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

改善诊断、治疗

• 批准号: 9089930
• 负责人: Geoffrey Scott Gottlieb
• 金额: $ 74.58万
• 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/9089930
• 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-1 protease; HIV-2; Health; Human immunodeficiency virus test; Immunoassay; Individual; Infection; Integrase Inhibitors; Lamivudine; Lead; Life; Ligation; Lopinavir; Lopinavir/Ritonavir; Mutation; Nucleosides; Nucleotides; Oligonucleotides; Outcome; Pathway interactions; Patient-Focused Outcomes; Patients; Phenotype; Positioning Attribute; Predisposition; Protease Inhibitor; Public Health; Receptor Cell; Recommendation; Regimen; 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; improved outcome; in vitro Model; inhibitor/antagonist; multidisciplinary; non-nucleoside reverse transcriptase inhibitors; novel; nucleic acid detection; programs; public health priorities; receptor; resistance mechanism; resistant strain; study population

 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（由申请人提供）：迫切需要针对 HIV-2 感染的安全有效的抗逆转录病毒治疗 (ART) 方案。在西非尤其如此 在 1-200 万 HIV-2 感染者中，绝大多数人生活在该地区，并且获得有效的 HIV-2 抗逆转录病毒疗法的机会有限。 HIV-2 对许多用于治疗 HIV-1 的标准抗逆转录病毒药物具有内在耐药性；包括非核苷类逆转录酶抑制剂（NNRTI）和融合抑制剂恩夫韦肽（T-20）。此外，在接受 ART 的患者的 HIV-2 中经常观察到赋予核苷/核苷酸逆转录酶抑制剂 (NRTI) 广泛耐药性的突变。尽管抗逆转录病毒蛋白酶抑制剂 (PI) 可有效用于治疗 HIV-2，但 HIV-1 和 HIV-2 在治疗方面也表现出重要差异。 研究表明，沙奎那韦 (SQV)、洛匹那韦 (LPV) 和达芦那韦 (DRV) 是唯一有效的抗 HIV-2 复制的 PI，并且交叉耐药性很常见。不幸的是，CCR5 共受体拮抗剂 (maraviroc) 的实用性因 HIV-2 使用多个共受体进入细胞的能力而受到阻碍。越来越多的证据支持整合酶抑制剂 (INI) 对抗 HIV-2 的潜在效用，但尚无临床试验来评估其有效性。这些限制对 HIV-2 治疗提出了重大挑战，特别是在 HIV-2 最流行的地区。目前的世卫组织指南和西非国家规划建议对 HIV-2 感染进行初始一线 ART：2 NRTI（通常为 AZT+3TC）+ 洛匹那韦/利托那韦 (LPV/r)。然而，临床和病毒学失败率 高且多类抗性的发展是常见的。西非大部分地区没有常规的 HIV-2 病毒载量或耐药性检测，这使得对 ART 失败的 HIV-2 患者的评估变得复杂。此外，尚无世卫组织推荐的、经过验证的或有效的二线 ART 方案来治疗 2 NRTI + LPV/r 失败的 HIV-2 感染者。然而，最近在塞内加尔，INI 拉替拉韦和第二代 PI 达芦那韦最近已通过塞内加尔抗逆转录病毒倡议 (ISAARV) 可用于治疗 HIV-2 感染的二线 ART，并且 ISARV 正在开发用于治疗 HIV-2 感染的算法。为了应对这些关键挑战，并为西非 HIV-2 感染者基于公共卫生的治疗和护理方法提供信息，我们将在拟议的赠款中实现以下目标。目标 1：在塞内加尔抗逆转录病毒倡议 (ISAARV) 计划中，为 HIV-2 感染患者的二线 ART 开发、实施和评估新的 HIV-2 病毒载量和 ARV 耐药性信息算法的结果。目标 2：确定 HIV-2 对新型和正在研发的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。目标 3：开发和验证新型 HIV-2 和 HIV-1 总核酸检测方法的临床诊断用途。我们长期开展多学科努力，为塞内加尔的 HIV-2 感染成人开发循证治疗和护理，具有显着改善患者治疗效果的巨大潜力。