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

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。目前在怀孕期间采用的抗逆转录病毒疗法对母婴传播艾滋病毒的风险产生了巨大影响。在分娩时病毒载量低于1000拷贝/mL的女性中，传播率在1 - 2%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）关于治疗非妊娠、无症状、慢性HIV感染成人的指南建议，应暂停抗逆转录病毒治疗，直至病毒载量达到55，000拷贝/mL或更高，或CD4+细胞计数低于350个细胞/mL。一旦开始治疗，建议使用含有三种或四种药物的方案，通常至少两种抗逆转录病毒药物，以最大限度地提高反应，最大限度地减少病毒耐药性的可能性，并优化治疗持久性。在为打算在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.将母婴传播艾滋病毒的风险降至可达到的最低水平2。最大限度地减少胎儿毒性的风险3。最大限度地减少母体药物副作用4.为母亲保留未来的治疗选择5。最大限度地减少对怀孕期间和将来使用的抗逆转录病毒药物产生耐药性的可能性。目前，实现这些目标的最佳手段尚不清楚。PACTG P1022旨在比较妊娠期间开始治疗的女性中含PI方案（ZDV/3TC/奈非那韦）与保留蛋白酶抑制剂（PI）方案（ZDV/3TC/奈韦拉平）。然而，由于研究奈韦拉平组中的几例受试者发生了显著不良事件，研究中止。三重核苷方案已被一些研究人员作为HIV-1感染成人的一线治疗进行了研究。最近的一项大型研究显示，接受司他夫定和去羟肌苷加茚地那韦或奈韦拉平或拉米夫定方案的受试者对治疗的反应相似。治疗48周后，病毒载量低于500拷贝/mL的受试者数量无显著差异（分别为57%、58.4%和58.7%）。阿巴卡韦是一种有效的NRTI。它已被广泛用于与齐多夫定和拉米夫定作为Trizivir联合使用，如本研究所提出的。研究表明，这种NRTI组合是一种有效和安全的治疗方案，在抗逆转录病毒初治和抗逆转录病毒经验丰富的患者。在第一项研究中，受试者接受阿巴卡韦/拉米夫定/齐多夫定或茚地那韦/拉米夫定/齐多夫定。治疗48周后，在初始病毒载量低于100，000拷贝/mL的患者中观察到病毒复制的等效抑制。每组中51%的受试者的病毒载量低于400拷贝/mL。在初始病毒载量大于100，000拷贝/mL的受试者中，在接受茚地那韦的受试者中观察到更大的应答。两个治疗组之间的CD4+细胞计数无差异。这些研究支持Trizivir用于合适的患者（病毒载量低于100，000拷贝/mL）。Trizivir在妊娠中的经验有些有限，尽管越来越多的临床医生在合适的患者中使用这种组合。截至2004年1月31日，抗逆转录病毒药物妊娠登记处收到了527例妊娠期使用阿巴卡韦的报告。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，没有围产期艾滋病毒传播，副作用极小。在10名孕妇中使用Trizivir的额外经验支持这些发现，9/10名患者的病毒抑制低于400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异质超敏反应的小风险相关。怀孕期间发生这种情况的风险尚未量化。PACTG P1039将解决其中的一些问题。本研究仅限于初始病毒载量低于55，000拷贝/mL和CD4+细胞计数大于350的女性。根据符合相同标准的非妊娠成人的已发表数据，我们预计两个治疗组对治疗的反应相同，疗效相同。虽然许多人认为NNRTI依法韦仑是初始治疗的重要组成部分，但其对胎儿的潜在毒性使其成为妊娠期间应避免的药物。蛋白酶抑制剂被许多专家认为是开始抗逆转录病毒治疗的个体的一线治疗。在妊娠期间，齐多夫定、拉米夫定和PI的组合已被证明在将母婴HIV传播降低到2%以下方面有效。洛匹那韦/利托那韦（Kaletra）是一种有效的蛋白酶抑制剂，已证明其在治疗HIV感染的成人中有效，目前被公共卫生指南委员会推荐为抗逆转录病毒治疗时的首选PI。蛋白酶抑制剂有记录的葡萄糖耐受不良和脂质代谢改变的副作用。这种代谢改变对母体、胎儿和新生儿健康的影响几乎没有探讨，可能对子宫内暴露于该药物的后代未来健康产生深远影响。

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.