HIV-1 Drug Resistance in Different Subtypes

不同亚型的 HIV-1 耐药性

• 批准号: 8139079
• 负责人: Rami Kantor
• 金额: $ 81.14万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8139079
• 关键词: AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Affect; Africa; Anti-HIV Agents; Anti-Retroviral Agents; Antiretroviral resistance; Asia; Biological Assay; Caring; China; Clinical Data; Codon Nucleotides; Collaborations; Country; Data; Databases; Diagnostic tests; Drug Exposure; Drug resistance; Effectiveness; Emergency Situation; Epidemic; Europe; Evolution; Failure; Frequencies; Genbank; Genetic; Genetic Polymorphism; Genotype; Goals; HIV; HIV drug resistance; HIV-1; Incidence; India; Individual; Infection; International; Knowledge; Life; Link; Literature; Methods; Monitor; Mutation; Patients; Pattern; Peptide Hydrolases; Persons; Pharmaceutical Preparations; Phylogenetic Analysis; Plasma; Population; Positioning Attribute; Predisposition; Prevalence; Principal Investigator; Protocols documentation; Public Health; Publishing; RNA-Directed DNA Polymerase; Recombinants; Regimen; Research; Research Infrastructure; Resistance; Resources; Sampling; Science; Sensitivity and Specificity; Shipping; Ships; Specimen; Surveillance Program; Testing; Thailand; Treatment Failure; Treatment Protocols; Validation; Variant; Vertebral column; Viral Genes; Viremia; Virus; Work; antiretroviral therapy; base; cohort; cost; design; experience; novel; pandemic disease; population based; programs; public health relevance; recombinant virus; resistance mutation; response; scale up; stem; transmission process; treatment center; treatment program; treatment strategy; working group

DESCRIPTION (provided by applicant): The human immunodeficiency virus (HIV-1) pandemic is due to multiple subtypes and emerging recombinant viruses that are widely distributed around the world. An important response to the epidemic is the global scale-up of access to antiretroviral treatment (ART) programs, potentially delivering ART to millions of infected individuals. A barrier to successful long term treatment is the emergence of drug resistance, caused by mutations selected in viral genes, which are both a cause and a consequence of ART failure. Knowledge about drug resistance comes largely from the US and Europe, focused on one HIV-1 variant, subtype B. However, 90% of infections globally, are in resource limited settings in Africa and Asia, where other distinct, non-B HIV-1 subtypes predominate. There is strong preliminary evidence that pre-therapy genotypes differ among subtypes and that distinct mutations at positions related to resistance may occur, even before treatment, among non-B subtypes. Furthermore, distinct, new mutations are detected in non-B subtypes after drug-exposure. Information on susceptibility and resistance of non-B viruses is critical for strategies to sustain the benefit of ART. Prevalence and incidence of transmitted and acquired drug resistance will drive decisions about diagnostic testing, initial and second-line therapies in public health HIV treatment programs in resource limited settings. The focus of this proposal is to build the scientific infrastructure for surveillance and monitoring of drug resistance in three Resource-limited settings, where specific non- B subtypes predominate. Through these studies we will develop a robust sequence database of HIV-1 non-B variants for genotypic analyses and phenotypic validation of resistance mutations and patterns. We have designed a program to first develop quality assured, low cost drug resistance monitoring strategies using dried filter specimens for resistance testing. These strategies will be implemented in Thailand, India and china, to study differences between HIV-1 subtypes in drug resistance to current first-line, WHO- recommended treatment regimens. In collaboration with Monogram Biosciences we will assess the importance of mutations and patterns in these samples using an advanced method for phenotypic resistance testing. The goals of this proposal are to (i) validate low-cost resistance testing; (ii) determine frequency and patterns of virological failure and drug resistance after 1 and 2 years of ART; and (iii) conduct genotypic analyses and phenotypic validation of subtype-specific mutations and patterns. PUBLIC HEALTH RELEVANCE: The HIV-1 pandemic is a global emergency caused by multiple subtypes. Evolution of anti-HIV drug resistance is the main cause and consequence of drug treatment failure. Most knowledge about drug resistance stems from work in the US and Europe on the relatively uncommon subtype B HIV-1. In resource limited settings, where the majority of the pandemic prevails, non-B subtypes and circulating recombinant forms (CRF) predominate. Treatment access programs are rapidly increasing the numbers of AIDS patients, throughout the world, who are receiving combinations of antiretroviral therapies (ART). Our long-term goal is to determine the how different subtypes of HIV-1 respond to treatment with antiretroviral drugs and the significance of subtype in the selection and the evolution of drug resistance.

描述（由申请人提供）：人类免疫缺陷病毒（HIV-1）大流行是由多种亚型和新出现的重组病毒引起的，它们广泛分布在世界各地。应对这一流行病的一项重要措施是在全球范围内扩大抗逆转录病毒治疗方案的可及性，可能为数百万感染者提供抗逆转录病毒治疗。长期治疗成功的一个障碍是耐药性的出现，耐药性是由病毒基因中选择的突变引起的，这既是抗逆转录病毒治疗失败的原因，也是其后果。关于耐药性的知识主要来自美国和欧洲，主要集中在一种HIV-1亚型b。然而，全球90%的感染发生在非洲和亚洲资源有限的环境中，在那里其他不同的非b型HIV-1亚型占主导地位。有强有力的初步证据表明，治疗前不同亚型的基因型不同，甚至在治疗前，在非b亚型中，与耐药性相关的位置可能发生明显的突变。此外，在药物暴露后，在非b亚型中检测到明显的新突变。关于非b型病毒的易感性和耐药性的信息对于维持抗逆转录病毒治疗的益处的战略至关重要。在资源有限的环境下，传播性和获得性耐药性的流行程度和发生率将推动公共卫生艾滋病毒治疗方案中关于诊断测试、初始和二线治疗的决定。本建议的重点是在三个资源有限的环境中建立监测和监测耐药性的科学基础设施，这些环境中特定的非B亚型占主导地位。通过这些研究，我们将开发一个强大的HIV-1非b变异体序列数据库，用于抗性突变和模式的基因型分析和表型验证。我们设计了一个方案，首先开发质量有保证、低成本的耐药性监测策略，使用干燥的过滤标本进行耐药性测试。这些战略将在泰国、印度和中国实施，以研究HIV-1亚型对目前世卫组织推荐的一线治疗方案的耐药性差异。与Monogram Biosciences合作，我们将使用一种先进的表型抗性测试方法来评估这些样本中突变和模式的重要性。本提案的目标是：(i)验证低成本的耐药性测试；确定1年和2年抗逆转录病毒治疗后病毒学失败和耐药性的频率和模式；（iii）对亚型特异性突变和模式进行基因型分析和表型验证。