HIV-1 chemoprophylaxis and archived drug resistance in infants

婴儿 HIV-1 化学预防和耐药性

• 批准号: 7876650
• 负责人: Deborah Persaud
• 金额: $ 39.46万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-30 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7876650
• 关键词: Acquired Immunodeficiency Syndrome; Affect; Africa South of the Sahara; African; Anti-Retroviral Agents; Archives; Biological Assay; Blood; Blood specimen; CD4 Positive T Lymphocytes; Cells; Chemoprophylaxis; Child; Clinical Trials; Combined Modality Therapy; Country; DNA; Data; Disease Progression; Dose; Drug resistance; Drug-sensitive; Enrollment; Exposure to; Genotype; Goals; HIV-1; Health Services Accessibility; Highly Active Antiretroviral Therapy; Infant; Infection; Kinetics; Laboratories; Lamivudine; Life; Long-Term Effects; Lopinavir; Low income; Maintenance; Maintenance Therapy; Minority; Molecular; Neoadjuvant Therapy; Nevirapine; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Phase; Plasma; Prevalence; Prevention; Protease Inhibitor; Randomized; Regimen; Reporting; Resistance; Rest; Role; Sampling; Spottings; Testing; Time; Treatment Failure; Variant; Viral; Viral Load result; Viremia; Virus; Virus Replication; Vulnerable Populations; Woman; antiretroviral therapy; base; mortality; nevirapine resistance; non-nucleoside reverse transcriptase inhibitors; prevent; prophylactic; resistance mutation; response; success; transmission process; treatment strategy

DESCRIPTION (provided by applicant): Nearly three million children worldwide have human immunodeficiency virus type 1 (HIV-1)/AIDS, and most live in sub-Saharan Africa where access to antiretroviral drugs is limited. Highly active antiretroviral therapy (HAART) reduces disease progression and mortality, but in low-income countries often the only HAART option is combination therapy with nevirapine (NVP). Single-dose NVP (SD-NVP) is also commonly used to prevent peripartum HIV-1 transmission, but it causes rapid selection of NVP-resistant (NVP-R) HIV-1 in up to 80% of subtype C infected women and infants. Within a year this chemoprophylaxis- induced NVP-R HIV-1 decays from the plasma and replicating cellular pools and is replaced with drug-sensitive wild-type HIV-1, providing a rationale for reusing NVP in HAART. We have shown in children that drug-resistant HIV-1 arising during non-suppressive antiretroviral therapy is archived in replication competent forms in resting CD4+T cells and is continuously activated to produce low level viremia even when viral loads are <50 copies/ml on HAART, precluding reuse of drugs from failed regimens. We will test the hypothesis that NVP reuse in subtype C infected infants with SD-NVP exposure causes selection of NVP-R variants and subsequent rebound viremia despite decay of NVP-R from plasma and even when virus replication had been controlled. In the context of two ongoing clinical trials using different approaches to reusing NVP to treat HIV-1 infected African infants (Neverest and PACTG P1060), we will use sensitive molecular and genotyping assays to analyze plasma and cellular samples to: 1. Quantify the extent of NVP-R HIV-1 cellular reservoirs in subtype C infected infants exposed to prophylactic SD-NVP. 2. Determine persistence of NVP-R HIV-1 variants in plasma of SD-NVP exposed infants whose first suppressive HAART regimen lacks an NNRTI, and emergence of lamivudine-resistance in these infants after re-exposure to NVP. 3. Characterize the kinetics and prevalence of NVP and lamivudine-resistant HIV-1 variants in subtype C infected infants during the first month of therapy with NVP-based HAART that includes lamivudine. Because so many women and infants live with HIV-1 infection worldwide, understanding the long-term effects on cellular reservoirs and treatment success caused by nevirapine resistance arising during chemoprophylaxis is critical for assessing prevention and treatment strategies for these vulnerable populations. Because so many women and infants live with HIV-1 infection worldwide, understanding the long-term effects on cellular reservoirs and treatment success caused by nevirapine resistance arising during chemoprophylaxis is critical for assessing prevention and treatment strategies for these vulnerable populations.

描述（由申请人提供）：全球近三百万儿童具有人类免疫缺陷病毒1型（HIV-1）/艾滋病，大多数人居住在撒哈拉以南非洲，那里有抗逆转录病毒药物受到限制。高度活跃的抗逆转录病毒疗法（HAART）降低了疾病的进展和死亡率，但是在低收入国家，唯一的HAART选择是与奈韦拉平（NVP）组合疗法。单剂量NVP（SD-NVP）也通常用于防止周围HIV-1传播，但在多达80％的亚型C受感染的妇女和婴儿中，它会引起NVP耐药（NVP-R）HIV-1的快速选择。在一年之内，这种化学预防诱导的NVP-R HIV-1从血浆中衰减并复制细胞池，并被药物敏感的野生型HIV-1取代，为HAART重复使用NVP提供了理由。我们在儿童中表明，在静止的CD4+T细胞中，在非抑制抗逆转录病毒疗法期间产生的耐药性HIV-1以复制统一的形式存档，并且在HAART上降低了失败方案的药物的重复使用，从而不断激活以产生低水平的病毒血症。我们将检验以下假设：尽管NVP-R变体的SD-NVP暴露的亚型感染的NVP再利用导致NVP-R变体的选择以及随后的反弹病毒性，尽管NVP-R从血浆中衰减，甚至在控制了病毒的情况下也受到了控制。在两项正在进行的临床试验的背景下，使用不同的方法来重复NVP治疗HIV-1感染的非洲婴儿（Neverest和Pactg p1060），我们将使用敏感的分子和基因分型测定法将血浆和细胞样品分析为：1。量化NVP-RHIV-1细胞储存库的程度。 2。确定SD-NVP暴露婴儿血浆中NVP-R HIV-1变异的持久性，其首次抑制性HAART方案缺乏NNRTI，并且在重新暴露于NVP后这些婴儿中lamivudine抗性的出现。 3。表征在基于NVP的HAART治疗的第一个月，NVP和抗lamivudine抗HIV-1变体的动力学和抗性HIV-1变体的患病率（包括Lamivudine）。由于许多妇女和婴儿在全球范围内生活在HIV-1感染中，因此了解对细胞储存库的长期影响以及因化学预防症在化学预防时产生的奈韦拉平的耐药性而引起的治疗成功，对于评估这些脆弱人群的预防和治疗策略至关重要。由于许多妇女和婴儿在全球范围内生活在HIV-1感染中，因此了解对细胞储存库的长期影响以及因化学预防症在化学预防时产生的奈韦拉平的耐药性而引起的治疗成功，对于评估这些脆弱人群的预防和治疗策略至关重要。

项目成果

Analysis of the optimal cut-point for HIV-p24 antigen testing to diagnose HIV infection in HIV-exposed children from resource-constrained settings.

分析 HIV-p24 抗原检测的最佳切点，以诊断资源有限环境中 HIV 暴露儿童的 HIV 感染。

• DOI: 10.1016/j.jcv.2011.01.012
• 发表时间: 2011
• 期刊: Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology
• 作者: Tamhane,M;Gautney,B;Shiu,C;Segaren,N;Jeannis,L;Eustache,C;Simeon-Fadois,Y;Chen,YH;De,D;Irivinti,S;Tamma,P;Thompson,CB;Khamadi,S;Siberry,GK;Persaud,D
• 通讯作者: Persaud,D