的患者相比,双重方案的患者出现VF的概率显著降低:6个月内保持病毒学抑制的概率分别为98.8%和90.5%(log秩p=0.031)。在2019年的日历期内,我们在675 PYFU期间观察到50次VF,比率为7.4/100 PYFU。病毒学抑制时间(aHR=0.96每月更长,95%CI 0.95–0.98,p<0.001)是唯一的
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引用次数: 2
Low prevalence of doravirine-associated resistance mutations among polish human immunodeficiency-1 (HIV-1)-infected patients. 波兰人免疫缺陷病毒1型(HIV-1)感染患者中多拉韦林相关耐药性突变的低患病率。
IF 1.2 4区 医学 Q4 INFECTIOUS DISEASES Pub Date : 2021-05-01 DOI: 10.1177/13596535211043044
Kaja Scheibe, A. Urbańska, P. Jakubowski, M. Hlebowicz, M. Bociąga-Jasik, A. Raczyńska, A. Szymczak, B. Szetela, W. Łojewski, M. Parczewski
INTRODUCTIONDoravirine (DOR) is a novel non-nucleoside reverse transcriptase inhibitor (NNRTI) that retains activity against common NNRTI resistance mutations. In this study, we aimed to investigate the prevalence of DOR resistance mutations compared with that of resistance mutations for other NNRTIs among HIV-1-infected treatment-experienced and -naïve patients from Poland.METHODSResistance to DOR and other NNRTIs was assessed in two datasets: 1760 antiretroviral treatment-naïve HIV-1 patients and 200 treatment-experienced patients. All 1960 sequences were derived from the patients using bulk sequencing. For resistance analyses, Stanford HIV drug resistance database scores were used.RESULTSOverall, DOR resistance was present in 32 patients (1.62%), of whom 13 (0.74%) were naïve and 19 (9.50%) were treatment-experienced. The most common DOR resistance mutations observed among the naïve patients were A98G and K101E (0.2% each), and those among cART-experienced patients were L100I (2.0%), K101E, V108I, H221Y, and P225H (1.5% each). Furthermore, among the naïve patients, less common resistance to DOR (0.7%) compared with that to nevirapine (NVP) (2.1%; p = 0.0013) and rilpivirine (5.40%; p < 0.0001) was observed. For sequences obtained from treatment-experienced patients, the frequency of resistance to DOR (9.5%) was lower than that for efavirenz (25.5%; p < 0.0001) and NVP (26.0%; p < 0.0001).CONCLUSIONSThe frequency of transmitted drug resistance to DOR is low, allowing for effective treatment of antiretroviral treatment-naïve patients and rapid treatment initiation. In cART-experienced patients, this agent remains an attractive NNRTI option with a higher genetic barrier to resistance.
多啦韦林(DOR)是一种新型的非核苷逆转录酶抑制剂(NNRTI),对常见的NNRTI耐药性突变保持活性。在这项研究中,我们旨在调查波兰有经验和天真的HIV-1感染治疗患者中DOR耐药性突变与其他NNRTI耐药性突变的患病率。方法在两个数据集中评估对DOR和其他NNRTI的耐药性:1760名接受抗逆转录病毒治疗的幼稚HIV-1患者和200名有治疗经验的患者。所有1960个序列都是使用批量测序从患者中获得的。耐药性分析采用斯坦福大学HIV耐药性数据库评分。结果总体而言,32例(1.62%)患者存在DOR耐药性,其中13例(0.74%)为幼稚患者,19例(9.50%)有治疗经验。在幼稚患者中观察到的最常见的DOR耐药性突变是A98G和K101E(各0.2%),而在经历cART的患者中,这些突变是L100I(2.0%)、K101E、V108I、H221Y和P225H(各1.5%)。此外,在幼稚患者中,观察到对DOR的常见耐药性(0.7%)低于对奈韦拉平(NVP)(2.1%;p=0.0013)和利匹韦林(5.40%;p<0.0001)。从有治疗经验的患者获得的序列中,对DOR的耐药性发生率(9.5%)低于依非韦伦(25.5%;p<0.0001)和NVP(26.0%;p<0.001)。结论对DOR传播耐药性的发生率较低,可以有效治疗未接受抗逆转录病毒治疗的患者并快速开始治疗。在有cART经验的患者中,这种药物仍然是一种有吸引力的NNRTI选择,具有更高的耐药性遗传屏障。
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引用次数: 3
Oseltamivir and acute hepatitis, reality association or coincidence? 奥司他韦与急性肝炎,现实关联还是巧合?
IF 1.2 4区 医学 Q4 INFECTIOUS DISEASES Pub Date : 2021-05-01 DOI: 10.1177/13596535211041494
A. Mastroianni, V. Vangeli, S. Greco, Filippo Urso, F. Greco, Luciana Chidichimo, M. Mauro
Oseltamivir is an orally administered antiviral medication that selectively inhibits the influenza neuraminidase enzymes that are essential for viral replication and it is active against both influenza A and B viruses. Oseltamivir is indicated for therapy or post-exposure prevention of influenza A and B. Side effects are uncommon and include mild nausea, gastrointestinal upset, dizziness, and headache. Despite widespread use, oseltamivir has not been associated with clinically apparent liver injury; however, there is growing evidence of possible toxic liver involvement during oseltamivir therapy. To the best of our knowledge, this is the first reported case in Italy linking the development of acute hepatitis and oseltamivir therapy, in a patient suffering from influenza H1N1 infection. We also present a review of the literature on cases of oseltamivir hepatotoxicity, through the consultation of PubMed database, the bibliographical references of various articles and an extensive search using Google. In view of the analyzed results, we suggest that experts should carefully consider the need for inclusion of potential serious liver reactions be added to the oseltamivir product label.
奥司他韦是一种口服抗病毒药物,可选择性抑制病毒复制所必需的流感神经氨酸酶,对甲型和乙型流感病毒都有活性。奥司他韦适用于甲型和乙型流感的治疗或暴露后预防。副作用不常见,包括轻度恶心、胃肠不适、头晕和头痛。尽管广泛使用,奥司他韦尚未与临床明显的肝损伤相关;然而,越来越多的证据表明,在奥司他韦治疗期间可能出现毒性肝脏受累。据我们所知,这是意大利首例将急性肝炎的发展与奥司他韦治疗联系起来的报告病例,发生在H1N1流感感染患者身上。我们还通过PubMed数据库的咨询、各种文章的参考书目和谷歌的广泛搜索,对奥司他韦肝毒性病例的文献进行了回顾。鉴于分析结果,我们建议专家应仔细考虑是否需要在奥司他韦产品标签中加入潜在的严重肝脏反应。
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引用次数: 1
Rilpivirine plus cobicistat-boosted darunavir as alternative to standard three-drug therapy in HIV-infected, virologically suppressed subjects: Final results of the PROBE 2 trial. 利匹韦林加钴司他体达芦那韦替代标准三药疗法治疗艾滋病毒感染、病毒抑制受试者:PROBE 2试验的最终结果。
IF 1.2 4区 医学 Q4 INFECTIOUS DISEASES Pub Date : 2021-05-01 DOI: 10.1177/13596535211042226
F. Maggiolo, N. Gianotti, L. Comí, E. di Filippo, L. Fumagalli, S. Nozza, L. Galli, D. Valenti, M. Rizzi, A. Castagna
BACKGROUNDPrimary analysis at 24 weeks showed that switching to rilpivirine plus darunavir/cobicistat was non-inferior to continuing a standard three-drug antiretroviral regimen in virologically suppressed people with HIV. We present efficacy and safety data from the 48-week analysis.METHODSPROBE 2 is a randomized, open-label trial. Adults who were on a three-drug therapy and had had <50 HIV-1 RNA copies/mL for at least 6 months were randomly assigned (1:1) to 25 mg rilpivirine plus 800/150 darunavir/cobicistat once daily (early switch group) or to continue their regimen for 24 weeks before switching (late switch group). In the 48-week analysis, the efficacy endpoint was the proportion of participants with <50 copies/mL of HIV-RNA (US Food and Drug Administration snapshot algorithm). The trial is registered with ClinicalTrials.gov, number NCT04064632.FINDINGS160 participants were recruited and randomized. At week 48, 70 (87.5%) in the early switch group and 76 (94.8%) in the late switch group maintained HIV-RNA <50 copies/mL. Virological failure (≥50 HIV-RNA copies/mL) was not seen in any patient of the early switch group and in 2 subjects in the late switch group none of which had treatment emergent resistance-associated mutation. Adverse events leading to treatment discontinuation occurred in 7 (8.7%) participants in the early switch group and in none in the late switch group.INTERPRETATIONThe combination of rilpivirine plus darunavir/cobicistat sustained virological suppression, was associated with a low frequency of virological failure, and had a favorable safety profile, which support its use as a nucleoside reverse transcriptase inhibitor-sparing and integrase inhibitor-sparing alternative to three-drug regimens.
背景24周时的初步分析表明,在病毒抑制的艾滋病毒感染者中,改用利匹韦林加达芦那韦/cobicstat并不劣于继续使用标准的三药抗逆转录病毒疗法。我们提供了48周分析的疗效和安全性数据。方法2是一项随机、开放标签的试验。接受三种药物治疗且至少6个月内HIV-1 RNA拷贝数<50个/mL的成年人被随机分配(1:1)至25 mg利匹韦林加800/150达芦那韦/钴司他,每日一次(早期切换组)或在切换前继续其方案24周(晚期切换组)。在48周的分析中,疗效终点是HIV-RNA拷贝数<50个/mL的参与者比例(美国食品药品监督管理局快照算法)。该试验在ClinicalTrials.gov上注册,编号为NCT04064632。招募并随机分配了FINDINGS160名参与者。在第48周,早期切换组70人(87.5%)和晚期切换组76人(94.8%)的HIV-RNA<50拷贝/mL。早期切换组的任何患者和晚期切换组的2名受试者均未出现病毒学失败(≥50个HIV-RNA拷贝数/mL),均未出现治疗引发的耐药性相关突变。早期转换组有7名(8.7%)参与者发生了导致治疗中断的不良事件,晚期转换组没有发生。解释利匹韦林联合达芦那韦/柯比司他联合用药可维持病毒学抑制,与病毒学失败频率低相关,且具有良好的安全性,这支持其作为三种药物方案的核苷逆转录酶抑制剂保留和整合酶抑制剂保留替代方案使用。
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引用次数: 0
Evaluation of doravirine-based regimen population target in a large Italian clinical center. 在意大利一家大型临床中心评估以多拉韦林为基础的方案人群目标。
IF 1.2 4区 医学 Q4 INFECTIOUS DISEASES Pub Date : 2021-05-01 DOI: 10.1177/13596535211056556
D. Farinacci, A. Ciccullo, F. Lombardi, D. Moschese, Anna D’Angelillo, V. Iannone, F. Lamanna, R. Passerotto, S. Giambenedetto
BACKGROUNDDoravirine (DOR) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) approved for HIV-1 infection treatment. Because of its genetic barrier, DOR appears to be a good alternative in switch strategies compared to other NNRTI. Our aim was to evaluate the percentage of people living with HIV (PLWHIV) followed in our center who could be eligible to a DOR-based regimen.METHODSWe collected data from all treatment-experienced PLWHIV, never exposed to DOR and with a demonstrated virological suppression. We analyzed previous genotypic analyses, clinical history, and previous exposure to NNRTIs.RESULTSWe analyzed data from 653 patients, whose characteristics are shown in Table 1. 59% of them presented no resistance mutation (RAM) at genotypic analysis. The most common DOR-related RAM were V106A, Y181V, and Y188L. We also analyzed RAM that can possibly interfere with combination therapy (mostly K65R and M184V). In the end, 81.8% of our patients results to be eligible for a DOR-based therapy regimen.CONCLUSIONSDOR represents a good option for switch strategies in virological suppressed PLWHIV. It seems to have a higher genetic barrier and a lower risk for resistance mutation development compared to other NNRTI. In our cohort, we found 81.8% of patients who could be eligible for a regimen containing DOR and almost 2/3 of patients who can be treated with the fixed-dose combination DOR/3TC/TDF.
doravirine (DOR)是一种被批准用于治疗HIV-1感染的非核苷类逆转录酶抑制剂(NNRTI)。由于其遗传屏障,与其他NNRTI相比,DOR似乎是一种很好的切换策略。我们的目的是评估在我们中心随访的符合dor方案的HIV感染者(PLWHIV)的百分比。方法:我们收集了所有接受过治疗的PLWHIV患者的数据,这些患者从未暴露于DOR,并且表现出病毒学抑制。我们分析了以前的基因型分析、临床病史和以前暴露于NNRTIs。结果我们分析了653例患者的数据,其特征见表1。在基因型分析中,59%未出现耐药突变(RAM)。最常见的与dor相关的RAM是V106A、Y181V和Y188L。我们还分析了可能干扰联合治疗的RAM(主要是K65R和M184V)。最终,81.8%的患者符合以dor为基础的治疗方案。结论sdor是病毒学抑制的plwhv切换策略的良好选择。与其他NNRTI相比,它似乎具有更高的遗传屏障和更低的抗性突变发展风险。在我们的队列中,我们发现81.8%的患者有资格接受含有DOR的方案,几乎2/3的患者可以接受固定剂量DOR/3TC/TDF联合治疗。
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引用次数: 1
An unexpected adverse effect: Elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide–induced cholestasis 意想不到的不良反应:依维替韦/可比司他/恩曲他滨/替诺福韦-阿拉芬胺诱导的胆汁淤积
IF 1.2 4区 医学 Q4 INFECTIOUS DISEASES Pub Date : 2021-01-01 DOI: 10.1177/13596535211045832
A. Ugarte, Lorena de la Mora, M. Martinez-Rebollar, J. Mallolas, M. Laguno
The morbidity and mortality of people living with HIV (PLWH) has decreased markedly after the introduction of highly effective antiretroviral therapy (ART). The safety profile of drugs used for HIV has improved over time, and nowadays, co-formulated combinations with excellent tolerability are available. One of the most commonly used is elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (EVG/COBI/FTC/TAF) due to its effectiveness in viral suppression and good tolerability [1-2]. PLWH are at greater risk of suffering hepatobiliary complications, not only caused by opportunistic infections or AIDS cholangiopathy related to advanced immunosuppression but also due to drug-induced hepatotoxicity, use of alcohol or other substances, coinfections with hepatitis virus or liver steatosis [3]. This article describes a case of a patient who developed a severe increase in cholestasis parameters after starting EVG/COBI/FTC/TAF regimen, probably related to integrase strand transfer inhibitor (InSTI). Liver enzyme elevation during InSTI-based therapy is an unusual finding. To our knowledge, this is the first report in the literature of EVG/COBI/FTC/TAF-associated cholestasis. The article tries to generate knowledge in order to strengthen pharmacovigilance of this adverse effect and reviews the available data on cholestasis in PLWH.
采用高效抗逆转录病毒疗法后,艾滋病毒感染者的发病率和死亡率显著下降。随着时间的推移,用于治疗艾滋病毒的药物的安全性有所改善,如今,可以获得具有良好耐受性的联合制剂。最常用的药物之一是艾维替拉韦/钴司他韦/恩曲他滨/替诺福韦-阿拉芬酰胺(EVG/COBI/FFTC/TAF),因为它对病毒的抑制作用和良好的耐受性[1-2]。PLWH患肝胆并发症的风险更大,这不仅是由机会性感染或与晚期免疫抑制相关的艾滋病胆道病引起的,也是由药物诱导的肝毒性、使用酒精或其他物质、肝炎病毒或肝脂肪变性共同感染引起的[3]。本文描述了一例患者在开始EVG/COBI/FTC/TAF方案后胆汁淤积参数严重增加,可能与整合酶链转移抑制剂(InSTI)有关。InSTI治疗期间肝酶升高是一个不寻常的发现。据我们所知,这是EVG/COBI/FTC/TAF相关胆汁淤积的文献中的第一篇报道。本文试图积累知识,以加强对这种不良反应的药物警惕,并回顾了PLWH胆汁淤积的现有数据。
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引用次数: 2
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Antiviral Therapy
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