RANDOMIZED TRIAL TO EVALUATE THE VIROLOGIC RESPONSE AND PHARMACOKINETICS OF TWO DIFFERENT POTENT REGIMENS IN HIV INFECTED WOMEN

评估两种不同有效方案对 HIV 感染女性的病毒学反应和药代动力学的随机试验

• 批准号: 9986560
• 负责人: BARBARA DRIVER
• 金额: $ 70万
• 依托单位: WESTAT, INC.
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-03-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9986560
• 关键词: Address; Adult; Anti-Retroviral Agents; Breast Feeding; Caring; Cell Count; Centers for Disease Control and Prevention (U.S.); Clinical Research; Clinical Trials; Conceptions; Contractor; Data; Developed Countries; Developing Countries; Drug Kinetics; Effectiveness; Enrollment; First Pregnancy Trimester; Funding; Genotype; Gestational Age; Goals; HIV; HIV-1; Human immunodeficiency virus test; IMPAACT; Immunologics; Incidence; Infant; Infection; Integrase Inhibitors; Intervention; Ireland; Laboratories; Life Cycle Stages; Medical; Mother-to-child HIV transmission; Mothers; Multicenter Studies; National Institute of Child Health and Human Development; Newborn Infant; Outcome; Participant; Perinatal transmission; Persons; Pharmaceutical Preparations; Pharmacology; Phase; Plasma; Pregnancy; Pregnant Women; Prenatal care; Prevention; Prevention trial; Protocols documentation; Public Hospitals; Publishing; RNA; Regimen; Resistance; Risk; Safety; Sampling; Schedule; Ships; Site; Specimen; State Hospitals; T-Lymphocyte; Test Result; Testing; United Kingdom; United States; Universities; Vertical Disease Transmission; Viral; Viral Load result; Washington; Woman; antiretroviral therapy; base; clinical research site; cohort; efavirenz; effectiveness measure; experience; follow-up; intrapartum; meetings; non-nucleoside reverse transcriptase inhibitors; perinatal HIV; pre-clinical; prospective; randomized trial; relative effectiveness; response; risk minimization; seroconversion; transmission process; virology

The current prevention of mother to child transmission (PMTCT) strategies based on the use of triple ARV regimens after the first trimester through labor, appropriate management of delivery, and avoidance of breastfeeding have been successful in lowering the rates of HIV perinatal transmission to less than 2%. Results of clinical trials for PMTCT suggest that women receiving triple antiretroviral (ARV) regimens that effectively reduce HIV-1 Ribonucleic Acid (RNA) to <1,000 copies/mL or undetectable levels are associated with significantly lower risk of perinatal HIV-1 transmission. Published data from a study in a cohort of HIV-infected pregnant women from the United Kingdom and Ireland in which the transmission rate was only 0.1% in 2,117 pregnant women on triple ARV regimens who achieved viral suppression. Also, there is evidence that being on a triple ARV regimen at conception and starting a triple ARV regimen earlier in pregnancy are associated with a lower risk of transmission after adjusting for viral load. This strategy is strongly dependent on early access to prenatal care and availability of ARVs for PMTCT with viral suppression and appropriate approach of mode of delivery. A considerable number of pregnant women enter prenatal care after the 20th to 28th week of gestation even in developed countries. Approximately one quarter of HIV-infected persons in the United States (US) are unaware that they are infected. The Mother-Infant Rapid Intervention at Delivery (MIRIAD) study, which was a prospective, multicenter study funded by the Centers for Disease Control and Prevention, offered voluntary, rapid HIV testing to women with undocumented HIV status late in pregnancy. Among 7,753 women with available test results from17 US hospitals, 52 (0.7%) were HIV-infected. Brazilian data published in 2007 from a cohort of HIV-infected pregnant women at a public hospital showed that the mean gestational age of initiation of prenatal care was 24 ± 8 weeks of gestation. Also, some pregnant women seroconvert late during pregnancy. A Brazilian study addressing primary HIV-1 infection during pregnancy showed an incidence of HIV-1 seroconversion of 0.8/1,000 (CI 95% 0.4-1.5/1,000). These women are more likely to transmit infection to their newborn, as plasma viral loads directly correlate with the risk of mother-to-child transmission (MTCT) of HIV-1. Decay dynamics of HIV-1 depend on the inhibited stage of the viral life cycle and are used as a measure of the effectiveness of ARV drugs and drug regimens. Therefore, the viral decay dynamics provided by different ARVs combinations could be critical for the effectiveness of the PMTCT effort. A more rapid reduction in viral load may be critical in minimizing both trans placental and intrapartum transmission of HIV-1 to the infant if ARV treatment is initiated late in pregnancy. Much virologic, immunologic and tolerability data derived from prospective clinical trials have shown the efficacy of various combinations of ARVs to treat HIV-1 infection. Most of these studies were done in HIV-infected adults with the primary efficacy outcomes based on the decline of plasma viral load within the first 20-48 weeks of starting therapy and on the durability of the virologic response, as well as changes in Cluster of Differentiation 4 (CD4+) T-cell counts aft 48 weeks of therapy. Suppressive ARV regimens containing the Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI) efavirenz have been extensively studied in non-pregnant adults, demonstrating rapid reduction in plasma HIV viral load. ARVs in the newest class to be approved, integrase inhibitors (IIs), have proven to be very potent in pre-clinical, and phase II and III clinical studies in adult participants, are generally well tolerated, and demonstrate strong efficacy with rapid reduction in plasma viral load in both treatment-naïve and treatment experienced participants. HIV-infected pregnant women presenting for care late in pregnancy need a rapid response and effective ART to minimize the risk of HIV transmission to their newborn. No data are available comparing the effects of NNRTIs and IIs in pregnant women. The goal of this protocol is to compare the safety, tolerance, virologic and pharmacologic responses of representatives of these two ARV classes in HIV-infected pregnant women presenting late for care.

目前预防母婴传播的战略是通过分娩在头三个月后使用三重抗逆转录病毒疗法，适当的分娩管理和避免母乳喂养，已成功地将艾滋病毒围产期传播率降低到2%以下。预防母婴传播的临床试验结果表明，接受三重抗逆转录病毒（ARV）治疗的妇女，有效地将HIV-1核糖核酸（RNA）降低到<1，000拷贝/mL或无法检测的水平，与围产期HIV-1传播的风险显著降低有关。来自一项艾滋病毒感染孕妇队列研究的已发表数据 来自联合王国和爱尔兰的2，117名接受三重抗逆转录病毒疗法并达到病毒抑制的孕妇中，传播率仅为0.1%。此外，有证据表明，在怀孕时接受三联抗逆转录病毒治疗方案和在怀孕早期开始三联抗逆转录病毒治疗方案与调整病毒载量后较低的传播风险相关。这一战略在很大程度上依赖于抢先体验和提供防止母婴传播的抗逆转录病毒药物，并抑制病毒和适当的提供方式。 即使在发达国家，也有相当多的孕妇在妊娠20至28周后进入产前护理。在美国，大约四分之一的艾滋病毒感染者不知道自己已被感染。母婴分娩快速干预（MIRIAD）研究是一项由疾病控制和预防中心资助的前瞻性多中心研究，为怀孕后期无记录艾滋病毒状态的妇女提供自愿，快速的艾滋病毒检测。在来自17家美国医院的7,753名妇女中，有52名（0.7%）感染了艾滋病毒。巴西2007年公布的一组在公立医院感染艾滋病毒的孕妇的数据显示，开始产前护理的平均胎龄为24 ± 8周。 此外，一些孕妇在怀孕后期血清转化。巴西一项针对怀孕期间艾滋病毒1型原发感染的研究显示，艾滋病毒1型血清转化的发生率为0.8/1 000（置信区间95%为0.4-1.5/1 000）。这些妇女更有可能将感染传染给新生儿，因为血浆病毒载量与母婴传播HIV-1的风险直接相关。HIV-1的衰减动力学取决于病毒生命周期的抑制阶段，并被用作衡量抗逆转录病毒药物和药物治疗方案的有效性。因此，不同抗逆转录病毒药物组合提供的病毒衰减动力学对于防止母婴传播工作的有效性至关重要。如果在妊娠晚期开始抗逆转录病毒治疗，病毒载量的更快减少可能对最大限度地减少经胎盘和分娩时HIV-1向婴儿的传播至关重要。 来自前瞻性临床试验的许多病毒学、免疫学和耐受性数据显示了各种抗逆转录病毒药物组合治疗HIV-1感染的疗效。这些研究中的大多数是在HIV感染的成人中进行的，主要疗效结局基于开始治疗的前20-48周内血浆病毒载量的下降和病毒学应答的持久性，以及治疗48周后分化抗原4（CD 4+）T细胞计数的变化。含有非核苷逆转录酶抑制剂（NNRTI）依法韦仑的抑制性ARV方案已在非妊娠成人中进行了广泛研究，证明血浆HIV病毒载量快速降低。最新批准的一类抗逆转录病毒药物整合酶抑制剂（IIs）已在成人受试者的临床前、II期和III期临床研究中证明非常有效，通常耐受性良好，并在未经治疗和有治疗经验的受试者中显示出快速降低血浆病毒载量的强大疗效。感染艾滋病毒的孕妇在怀孕后期就诊时需要快速反应和有效的抗逆转录病毒疗法，以尽量减少艾滋病毒传染给新生儿的风险。目前尚无比较NNRTI和IIs对孕妇影响的数据。本方案的目的是比较这两种抗逆转录病毒药物在晚期就诊的HIV感染孕妇中的安全性、耐受性、病毒学和药理学反应。