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Supreme Court decision on genotypic tests for antiretroviral drugs resistance: Joint Criminal Divisions. 最高法院关于抗逆转录病毒药物耐药性基因型检测的决定:联合刑事司。
F Dianzani, E Frascione
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引用次数: 0
Genotypic resistance tests for the management of structured therapeutic interruptions after multiple drug failure. 基因型耐药试验对多种药物失败后结构性治疗中断的管理。
Maria Montroni, Antonella D'Arminio Monforte

Witness for the prosecution: Structured treatment interruption (STI) has been considered among the possible therapeutic options for multidrug experienced HIV-infected individuals facing virological failure, since early studies suggested the possibility of viral reversion from drug-resistant mutated species to drug-sensitive wild-type virus following the release of drug pressure. However, the persistence of mutated viral populations during STI has been observed. The lack of detection of resistance mutations in plasma is mainly due to the low sensitivity of the currently available genotypic resistance testing, which is unable to detect resistant less fit virus masked by overwhelming re-emerged wild-type quasi-species. Restarting antiretroviral therapy (ART) is frequently followed by the reappearance of resistant virus, as well as by disease progression. STI should be applied with extreme caution in multidrug experienced HIV-infected individuals with virological failure. Use of genotype resistance testing in this particular setting, although useful in controlled clinical trials, should be considered of little help in clinical practice. Witness for the defence: The rationale for salvage STI has been elucidated. Data from observational and randomized studies have been revised, and the following conclusions in defence of salvage STI are: in more than 60% of patients undergoing salvage STI for at least 3 months there is a reversion of drug-associated mutations. Concurrently, increases in HIV-RNA and decreases in CD4 cells occur. Few clinical events have been reported in patients with CD4 counts of < 200 cells/mm3. New resistance-driven salvage regimens, including at least 1 new drug, result in good virological outcome in a short-term follow-up. Warnings are related to possible clinical progression and to the course of the infection in reservoirs. Randomized studies are required to elucidate these findings.

控方证人:结构化治疗中断(STI)已被认为是面临病毒学失败的多种药物经验的艾滋病毒感染者的可能治疗选择之一,因为早期研究表明,在药物压力释放后,病毒可能从耐药突变物种逆转为对药物敏感的野生型病毒。然而,已经观察到在性传播感染期间突变病毒种群的持久性。血浆中缺乏耐药突变的检测主要是由于目前可用的基因型耐药检测灵敏度低,无法检测被大量重新出现的野生型准物种掩盖的耐药度较低的病毒。重新开始抗逆转录病毒治疗(ART)之后,经常出现耐药病毒的重新出现以及疾病进展。在病毒学失败的有多种药物经验的艾滋病毒感染者中,应极其谨慎地应用性传播感染。在这种特殊情况下使用基因型耐药检测,尽管在对照临床试验中有用,但在临床实践中应被认为帮助不大。辩方证人:打捞性STI的理由已经阐明。来自观察性研究和随机研究的数据已经被修订,以下结论可以为补救性性传播感染辩护:在60%以上接受补救性性传播感染至少3个月的患者中,药物相关突变出现逆转。同时,HIV-RNA增加,CD4细胞减少。CD4计数< 200 cells/mm3的患者很少有临床事件报道。新的耐药挽救方案,包括至少一种新药,在短期随访中产生良好的病毒学结果。警告与可能的临床进展和水库感染的过程有关。需要随机研究来阐明这些发现。
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引用次数: 0
Viral resistance to chemotherapeutic agents: an expectable unexpected phenomenon. 病毒对化疗药物的耐药性:一种意料之外的现象。
Pub Date : 2003-01-01 DOI: 10.1080/03008870310016238
Ferdinando Dianzani
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引用次数: 3
Genotypic resistance tests for the clinical management of patients with primary HIV infection. 基因型耐药试验在原发性HIV感染患者临床管理中的应用。
Pasquale Narciso, Adriano Lazzarin

Witness for the prosecution: Assays to detect antiretroviral drug resistance have recently become available, but several factors limit the clinical utility of resistance testing in patients with primary HIV infection (PHI). First, there is a great uncertainty in the prevalence of PHI due to resistant virus, which may vary from 2% to over 50%. Moreover, studies on temporal trends give discordant results. Secondly, the reported degree of resistance is also variable since low levels of resistance are reported in some cases. The clinical significance of such low-level baseline reduced susceptibility to some antiretrovirals is uncertain. Thirdly, current resistance testing might not detect minority populations of drug-resistant species. Reversion of mutations conferring drug resistance was described in patients who acquired drug-resistant strains, and viral strains harbouring drug-resistant mutations may become minor species in untreated patients owing to the absence of drug pressure. Finally, no prospective clinical trials have been conducted to test the clinical or virological utility of resistance testing in PHI. Witness for the defence: A suboptimal initial regimen in subjects infected with drug-resistant virus may be associated with multiple treatment failures in the early stage of the disease and hence with a more rapid disease progression. When treating PHI, immediate, complete and long-lasting suppression of virus replication is desired both to limit total body viral burden and to preserve HIV-1 specific immune responses. Transmission of resistant virus has been identified for each therapeutic class. A greater than 2.5-fold resistance to one or more antiretroviral agent has been observed in 26% of patients with PHI and resistance among newly infected patients has increased over the past 3 y. Treatment should not be delayed to wait for the result of the test. However, once a resistant virus has been identified, one or more drugs can be readily substituted. Prospective randomized studies to address the need for baseline resistance testing in the setting of PHI are warranted.

控方证人:检测抗逆转录病毒药物耐药性的检测方法最近已经可用,但有几个因素限制了耐药性检测在原发性艾滋病毒感染(PHI)患者中的临床应用。首先,由于耐药病毒,PHI的流行率存在很大的不确定性,可能从2%到50%以上不等。此外,对时间趋势的研究得出了不一致的结果。其次,报告的耐药程度也不同,因为在某些情况下报告了低水平的耐药。这种低水平基线降低对某些抗逆转录病毒药物易感性的临床意义尚不确定。第三,目前的耐药检测可能无法检测到少数耐药物种。在获得耐药菌株的患者中描述了赋予耐药的突变的逆转,并且由于缺乏药物压力,携带耐药突变的病毒菌株可能在未经治疗的患者中成为次要物种。最后,没有进行前瞻性临床试验来测试PHI耐药试验的临床或病毒学效用。辩方证人:在感染耐药病毒的受试者中,不理想的初始治疗方案可能与疾病早期多次治疗失败有关,因此与疾病进展更快有关。在治疗PHI时,需要立即、完全和持久地抑制病毒复制,以限制全身病毒负担并保持HIV-1特异性免疫反应。已确定每个治疗类别都有耐药病毒的传播。26%的PHI患者对一种或多种抗逆转录病毒药物的耐药性大于2.5倍,在过去3年中,新感染患者的耐药性有所增加。不应延迟治疗以等待检测结果。然而,一旦发现一种耐药病毒,就可以很容易地用一种或多种药物替代。有必要进行前瞻性随机研究,以解决在PHI背景下基线耐药测试的需要。
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引用次数: 0
Cellular issues relating to the resistance of HIV to antiretroviral agents. 与艾滋病毒对抗逆转录病毒药物的耐药性有关的细胞问题。
Pub Date : 2003-01-01 DOI: 10.1080/03008870310009669
Ombretta Turriziani, Carolina Scagnolari, Francesca Bellomi, Isabella Solimeo, Federico Focher, Guido Antonelli

It has been proposed that the declining efficiency of antiretroviral agents in human immunodeficiency virus (HIV) infection may also depend on cellular factors at their site of action. Two in particular have been proposed: (i) the defective intracellular metabolism of NRTI in target cells and the altered uptake; and (ii) efflux of nucleoside reverse transcriptase inhibitors (NRTI) and protease inhibitors (PI) by cellular transporter molecules. Several studies have shown that: changes in the activities of various purine and pyrimidine biosynthetic enzymes may occur in lymphocytes of HIV-infected patients; HIV-infected patients on prolonged treatment with nucleoside analogues, e.g. zidovudine, show significantly decreased activity of thymidine kinase (TK) compared with untreated HIV-infected people; and NRTI and PI are substrates for the multidrug membrane transporters. With regard to the latter issue, it is known that the ATP-binding cassette transporter proteins such as the P-glycoprotein (MDR), and the newly discovered family of multidrug resistance-associated proteins (MRP1-6), promote the active extracellular efflux of a wide variety of therapeutics drugs and overexpression of some of them lowers intracellular concentration of PI. In the very near future such mechanisms, also called 'cellular drug resistance', might be taken into account, together with other immunological, virological and behavioural factors, to explain the 'drug failure' and/or the variability of response in HIV patients undergoing antiretroviral treatment.

有人提出,抗逆转录病毒药物在人类免疫缺陷病毒(HIV)感染中的效率下降也可能取决于其作用部位的细胞因子。提出了两个特别的问题:(i) NRTI在靶细胞中的细胞内代谢缺陷和摄取改变;(ii)核苷类逆转录酶抑制剂(NRTI)和蛋白酶抑制剂(PI)通过细胞转运体分子外排。多项研究表明:hiv感染者淋巴细胞中各种嘌呤和嘧啶生物合成酶的活性可能发生变化;与未经治疗的艾滋病毒感染者相比,长期接受核苷类似物(如齐多夫定)治疗的艾滋病毒感染者胸苷激酶(TK)活性显著降低;NRTI和PI是多药膜转运体的底物。关于后一个问题,我们知道atp结合盒转运蛋白如p -糖蛋白(MDR)和新发现的多药耐药相关蛋白家族(MRP1-6)可促进多种治疗药物的活跃细胞外外排,其中一些蛋白的过表达可降低细胞内PI浓度。在不久的将来,可能会考虑到这种机制,也称为“细胞耐药性”,以及其他免疫学、病毒学和行为因素,以解释接受抗逆转录病毒治疗的艾滋病毒患者的“药物失败”和/或反应的可变性。
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引用次数: 8
Interpretation systems for genotypic drug resistance of HIV-1. HIV-1基因型耐药解释系统。
Pub Date : 2003-01-01 DOI: 10.1080/03008870310009623
Andrea De Luca, Andrea Antinori, Simona Di Giambenedetto, Antonella Cingolani, Manuela Colafigli, Carlo Federico Perno, Roberto Cauda

Genotypic assays are widely used tools for determining human immunodeficiency virus type 1 (HIV-1) drug resistance and for guiding treatment changes in patients failing antiretroviral therapy. Several systems have been developed to interpret the complex influence of key amino acid substitutions of the enzymes targeted by therapy on the phenotypic susceptibility or clinical response to available antiretroviral agents. This overview identifies 21 systems giving an interpretation on how amino acid substitutions affect phenotypic drug susceptibility or clinical activity of anti-HIV-1 agents. There was substantial variability in the mechanisms underlying the interpretations, the nature of the systems, their intended use, the source type of their knowledge base, and their update and output. Most of the systems could be accessed for free on the internet, functioned as rule-based algorithms updated by experts and at least partially based on literature evidence, and offered an automated report through a software. Nevertheless, the rule base was not always clarified. An update of the rules and the clinical validation of the systems are presented to help in the critical evaluation of their possible use. Importantly, only 8 systems were intended for clinical use and 5 of these had at least partially undergone clinical validation.

基因型检测是广泛使用的工具,用于确定人类免疫缺陷病毒1型(HIV-1)耐药性,并指导抗逆转录病毒治疗失败患者的治疗变化。已经开发了几个系统来解释治疗靶向酶的关键氨基酸取代对表型易感性或对可用抗逆转录病毒药物的临床反应的复杂影响。本综述确定了21个系统,解释了氨基酸取代如何影响抗hiv -1药物的表型药物敏感性或临床活性。在解释的基础机制、系统的性质、它们的预期用途、它们的知识库的来源类型以及它们的更新和输出方面存在着大量的变化。大多数系统可以在互联网上免费访问,作为基于规则的算法,由专家更新,至少部分基于文献证据,并通过软件提供自动报告。然而,规则基础并不总是得到澄清。规则的更新和系统的临床验证被提出,以帮助在其可能使用的关键评估。重要的是,只有8个系统用于临床使用,其中5个至少部分经历了临床验证。
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引用次数: 15
Brief summary of the legal proceeding. 法律程序的简要总结。
Pub Date : 2003-01-01 DOI: 10.1080/03008870310009849
Emanuele Nicastri

The panel, held in Rome in April 2002 with the participation of more than 100 Italian directors of infectious diseases wards, followed a systematic approach to reviewing the evidence of any specific use of the genotypic assays to detect antiretroviral resistance. The single recommendations have been developed using a rating scheme based on consideration of the evidence and, when direct evidence was lacking, on expert opinion. Another emerging issue approached during this meeting is represented by the reproducibility of HIV-1 reverse transcriptase and protease sequencing in clinical settings. The degree of concordance of genotypic assays among 12 experienced laboratories is also reported.

该小组于2002年4月在罗马举行,有100多名意大利传染病病房主任参加。该小组采用了一种系统的方法,审查任何具体使用基因型测定法检测抗逆转录病毒耐药性的证据。这些单一的建议是使用一种评级方案制定的,该方案基于对证据的考虑,在缺乏直接证据时,根据专家意见。本次会议讨论的另一个新问题是HIV-1逆转录酶和蛋白酶测序在临床环境中的可重复性。还报告了12个有经验的实验室的基因型测定的一致性程度。
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引用次数: 1
HIV fitness and resistance as covariates associated with the appearance of mutations under antiretroviral treatment. 艾滋病毒适应度和耐药性作为协变量与抗逆转录病毒治疗下突变的出现相关。
Pub Date : 2003-01-01 DOI: 10.1080/03008870310009641
Carlo Federico Perno, Alessandra Cenci, Cristina Piro, Roberta D'Arrigo, Luisa Marcon, Francesca Ceccherini-Silberstein, Franca Ascoli Marchetti, Raffaele Caliò, Andrea Antinori

The ability of human immunodeficiency virus (HIV) strains to replicate in human target cells represents a major driving force of the progression of the disease. Despite antiretroviral treatment, HIV overcomes drug pressure by adding new (compensatory) mutations, appearing in a specific and sequential order, that modulate its replication capacity and favour viral escape. In the case of M184V (a mutation involving the catalytic site of HIV reverse transcriptase), no pathways of viral escape have been defined so far; it is thus conceivable that the mutated virus maintains a relatively low replicative capacity. At the time of interruption of specific viral pressure (lamivudine in the case of M184V), wild-type virus easily overgrows mutated strains. A deep molecular analysis (90 clones) conducted on proviral DNA of lymphocytes demonstrates that M184V strains are no longer detected in plasma and proviral DNA shortly after interruption of therapeutic regimens including lamivudine (even if a new therapeutic regimen has been started). This supports the concept that the low fitness of M184V strains is not easily compensated by additional mutations. Taken together, the results suggest that the assessment of viral fitness, either direct (through biological methods) or indirect (through the identification of specific mutations that affect the replicative capacity), may provide substantial advancements in the definition of the long-term efficacy of antiretroviral therapy.

人类免疫缺陷病毒(HIV)毒株在人类靶细胞中复制的能力是该疾病进展的主要驱动力。尽管有抗逆转录病毒治疗,艾滋病毒还是通过增加新的(代偿性)突变来克服药物压力,这些突变以特定的顺序出现,调节其复制能力并有利于病毒逃逸。以M184V(一种涉及HIV逆转录酶催化位点的突变)为例,迄今为止还没有确定病毒逃逸的途径;因此可以想象,突变病毒保持了相对较低的复制能力。在特定病毒压力中断时(M184V病例中使用拉米夫定),野生型病毒容易过度生长突变株。对淋巴细胞前病毒DNA进行的深度分子分析(90个克隆)表明,在包括拉米夫定在内的治疗方案中断后不久(即使已经开始新的治疗方案),血浆和前病毒DNA中不再检测到M184V菌株。这支持了M184V菌株的低适应度不易通过额外突变来补偿的概念。综上所述,这些结果表明,对病毒适应性的评估,无论是直接(通过生物学方法)还是间接(通过确定影响复制能力的特定突变),都可能在定义抗逆转录病毒治疗的长期疗效方面取得实质性进展。
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引用次数: 4
Cost-effectiveness analysis of using antiretroviral drug resistance testing. 使用抗逆转录病毒药物耐药性检测的成本效益分析。
Pub Date : 2003-01-01 DOI: 10.1080/03008870310009687
Francesco Nicola Lauria, Claudio Angeletti

Human immunodeficiency virus (HIV)-infected patients failing highly active antiretroviral therapy (HAART) have a substantially lower chance of clinical success than naive patients given their first antiretroviral therapy. This suggests that HAART failure is a determinant for an increase in the cost of treatment. A review of the literature regarding cost and impact of antiretroviral drug-resistance testing was performed. Examination of existing methods to execute a cost-effectiveness analysis on the use of these tests in clinical practice was also undertaken. The cost of treatment failure in HIV-infected patients has been quantified in several retrospective studies. The cost of care for patients with virological suppression was significantly lower than those with a single virological failure. Moreover, the latter group had lower costs than patients with multiple failures. The result of the cost-effective analysis based on a specific model application using genotypic resistance assays to guide the choice of a subsequent therapy in HIV disease, is cost-effective under a wide range of assumptions regarding effectiveness and costs. The available studies on the cost-effective evaluation of genotypic tests are limited, and the respective studies supply important indications on cost-effective evaluations. Despite its demonstrated benefits, antiretroviral drug resistance testing presents features and limitations that also restrict the cost-effectiveness analysis.

人类免疫缺陷病毒(HIV)感染的患者未能接受高效抗逆转录病毒治疗(HAART),其临床成功的机会大大低于初次接受抗逆转录病毒治疗的患者。这表明HAART治疗失败是治疗费用增加的决定因素。对有关抗逆转录病毒耐药性检测的成本和影响的文献进行了回顾。还审查了现有方法,以便对在临床实践中使用这些测试进行成本效益分析。在几项回顾性研究中,对艾滋病毒感染患者治疗失败的成本进行了量化。病毒学抑制患者的护理费用明显低于单一病毒学失败患者。此外,后者比多次失败的患者成本更低。基于特定模型应用的成本效益分析结果,使用基因型耐药性测定来指导艾滋病毒疾病后续治疗的选择,在关于有效性和成本的广泛假设下具有成本效益。关于基因型检测的成本效益评价的现有研究是有限的,各自的研究提供了成本效益评价的重要指标。尽管抗逆转录病毒耐药检测显示出益处,但其特点和局限性也限制了成本效益分析。
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引用次数: 8
The legal proceeding: introduction of the witnesses. 法律程序:介绍证人。
Pub Date : 2003-01-01 DOI: 10.1080/03008870310009731
Emanuele Nicastri
For the purposes of this proceeding, either the witness for defence or the plaintiff will discuss the strength and the level of each single indication for the use of genotypic assays for the detection of antiretroviral resistance. The witnesses will consider the peer-reviewed medical literature and the experts’ opinions expressed during international scientific congresses to promote or not to promote the use of genotypic assays.
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引用次数: 0
期刊
Scandinavian journal of infectious diseases. Supplementum
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