PACTG 1039 (VERSION 10) A PHASE III RANDOMIZED TRIAL OF THE SAFETY AND ANTIR

PACTG 1039（版本 10）安全性和抗病毒性的 III 期随机试验

• 批准号: 7375009
• 负责人: William Thomas Shearer
• 金额: $ 0.49万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-12-01 至 2006-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7375009
• 关键词: PACTG; 1039; VERSION; 10; PHASE

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The current approach to antiretroviral therapy in pregnancy has had a dramatic effect on the risk of maternal to child transmission of HIV. In women whose viral load at the time of delivery is less than 1000 copies/mL, transmission rates are in the 1-2% range, regardless of the treatment regimen applied to achieve such a viral load. Public Health Service (PHS) guidelines for the treatment of non-pregnant, asymptomatic, chronically HIV-infected adults suggest that antiretroviral treatment be withheld until a viral load of 55,000 copies/mL or greater is reached, or CD4+ cell counts fall below 350 cells/mL. Once therapy is initiated, a regimen containing three or four drugs from usually at least two classes of antiretrovirals is recommended to maximize response, minimize the likelihood of development of viral resistance and optimize therapeutic durability. Important issues that must be considered when providing treatment to pregnant women who intend to discontinue treatment postpartum include: 1. Reduction of the risk of maternal to child transmission of HIV to the lowest attainable level 2. Minimization of the risk of fetal toxicity 3. Minimization of maternal drug side effects 4. Preservation of therapeutic options for the mother for the future 5. Minimization of the likelihood of developing resistance to antiretrovirals used during pregnancy and in the future. At present, the optimum means to attain these goals are unknown. PACTG P1022 was designed to compare a PI containing regimen (ZDV/3TC/Nelfinavir) to a protease inhibitor (PI)-sparing regimen (ZDV/3TC/Nevirapine) in women who initiate treatment during pregnancy. However, the study was discontinued because of significant adverse events in several of the subjects in the nevirapine arm of the study. Triple nucleoside regimens have been studied by several investigators as first line treatment for HIV-1 infected adults. One recent large study showed similar responses to treatment in subjects receiving regimens consisting of stavudine and didanosine plus indinavir or nevirapine or lamivudine. After 48 weeks of therapy there was no significant difference in the number of subjects with viral loads less than 500 copies/mL (57%, 58.4% and 58.7% respectively). Abacavir is a potent NRTI. It has been widely used in combination with zidovudine and lamivudine as Trizivir as proposed in the present study. Studies have shown that this NRTI combination is an effective and safe treatment regimen in both antiretroviral naive and antiretroviral experienced patients. In the first of these studies, subjects received either abacavir/lamivudine/zidovudine or indinavir/lamivudine/zidovudine. After 48 weeks of therapy an equivalent suppression of viral replication was seen in patients whose initial viral load was less than 100,000 copies/mL. A viral load less than 400 copies/mL was obtained in 51% of subjects in each group. In subjects with initial viral loads greater than 100,000 copies/mL a greater response was seen in subjects receiving indinavir. There were no differences in CD4+ cell counts between the two treatment arms. These studies support the use of Trizivir in suitable patients (viral load less than 100,000 copies/mL). Experience of Trizivir in pregnancy is somewhat limited although a growing number of clinicians are using this combination in suitable patients. There have been 527 cases of abacavir use in pregnancy reported to the Antiretroviral Pregnancy Registry as of the 31 January 2004 report. A recent study showed excellent suppression of viral load, no perinatal transmission of HIV and minimal side effects in 30 treated mother-infant pairs. Additional experience with Trizivir use in 10 pregnant women supports these findings, with viral suppression to less than 400 copies in 9/10 patients and no perinatal transmission. Abacavir therapy is associated with a small risk of idiosyncratic hypersensitivity which may be life threatening. The risk of this in pregnancy is, as yet, unquantified. PACTG P1039 will address some of these issues. The present study is limited to women with initial viral loads less than 55,000 copies/mL and CD4+ cell counts greater than 350. We expect to see an equivalent response to therapy with equal efficacy in both treatment arms based on published data in non pregnant adults meeting the same criteria. Although the NNRTI efavirenz is considered by many to be an important component to initial treatment, its potential toxicity to the fetus makes it a drug to be avoided during pregnancy. Protease inhibitors are considered by many experts as first line treatment for individuals initiating antiretroviral therapy. During pregnancy a combination of zidovudine, lamivudine and a PI has demonstrated efficacy in reducing mother-to-infant HIV transmission to less than 2%. Lopinavir/ritonavir (Kaletra) is a potent protease inhibitor that has demonstrated efficacy in the treatment of HIV- infected adults and is currently recommended by the Public Health Guidelines Committee as the preferred PI of choice when instituting antiretroviral therapy. Protease inhibitors have the documented side effects of glucose intolerance and altered lipid metabolism. The impact of such alterations in metabolism on maternal, fetal and newborn health have been little explored and may have far reaching implications for the future health of offspring exposed to this drug in utero.

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。目前在怀孕期间进行抗逆转录病毒治疗的方法对艾滋病毒母婴传播的风险产生了巨大影响。在分娩时病毒载量低于1000拷贝/毫升的妇女中，传播率在1-2%的范围内，无论采用何种治疗方案来实现这样的病毒载量。公共卫生服务(PHS)关于非怀孕、无症状、慢性艾滋病毒感染成人的治疗指南建议，在病毒载量达到55000拷贝/毫升或更高，或CD4+细胞计数降至350个/毫升以下之前，暂停抗逆转录病毒治疗。一旦开始治疗，建议采用包含三到四种药物的方案，这些药物通常来自至少两类抗逆转录病毒药物，以最大限度地提高疗效，最大限度地减少病毒耐药性发展的可能性，并优化治疗持久性。在为打算产后停止治疗的孕妇提供治疗时必须考虑的重要问题包括：1.将艾滋病毒母婴传播的风险降低到可达到的最低水平2.将胎儿毒性的风险降至最低3.将母亲的药物副作用降至最低4.为母亲保留未来的治疗选择5.将怀孕期间和未来使用的抗逆转录病毒药物产生耐药性的可能性降至最低。目前，实现这些目标的最佳手段尚不清楚。PACTG P1022的设计是为了在妊娠期开始治疗的妇女中比较含有PI的方案(ZDV/3TC/Nelfinavir)和不使用蛋白酶抑制剂(PI)的方案(ZDV/3TC/NeviRapine)。然而，由于奈韦拉平试验组的几名受试者发生了严重的不良反应，这项研究被中止。几位研究人员已经研究了三重核苷方案，作为HIV-1感染成人的一线治疗方法。最近的一项大型研究显示，接受司他夫定和地达诺辛加吲哚那韦、奈韦拉平或拉米夫定的治疗方案的受试者对治疗的反应相似。治疗48周后，病毒载量<500拷贝/毫升的受试者数差异无统计学意义(分别为57%、58.4%和58.7%)。阿巴卡韦是一种有效的NRTI。已广泛与齐多夫定和拉米夫定联合使用，作为本研究建议的曲齐韦。研究表明，这种NRTI联合疗法对初治抗逆转录病毒和有抗逆转录病毒经验的患者都是一种有效和安全的治疗方案。在第一项研究中，受试者接受阿巴卡韦/拉米夫定/齐多夫定或依地那韦/拉米夫定/齐多夫定。经过48周的治疗，在初始病毒载量低于100,000拷贝/毫升的患者中，病毒复制得到了同等的抑制。每组中51%的受试者病毒载量低于400拷贝/毫升。在初始病毒载量大于100,000拷贝/毫升的受试者中，接受依地那韦的受试者有更大的反应。两个治疗组之间的CD4+细胞计数没有差异。这些研究支持在合适的患者(病毒载量低于100,000拷贝/毫升)中使用曲齐韦。尽管越来越多的临床医生在合适的患者中使用Trizivir联合用药，但在妊娠期间使用Trizivir的经验有些有限。截至2004年1月31日的报告，向抗逆转录病毒妊娠登记处报告的妊娠期间使用阿巴卡韦的病例有527例。最近的一项研究表明，在30对接受治疗的母婴中，病毒载量得到了极好的抑制，没有艾滋病毒的围产期传播，副作用最小。在10名孕妇中使用Trizivir的其他经验支持这些发现，9/10名患者的病毒抑制低于400个拷贝，并且没有围产期传播。阿巴卡韦治疗与可能危及生命的特殊超敏反应的小风险有关。到目前为止，怀孕期间发生这种情况的风险还没有量化。PACTG P1039将解决其中一些问题。目前的研究仅限于初始病毒载量低于55000拷贝/毫升且CD4+细胞计数超过350的女性。根据公布的数据，在符合相同标准的非怀孕成年人中，我们预计在两个治疗组中都能看到相同的治疗反应和相同的疗效。尽管NNRTI efavirenz被许多人认为是初始治疗的重要组成部分，但它对胎儿的潜在毒性使其成为怀孕期间应避免使用的药物。许多专家认为，蛋白酶抑制剂是开始抗逆转录病毒治疗的一线治疗药物。在怀孕期间，齐多夫定、拉米夫定和PI的组合已证明有效地将母婴艾滋病毒传播率降低到2%以下。Lopinavir/ritonavir(Kaletra)是一种有效的蛋白水解酶抑制剂，已证明对成人HIV感染者有效，目前被公共卫生指南委员会推荐为开展抗逆转录病毒治疗的首选PI。蛋白水解酶抑制剂有葡萄糖不耐受和脂代谢改变的副作用。这种代谢变化对产妇、胎儿和新生儿健康的影响很少被探索，可能会对在子宫内接触这种药物的后代的未来健康产生深远的影响。