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

 描述（由申请人提供）：迫切需要安全有效的抗逆转录病毒治疗（ART）方案治疗HIV-2感染。在西非尤其如此 在100万至200万HIV-2感染者中，绝大多数人生活在这些地区，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中经常观察到赋予对核苷/核苷酸逆转录酶抑制剂（NRTI）的广泛耐药性的突变。尽管抗逆转录病毒蛋白酶抑制剂（PI）可有效地用于治疗HIV-2，但HIV-1和HIV-2在其耐药性方面也表现出重要差异。 研究表明沙奎那韦（SQV）、洛匹那韦（LPV）和地瑞那韦（DRV）是唯一有效的抗HIV-2复制的PI，交叉耐药性频繁。不幸的是，CCR 5共受体拮抗剂（马拉韦罗）的效用受到HIV-2使用多种共受体进入细胞的能力的阻碍。越来越多的证据支持整合酶抑制剂（INI）对HIV-2的潜在效用，但还没有临床试验来评估其有效性。这些局限性对HIV-2治疗提出了重大挑战，特别是在其最流行的地区。目前世卫组织指南和西非国家方案建议对HIV-2感染进行初始一线ART：2 NRTI（通常为AZT+3 TC）+洛匹那韦/利托那韦（LPV/r）。然而，临床和病毒学失败率 多类耐药性普遍存在。在西非大部分地区，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，没有WHO推荐的、经证实或有效的二线ART方案来治疗2次NRTI + LPV/r失败的HIV-2感染者。然而，最近在塞内加尔，INI（雷特格韦）和第二代PI（达芦那韦）最近通过塞内加尔抗逆转录病毒接入倡议（ISAARV）可用于HIV-2感染的二线ART，ISAARV正在开发用于HIV-2感染的算法。为了应对这些重大挑战，并为西非艾滋病毒-2感染者的治疗和护理提供基于公共卫生的方法，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治疗倡议（ISAARV）项目中，为艾滋病毒2型感染患者的二线抗逆转录病毒治疗制定、实施和评估新的艾滋病毒2型病毒载量和抗逆转录病毒药物耐药性知情算法的结果。目标2：确定HIV-2对新型抗逆转录病毒药物的基因型和表型易感性、耐药机制和途径。目的3：开发和验证用于临床诊断的新型HIV-2和HIV-1总核酸检测方法。我们为塞内加尔感染HIV-2的成年人开发循证治疗和护理的长期多学科努力具有显著改善患者预后的巨大潜力。

 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.