Single-dose nevirapine and drug resistance: the more you look, the more you find.
Single-dose nevirapine and drug resistance: the more you look, the more you find.
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单剂量奈韦拉平与耐药性：你看得越多，发现的就越多。
DOI：
10.1086/430745
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发表时间：
2005
期刊：
影响因子：
--
通讯作者：
Hammer,ScottM
中科院分区：
文献类型：
--
作者：
Hammer,ScottM
在治疗艾滋病毒感染药物的历史发展背景下，也许没有任何主题比使用这些药物阻断HIV-1的母婴传播（MTCT）更具争议性。艾滋病临床试验组076号方案是过去20年来治疗方面最值得注意的进展之一，在该方案中，产前和产时给予母亲以及出生后前6周给予婴儿齐多夫定（ZDV），可使HIV-1的母婴传播率降低70%。然而，该议定书的拟订阶段充满了激烈的辩论，特别是关于审判的道德问题。艾滋病毒1型经母体感染的比例从25%降至8%，立即导致发达国家公共卫生政策的改变，随着随后对母亲使用强效抗逆转录病毒药物组合和明智地使用剖腹产，新生儿艾滋病毒1型感染现在在资源不受限制的环境中已是罕见事件。在过去两年中，一种将抗逆转录病毒疗法的拯救生命的益处带给发展中世界的革命性承诺是显而易见的。总统的艾滋病紧急救援计划、世界卫生组织的3.5倡议和全球抗击艾滋病、结核病和疟疾基金是这一努力中最广为宣传的方面。然而，早在最近采取这些行动为数百万艾滋病毒感染者提供治疗之前，世界各地的临床研究人员就在试图开发比相对复杂的076方案更具成本效益的战略，以减少艾滋病毒1的母婴传播。已经测试了许多策略，但影响最大并引起最大轰动的是使用单剂量奈韦拉平（SD-NVP）。1999年，在乌干达进行的艾滋病毒预防试验网络（HIVNET）012试验报告说，在分娩时给予母亲单次200 mg剂量的NVP，随后在出生后72小时内给予婴儿单次2 mg/kg剂量，与短期ZDV相比，治疗后14-16周的MTCT降低了50%，其持续获益延长至治疗后18个月[2，3]。这一结果被誉为一个巨大的突破，因为它是一种易于管理的方案，价格低廉，不需要额外的医疗基础设施，甚至可以在最偏远的地区广泛而迅速地部署。近几个月来，HIVNET 012试验受到了新的审查[4]，促使医学研究所进行审查。与任何新的医疗干预一样，无论是预防性的还是治疗性的，都有不可避免的权衡。接受SD-NVP的母亲或婴儿未出现重大安全性问题。然而，在SD-NVP背景下出现的耐药性对科学、临床研究和公共卫生界造成了越来越大的挑战。回顾过去，与非核苷类逆转录酶抑制剂（NNRTI）耐药相关的突变会随着药物给药而出现并不奇怪，多年来已描述了快速、单步、高水平耐药和半衰期延长[5]。同样重要的是要记住，HIV的复制动力学和逆转录的性质导致病毒基因组中恒定且不可避免的突变率，因此在不暴露于任何药物的情况下发生耐药性相关突变。在暴露于药物期间和之后，抗逆转录病毒药物的选择压力极大地促进了新突变的发生，特别是如果它是...
Within the context of the historic development of drugs to treat HIV infection, there is perhaps no subject that has created more controversy than the use of these agents to interrupt the mother-tochild transmission (MTCT) of HIV-1. No one now takes issue with the fact that the AIDS Clinical Trials Group Protocol 076—in which zidovudine (ZDV), given to the mother pre-and intrapartum and to the infant for the first 6 weeks of life, reduced MTCT of HIV-1 by 70%—has been one of the most noteworthy advances in treatment of the past 20 years [1]. However, the development phase of that protocol was fraught with intense debate, particularly with respect to the ethics of the trial. The reduction in MTCT of HIV-1 from 25% to 8% immediately led to changes in public health policy in the developed world and, with the subsequent application of potent combinations of antiretroviral drugs for the mother and judicious use of caesarean section, neonatal HIV-1 infection is now a rare event in resource-unconstrained settings. During the past 2 years, a revolutionary commitment to bring the life-saving benefits of antiretroviral treatment to the developing world has been evident. The President’s Emergency Plan for AIDS Relief, the World Health Organization’s 3 5 Initiative, and the Global Fund to Fight AIDS, Tuberculosis, and Malaria are the most publicized aspects of this effort. However, well before these recent actions to provide treatment to millions of persons with HIV, clinical researchers around the world were attempting to develop more cost-effective strategies than the relatively complex 076 regimen to reduce MTCT of HIV-1. A number of strategies have been tested, but the one that has had the greatest impact and has created the greatest stir is the use of single-dose nevirapine (SD-NVP). In 1999, the HIV Network for Prevention Trials (HIVNET) 012 trial, performed in Uganda, reported that a single 200-mg dose of NVP given to the mother at the time of delivery followed by a single 2-mg/kg dose given to the infant within 72 h of birth resulted in a reduction in MTCT of 50% at 14–16 weeks after treatment, compared with a short course of ZDV, and its persistent benefit extended to 18 months after treatment [2, 3]. This result was hailed as a dramatic breakthrough, because it was an easy regimen to administer, was inexpensive, required no additional health care infrastructure, and could potentially be deployed widely and rapidly in even the most rural of settings. In recent months, the HIVNET 012 trial has come under renewed scrutiny [4], prompting an Institute of Medicine review. As with any new medical intervention, whether prophylactic or therapeutic, there are inevitable trade-offs. No major safety issues have arisen for mothers or infants who have received SD-NVP. However, the emergence of drug resistance in the setting of SD-NVP has created a gradually increasing challenge to the scientific, clinical research, and public health communities. In retrospect, it is not surprising that mutations associated with nonnucleoside reverse-transcriptase inhibitor (NNRTI) resistance would emerge with the administration of a drug for which the occurrence of rapid, single-step, high-level resistance and a prolonged half-life have been described for years [5]. It is also important to remember that the replication kinetics of HIV and the nature of reverse transcription result in a constant and inevitable mutation rate in the viral genome, such that drug resistance–associated mutations occur in the absence of exposure to any drug. The occurrence of new mutations during and after exposure to a drug is greatly facilitated by the selective pressure of an antiretroviral agent, particularly if it is …
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影响因子：
6.4
作者：
Eshleman, SH;Hoover, DR;Taha, T
通讯作者：
Taha, T
原发性 HIV-1 感染中含有特定耐药性突变的 HIV-1 变异体的代表性减少
DOI：
10.1097/00126334-200412150-00017
发表时间：
2004
期刊：
JAIDS Journal of Acquired Immune Deficiency Syndromes
影响因子：
--
作者：
D. Turner;B. Brenner;J. Routy;D. Moisi;Z. Rosberger;M. Roger;M. Wainberg
通讯作者：
M. Wainberg
指控引发人们对艾滋病预防策略遭到强烈抵制的担忧
影响因子：
56.9
作者：
L. Rüschendorf;W. Thomsen
通讯作者：
W. Thomsen
影响因子：
6.4
作者：
Johnson, JA;Li, JF;Heneine, W
通讯作者：
Heneine, W
产时单剂量奈韦拉平加齐多夫定预防后，产后期间奈韦拉平的持续暴露，以预防 HIV-1 母婴传播
DOI：
10.1097/01.qai.0000149791.37205.b1
发表时间：
2005
期刊：
JAIDS Journal of Acquired Immune Deficiency Syndromes
影响因子：
--
作者：
T. Cressey;G. Jourdain;M. Lallemant;S. Kunkeaw;J. B. Jackson;P. Musoke;E. Capparelli;M. Mirochnick
通讯作者：
M. Mirochnick