HIV-1 chemoprophylaxis and archived drug resistance in infants

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，那里获得抗逆转录病毒药物的机会有限。高效抗逆转录病毒疗法（HAART）可减少疾病进展和死亡率，但在低收入国家，HAART的唯一选择往往是与奈韦拉平（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耐NVP（NVP-R）HIV-1。在一年内，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，这为在HAART中重复使用NVP提供了理论基础。我们已经在儿童中发现，在非抑制性抗逆转录病毒治疗期间产生的耐药HIV-1以可复制的形式在静息的CD 4 +T细胞中存档，并且即使在HAART的病毒载量<50拷贝/ml时也会持续活化以产生低水平的病毒血症，从而排除了失败方案的药物的重复使用。我们将检验这样的假设，即在SD-NVP暴露的C亚型感染婴儿中NVP重复使用导致NVP-R变异体的选择和随后的反弹病毒血症，尽管血浆中的NVP-R衰减，甚至当病毒复制已被控制。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.定量暴露于预防性SD-NVP的C亚型感染婴儿中NVP-R HIV-1细胞储库的程度。2.确定暴露于SD-NVP的婴儿血浆中NVP-R HIV-1变异体的持续性，这些婴儿首次接受抑制性HAART方案时缺乏NNRTI，并在再次暴露于NVP后出现拉米夫定耐药。3.在使用包括拉米夫定在内的NVP为基础的HAART治疗的第一个月内，描述C亚型感染婴儿中NVP和拉米夫定耐药HIV-1变异体的动力学和患病率。由于世界范围内有如此多的妇女和婴儿感染HIV-1，因此了解在化学预防期间出现的奈韦拉平耐药性对细胞储库和治疗成功的长期影响对于评估这些脆弱人群的预防和治疗策略至关重要。由于世界范围内有如此多的妇女和婴儿感染HIV-1，因此了解在化学预防期间出现的奈韦拉平耐药性对细胞储库和治疗成功的长期影响对于评估这些脆弱人群的预防和治疗策略至关重要。

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.