HIV-1 chemoprophylaxis and archived drug resistance in infants

婴儿 HIV-1 化学预防和耐药性

• 批准号: 7658308
• 负责人: Deborah Persaud
• 金额: $ 65.55万
• 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 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7658308
• 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; Reporting; Resistance; Rest; Role; Sampling; Spottings; Testing; Time; Treatment Failure; Treatment Protocols; 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）：全世界有近 300 万儿童患有人类免疫缺陷病毒 1 型 (HIV-1)/艾滋病，其中大多数生活在撒哈拉以南非洲地区，那里获得抗逆转录病毒药物的机会有限。高效抗逆转录病毒治疗 (HAART) 可减少疾病进展和死亡率，但在低收入国家，通常唯一的 HAART 选择是与奈韦拉平 (NVP) 联合治疗。单剂量 NVP (SD-NVP) 也常用于预防围产期 HIV-1 传播，但它会导致高达 80% 的 C 亚型感染妇女和婴儿快速选择出 NVP 耐药 (NVP-R) HIV-1。一年之内，这种化学预防诱导的 NVP-R HIV-1 从血浆和复制细胞库中衰减，并被药物敏感的野生型 HIV-1 取代，为在 HAART 中重复使用 NVP 提供了理由。我们在儿童身上发现，非抑制性抗逆转录病毒治疗期间产生的耐药性 HIV-1 以复制能力的形式储存在静息 CD4+T 细胞中，并且即使在 HAART 上病毒载量<50 拷贝/ml 时也会持续被激活以产生低水平的病毒血症，从而防止重复使用失败治疗方案中的药物。我们将检验以下假设：尽管 NVP-R 从血浆中衰减，甚至在病毒复制已得到控制的情况下，在暴露于 SD-NVP 的 C 亚型感染婴儿中，NVP 重复使用会导致 NVP-R 变体的选择和随后的病毒血症反弹。在两项正在进行的临床试验中，使用不同的方法重复使用 NVP 来治疗 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来分析血浆和细胞样本，以： 1. 量化暴露于预防性 SD-NVP 的 C 亚型感染婴儿中 NVP-R HIV-1 细胞储存的程度。 2.确定首次抑制性HAART方案缺乏NNRTI的SD-NVP暴露婴儿血浆中NVP-R HIV-1变异的持续性，以及这些婴儿在再次暴露于NVP后出现拉米夫定耐药性。 3. 描述 C 亚型感染婴儿在使用基于 NVP 的 HAART（包括拉米夫定）治疗的第一个月内 NVP 和拉米夫定耐药 HIV-1 变异体的动力学和患病率。由于全世界有如此多的妇女和婴儿感染 HIV-1，因此了解化学预防期间出现的奈韦拉平耐药性对细胞储存库和治疗成功的长期影响对于评估这些弱势群体的预防和治疗策略至关重要。由于全世界有如此多的妇女和婴儿感染 HIV-1，因此了解化学预防期间出现的奈韦拉平耐药性对细胞储存库和治疗成功的长期影响对于评估这些弱势群体的预防和治疗策略至关重要。