Improving Diagnosis, Treatment & Detection of Drug Resistance in HIV-2 Infection

改善诊断、治疗

• 批准号: 8991978
• 负责人: Geoffrey Scott Gottlieb
• 金额: $ 77.62万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-15 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8991978
• 关键词: 18 year old; Address; Adult; Africa; African; Algorithms; Anti-Retroviral Agents; Antiretroviral resistance; Area; Biological Assay; Blood; CCR5 gene; Caring; Centers for Disease Control and Prevention (U.S.); Clinical; Clinical Research; Clinical Trials; Collaborations; Computer Simulation; Counseling; Detection; Development; Diagnosis; Diagnostic; Drug resistance; Effectiveness; Enrollment; Evaluation; Evidence based treatment; Exhibits; Failure; Generations; Genetic; Genotype; Goals; Grant; Guidelines; HIV; HIV-1; HIV-2; Human immunodeficiency virus test; Immunoassay; Individual; Infection; Integrase Inhibitors; Lamivudine; Lead; Life; Ligation; Lopinavir; Lopinavir/Ritonavir; Mutation; Nucleosides; Nucleotides; Oligonucleotides; Outcome; Pathway interactions; Patients; Phenotype; Population Study; Positioning Attribute; Predisposition; Protease Inhibitor; Public Health; Receptor Cell; Recommendation; Regimen; Relative (related person); Resistance; Resistance profile; Resources; Reverse Transcriptase Inhibitors; Saquinavir; Senegal; Serological; Site; Specificity; Spottings; T-20; Technology; Testing; Time; Treatment Protocols; Universities; Validation; Viral Load result; Washington; Zidovudine; antiretroviral therapy; base; evidence base; experience; improved; in vitro Model; inhibitor/antagonist; multidisciplinary; non-nucleoside reverse transcriptase inhibitors; novel; nucleic acid detection; programs; public health priorities; public health relevance; receptor; resistance mechanism; resistant strain

 DESCRIPTION (provided by applicant): There is a critical need for safe and effective antiretroviral treatment (ART) regimens for HIV-2 infection. This is especially true in West Africa where the vast majority of the 1-2 million individuals infected with HIV-2 live and were access to effective ART for HIV-2 is limited. HIV-2 is intrinsically resistant to many of the standard antiretrovirals used to treat HIV-1; including the non-nucleoside reverse transcriptase inhibitors (NNRTI) and the fusion inhibitor enfuvirtide (T-20). In addition, mutations conferring broad resistance to nucleoside/nucleotide reverse transcriptase inhibitors (NRTI) are frequently observed in HIV-2 from patients receiving ART. Although antiretroviral protease inhibitors (PI) can be used effectively to treat HIV-2, HIV-1 and HIV-2 also exhibit important differences in their susceptibilities with studies indicating that saquinavir (SQV), lopinavir (LPV), and darunavir (DRV) are the only potent PI's against HIV-2 replication and cross-resistance is frequent. Unfortunately, the utility of CCR5 co-receptor antagonists (maraviroc) is hampered by HIV-2's ability to use multiple co-receptors for cell entry. An increasing body of evidence supports the potential utility of integrase inhibitors (INI) against HIV-2, however there have been no clinical trials to assess their effectiveness. These limitations present major challenges to HIV-2 treatment, particularly in the areas in which it is most prevalent. Current WHO guidelines and National Programs in West Africa recommend for initial, 1st-line ART for HIV-2 infection: 2 NRTI (typically AZT+3TC) + lopinavir/ritonavir (LPV/r). However clinical and virologic failure rates are high and development of multiclass resistance is common. Complicating assessment of HIV-2 patients failing ART, there is no routine HIV-2 viral load or drug resistance testing available in most of West Africa. In addition, there are no WHO recommended, proven or effective 2nd-line ART regimens to treat HIV-2 infected individuals failing 2 NRTI + LPV/r. Recently however, in Senegal, the INI, raltegravir and the 2nd- generation PI, darunavir, recently have become available for 2nd-line ART in HIV-2 infection through the Initiative Sénégalaise d'Accès aux Antirétroviraux (ISAARV) and algorithms for their use in HIV-2 infection are being developed by ISAARV. In order to address these critical challenges and to inform public health based approached to treatment and care of HIV-2 infected individuals in West Africa, we will undertake the following aims in our proposed grant. AIM 1: Develop, implement and evaluate outcomes of a new HIV-2 viral load and ARV resistance-informed algorithm for 2nd-line ART in HIV-2 infected patients in the Initiative Sénégalaise d'Accès aux Antirétroviraux (ISAARV) program. AIM 2: Determination of genotypic and phenotypic susceptibility, resistance mechanisms and pathways, of HIV-2 to novel and pipeline antiretroviral agents. AIM 3: Development and validation for clinical diagnostic use of a novel HIV-2 and HIV-1 total nucleic acid detection assay. Our longstanding, multidisciplinary effort to develop evidence-based treatment and care for HIV-2 infected adults in Senegal has high potential to significantly improve patient outcomes.

 描述（由应用提供）：对HIV-2感染的安全有效抗逆转录病毒治疗（ART）方案至关重要。在西非尤其如此 在感染HIV-2的1-200万个人中，绝大多数人活着并获得了HIV-2的有效艺术是有限的。 HIV-2在本质上对用于治疗HIV-1的许多标准抗逆转录病毒具有抗性。包括非核苷逆转录酶抑制剂（NNRTI）和融合抑制剂Enfuvirtide（T-20）。此外，尽管抗逆转录病毒蛋白酶抑制剂（PI）可以有效地治疗HIV-2，HIV-1和HIV-2，但对核外侧/核苷逆转录酶抑制剂（NRTI）的突变抗性广泛的耐药性也暴露了重要差异。 研究表明，Saquinavir（SQV），Lopinavir（LPV）和Darunavir（DRV）是唯一反对HIV-2复制和交叉抗性的PI。不幸的是，CCR5共受体拮抗剂（Maraviroc）的效用受HIV-2使用多个共受体进行细胞进入的能力的阻碍。越来越多的证据支持对HIV-2的整合酶抑制剂（INI）的潜在效用，但是没有进行临床试验来评估其有效性。这些局限性面临HIV-2治疗的主要挑战，尤其是在最普遍的领域。当前的WHO WHO在西非的指南和国家计划建议对HIV-2感染的初始，第一线艺术：2 NRTI（通常为AZT + 3TC） + lopinavir/Ritonavir（LPV/R）。但是临床和病毒衰竭率是 高和多类抗性的发展很常见。对于HIV-2患者的评估使ART失败的评估复杂化，西非大部分地区都没有常规的HIV-2病毒载荷或耐药性测试。此外，没有谁推荐，证明或有效的第二线艺术方案来治疗失败的HIV-2感染的人，失败了2 NRTI + LPV/R。然而，最近，在塞内加尔，INI，Raltegravir和第二代PI，Darunavir最近已通过主动性SénégalaiseD'AccèsAuxAccèsAuxAccèsAuxtirétroviraux（Isaarv（Isaarv）（Isaarv（Isaarv）（ISAARV）和Algorithms的使用，可用于HIV-2的第二层艺术，并由其在HIV-2中使用。为了应对这些关键挑战，并为西非的HIV-2感染者提供基于公共卫生的治疗和护理方法，我们将在提案中实现以下目标。授予。 AIM 1：针对HIV-2感染的患者在Sénégalaised'AccèsD'AccèsAuxAux AuxAntirétroviraux（Isaarv）计划中，针对HIV-2感染的患者的第二线ART的新型HIV-2病毒负载和ARV抗性信息的结果开发，实施和评估。 AIM 2：HIV-2对新型和管道抗逆转录病毒药物的基因型和表型敏感性，耐药机制和途径的确定。 AIM 3：用于临床诊断新型HIV-2和HIV-1总核酸检测测定法的开发和验证。我们为塞内加尔的HIV-2感染成年人开发基于证据的治疗和护理的长期多学科努力具有显着改善患者预后的高潜力。