HIV Drug Resistance During HAART in Adolescents

青少年 HAART 期间的 HIV 耐药性

• 批准号: 7175359
• 负责人: Deborah Persaud
• 金额: $ 42.2万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7175359
• 关键词: AIDS/HIV problem; Adherence; Adolescent; Adolescent Medicine Trials Network; Anti-Retroviral Agents; Appearance; Archives; Biological Assay; Biological Preservation; Blood Circulation; CD4 Positive T Lymphocytes; Cells; Clinical; Clinical Trials; Development; Drug resistance; Evolution; Funding; Future; Genotype; HIV; HIV drug resistance; HIV-1; HIV-1 drug resistance; Highly Active Antiretroviral Therapy; Immune response; Infection; Interruption; Intervention; Laboratories; Life; Longitudinal Studies; Maintenance; Maintenance Therapy; Measures; Methods; Molecular; Mutation; Pathogenesis; Patients; Pharmaceutical Preparations; Plasma; Population; Population Heterogeneity; Prevalence; Randomized Controlled Trials; Resources; Rest; Specimen; Standards of Weights and Measures; Structure; Therapeutic; Time; Toxic effect; Treatment Failure; Treatment Protocols; United States; United States National Institutes of Health; Variant; Viral; Viremia; Virus; base; drug resistant virus; improved; monocyte; novel; nucleoside analog; peripheral blood; sample fixation; young adult

The prevalence of HIV is increasing dramatically among adolescents and young adults in the United States. The NIH funded Adolescent Trials Network (ATN) will soon be implementing several different randomized controlled trials of novel treatment strategies aimed at improving adherence, minimizing toxicity, and enhancing HIV- specific immune responses in this group. These include structured treatment interruptions (STIs) and induction- maintenance (IM) treatment regimens. A concern arising from these non-standard approaches is the selection of drug resistant HIV that may become stably fixed in the latent reservoir of resting CD4+ T-cells. The fixation of drug -resistant HIV in the latent reservoir could have a dramatic impact on future therapeutic options because it guarantees life-long persistence of archival drug- resistant HIV. We hypothesize that treatment which allows for fluctuations in antiretroviral drug levels or that are less able to inhibit ongoing rounds of viral replication will give rise to drug- resistant variants that can be detected before overt treatment failure ensues, and that these variants may become permanently archived in the latent reservoir in resting CD4+ T cells. The first specific aim is to evaluate the evolution of genotypic drug resistance during novel treatment strategies that employ STIs or indcution-maintenance regimens. Sensitive molecular methods for genotyping plasma virus at <50 copies/ml will be used for longitudinal assessment of drug- resistant HIV emerging after STIs or during switches to less potent regimens. The second specific aim is to measure new infection of susceptible cells by drug- resistant variants arising during novel treatment strategies in infected adolescents. Infection of monocytes, a recently arising population with limited circulation time, will be assessed longitudinally to determine whether newly emergent drug- resistant viruses are fully infectious. The third specific aim is to determine the capacity of recently generated drug- resistant HIV variants arising during novel treatment strategies to become fixed in the latent reservoir for HIV in resting CD4+ T-cells. The entry of newly generated drug-resistant HIV in the latent reservoir will be assessed in longitudinal studies of adolescents receiving novel HAART. The clinical specimens and analytic resources available within the ATN provide a unique opportunity to study HIV pathogenesis in infected adolescents.

在美国青少年和年轻人中，艾滋病毒的流行率正在急剧上升。 美国国立卫生研究院 (NIH) 资助的青少年试验网络 (ATN) 将很快实施几种不同的随机试验 新型治疗策略的对照试验旨在提高依从性、最大限度地减少毒性和 增强该群体的艾滋病毒特异性免疫反应。其中包括结构化治疗中断 （性传播感染）和诱导维持（IM）治疗方案。这些非标准引起的担忧 方法是选择具有耐药性的艾滋病毒，这些艾滋病毒可能会稳定地固定在潜在的病毒储存库中。 静息 CD4+ T 细胞。耐药艾滋病毒在潜伏病毒库中的固定可能会产生巨大影响 未来的治疗选择，因为它保证了档案耐药性艾滋病毒的终生持续存在。我们 假设治疗允许抗逆转录病毒药物水平波动或不太能够 抑制正在进行的病毒复制将产生耐药变异，这些变异可以在病毒复制之前被检测到 随之而来的是明显的治疗失败，并且这些变体可能会永久存档在潜在的 静息 CD4+ T 细胞中的储存库。第一个具体目标是评估基因型药物的进化 采用性传播感染或诱导维持方案的新治疗策略期间的耐药性。敏感的 血浆病毒基因分型<50拷贝/毫升的分子方法将用于纵向评估 性传播感染后或改用效力较低的治疗方案期间出现耐药性艾滋病毒。第二个具体目标 是测量新治疗期间出现的耐药变异对易感细胞的新感染 感染青少年的策略。单核细胞感染，这是最近出现的一个数量有限的群体 循环时间，将纵向评估，以确定是否有新出现的耐药病毒 是完全具有传染性的。第三个具体目标是确定最近产生的耐药性的能力 在新的治疗策略中产生的艾滋病毒变异体被固定在艾滋病毒的潜在储存库中 静息 CD4+ T 细胞。将评估潜伏病毒库中新产生的耐药艾滋病毒的进入情况 对接受新型 HAART 的青少年进行纵向研究。临床标本和分析资源 ATN 内提供的信息为研究受感染青少年的 HIV 发病机制提供了独特的机会。

项目成果

Analyses of HIV-1 drug-resistance profiles among infected adolescents experiencing delayed antiretroviral treatment switch after initial nonsuppressive highly active antiretroviral therapy.

对初始非抑制性高活性抗逆转录病毒治疗后延迟抗逆转录病毒治疗转换的感染青少年的 HIV-1 耐药谱进行分析。

• 发表时间: 2008-07
• 影响因子: 4.9
• 作者: Agwu, Allison;Lindsey, Jane C;Ferguson, Kimberly;Zhang, Haili;Spector, Stephen;Rudy, Bret J;Ray, Stuart C;Douglas, Steven D;Flynn, Patricia M;Persaud, Deborah;Pediatric AIDS Clinical Trials Group 381 Study Team
• 通讯作者: Pediatric AIDS Clinical Trials Group 381 Study Team

A sensitive genotyping assay for detection of drug resistance mutations in reverse transcriptase of HIV-1 subtypes B and C in samples stored as dried blood spots or frozen RNA extracts.

一种灵敏的基因分型测定，用于检测以干血斑或冷冻 RNA 提取物形式储存的样品中 HIV-1 B 和 C 亚型逆转录酶的耐药性突变。

• 发表时间: 2006-09
• 影响因子: 3.1
• 作者: Ziemniak, Carrie;George;Moss, William J;Ray, Stuart C;Persaud, Deborah
• 通讯作者: Persaud, Deborah

Slow human immunodeficiency virus type 1 evolution in viral reservoirs in infants treated with effective antiretroviral therapy.

接受有效抗逆转录病毒治疗的婴儿的病毒库中人类免疫缺陷病毒 1 型的进化速度缓慢。

• 发表时间: 2007-03
• 影响因子: 1.5
• 作者: Persaud, Deborah;Ray, Stuart C;Kajdas, Joleen;Ahonkhai, Aima;Siberry, George K;Ferguson, Kimberly;Ziemniak, Carrie;Quinn, Thomas C;Casazza, Joseph P;Zeichner, Steven;Gange, Stephen J;Watson, Douglas C
• 通讯作者: Watson, Douglas C