Novel mechanisms of HIV resistance to RTIs

HIV对RTIs耐药的新机制

• 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
• 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

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（由申请人提供）：过去十年，抗逆转录病毒疗法 (ART) 在全球范围内得到了巨大的推广，尽管 ART 的广泛应用极大地降低了 HIV/艾滋病相关的死亡率，但目前的数据表明，高达 24% 的死亡率。在撒哈拉以南非洲接受一线 ART 的患者在开始治疗后 12 个月内出现病毒学失败，其中 53% 至 90% 的病毒具有临床上重要的 HIV-1 耐药性。因此，抗逆转录病毒耐药性是全球控制 HIV-1 的主要威胁之一。由于非核苷类逆转录酶 (RT) 抑制剂 (NNRTI) 的广泛使用，NNRTI 耐药性显着增加。和传播 NNRTI 耐药性，尽管在未接受过 ART 治疗和经历过 HIV 感染者中出现 NNRTI 耐药性变异的频率不断增加，但下一代二芳基嘧啶 (DAPY) NNRTIs - 达匹韦林 (TMC120)、依曲韦林 (ETV) 和利匹韦林 (RIL) 预计将越来越多地用于在资源有限的环境中治疗和预防 HIV-1 感染。撒哈拉非洲国家已经可以使用 ETV，该药物已被批准用于治疗经历过 ART 的个体的 HIV 感染，该药物已获得批准。与恩曲他滨和替诺福韦共同配制，正在等待批准作为撒哈拉以南非洲地区的一线 ART 治疗方案。 ASPIRE研究目前正在评估当每月更换一次的硅胶环在阴道中持续释放TMC120时是否可以安全地预防HIV-1感染。大多数研究都是针对HIV-1药物。耐药性主要集中在 B 亚型病毒上，但全球 90% 的感染是由非 B 亚型病毒株引起的。重要的是，越来越多的证据表明耐药性存在亚型差异，因此该项目的主要目标是研究耐药性。非 B 亚型病毒中 RIL、ETV 和 TMC120 的交叉耐药途径。