Novel mechanisms of HIV resistance to RTIs

HIV对RTIs耐药的新机制

基本信息

批准号：
9265402
负责人：
NICOLAS PAUL SLUIS-CREMER
金额：
$ 38.5万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9265402
关键词：
AIDS prevention Address Africa South of the Sahara Anisotropy Antiretroviral drug resistance Atopobium vaginae Biological Assay Clinical Country Data Development Drug resistance Failure Fluorescence Formulation Frequencies Generations Genetic Polymorphism Geographic Locations Goals HIV HIV Infections HIV resistance HIV-1 HIV-1 drug resistance Individual Infection Measurement Measures Minority Mutation NNRTI-resistance Nevirapine Nucleic Acids Nucleotides Pathway interactions Patients Pharmaceutical Preparations Phenotype Predisposition Prevention RNA-Directed DNA Polymerase Regimen Research Resistance Resources Sampling Silicones TMC120-R147681 Technology Tenofovir Treatment Failure Variant Virus analog antiretroviral therapy base biophysical techniques clinically relevant efavirenz emtricitabine experience fitness insight mortality next generation non-nucleoside reverse transcriptase inhibitors novel novel therapeutics pre-exposure prophylaxis predicting response prevent public health relevance resistance mutation scale up single molecule treatment response virology

项目摘要

DESCRIPTION (provided by applicant): The past decade has seen an enormous global scale-up of antiretroviral therapy (ART). Although this widespread distribution of ART has dramatically reduced HIV/AIDs-related mortality, current data suggests that up to 24% of individuals receiving 1st-line ART in sub-Saharan Africa experience virologic failure within 12 months of initiation of therapy. Between 53 to 90% of these have viruses with clinically important HIV-1 drug resistance mutations. As such, antiretroviral drug resistance is one of the main threats to the global control of HIV-1. Due to the extensive use of nonnucleoside reverse transcriptase (RT) inhibitors (NNRTIs), there has been a significant increase in NNRTI drug resistance, and transmitted NNRTI drug resistance, in regions of sub-Saharan Africa. Despite the escalating frequency of NNRTI-resistant variants present in ART-na�ve and - experienced HIV-infected individuals, the next-generation diarylpyrimidine (DAPY) NNRTIs - dapivirine (TMC120), etravirine (ETV) and rilpivirine (RIL) are expected to be increasingly used for the treatment and prevention of HIV-1 infection in resource-limited settings. Indeed, many sub-Saharan Africa countries already have access to ETV, which has been approved for the treatment of HIV-infection in ART-experienced individuals. RIL, which has been co-formulated with emtricitabine and tenofovir, is pending approval as a 1st- line ART regimen in sub-Saharan Africa. A long-acting RIL formulation is also in development as a pre- exposure prophylaxis agent for use in resource-limited settings. Finally, the ASPIRE study is currently assessing whether TMC120 can safely prevent HIV-1 infection when continuously released in the vagina from a silicone ring replaced once a month. The majority of research into HIV-1 drug resistance has focused on subtype B viruses, yet non-subtype B strains are responsible for 90% of global infections. Importantly, there is increasing evidence of subtype differences in drug resistance. As such, the primary goals of this project are to study the resistance and cross-resistance pathways for RIL, ETV and TMC120 in non-subtype B viruses.

描述（由适用提供）：过去十年来，抗逆转录病毒疗法（ART）的全球范围很大。尽管这种艺术的这种宽度分布大大降低了与艾滋病毒/艾滋病相关的死亡率，但当前数据表明，在撒哈拉以南非洲地区接受第一线艺术的个人中，多达24％的人在开始治疗后的12个月内经历了病毒衰竭。其中53％至90％的病毒患有临床上重要的HIV-1耐药性突变。因此，抗逆转录病毒耐药性是对全球HIV-1控制的主要威胁之一。由于广泛使用非核苷逆转录酶（RT）抑制剂（NNRTIS），在撒哈拉以南非洲地区，NNRTI药物耐药性和传播NNRTI耐药性的显着增加。尽管Art-Nave和 - 经验丰富的HIV感染的个体中存在抗NNRTi抗性变体的频率不断增加，但下一代二维亚二吡啶（DAPY）NNRTIS- dapivirine（TMC120），Etravirine（Etravirine（ETV）（ETV）和RILPIVIRINE（RIL）的使用（RIL）被预期用于治疗和预期HHIV和无意义。实际上，许多撒哈拉以南非洲国家已经可以使用ETV，ETV已被批准用于治疗具有艺术经验的人的艾滋病毒感染。与Emtricerabine和Tenofovir共同成型的RIL正等待批准为撒哈拉以南非洲的一线艺术方案。长效的RIL公式也正在开发中，作为用于资源限制设置的暴露前预防剂。最后，Aspire研究目前正在评估TMC120是否可以从每月更换一次硅环中连续释放在阴道中时是否可以安全防止HIV-1感染。大多数对HIV-1耐药性的研究都集中在亚型B病毒上，但是非囊型B菌株造成了90％的全球感染。重要的是，越来越多的证据表明耐药性差异。因此，该项目的主要目标是研究非囊型B病毒中RIL，ETV和TMC120的抗性和交叉抗性途径。