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)方案来治疗艾滋病毒-2感染。这在西非尤其如此 在100-200万感染艾滋病毒-2的人中，绝大多数人生活和获得有效的艾滋病毒-2抗逆转录病毒药物治疗的机会有限。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抗药性；包括非核苷类逆转录酶抑制剂(NNRTI)和融合抑制剂恩福韦肽(T-20)。此外，在接受抗逆转录病毒治疗的患者的HIV-2中，经常观察到对核苷/核苷酸逆转录酶抑制剂(NRTI)产生广泛耐药性的突变。尽管抗逆转录病毒蛋白水解酶抑制剂(PI)可以有效地治疗HIV-2，但HIV-1和HIV-2在其 易感性的研究表明，沙奎那韦(SQV)、洛匹那韦(LPV)和达鲁那韦(DRV)是唯一有效的抗HIV-2复制的PI，并且经常出现交叉耐药。不幸的是，CCR5共受体拮抗剂(马拉韦罗)的实用受到艾滋病毒-2‘S利用多个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，然而还没有临床试验来评估它们的有效性。这些限制给艾滋病毒-2治疗带来了重大挑战，特别是在艾滋病毒最流行的地区。世卫组织目前在西非的指南和国家方案建议对HIV-2感染进行初始、一线抗逆转录病毒治疗：2NRTI(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是 多级抗性的高发是常见的。使未能通过抗逆转录病毒治疗的艾滋病毒-2患者的评估复杂化，西非大部分地区没有常规的艾滋病毒-2病毒载量或耐药性检测。此外，目前还没有世卫组织推荐、证明或有效的二线抗逆转录病毒治疗方案来治疗艾滋病毒-2感染者。然而，最近在塞内加尔，通过S抗逆转录病毒倡议(ISAARV)，INI、Raltegravir和第二代PI Darunavir已可用于艾滋病毒-2感染的二线抗逆转录病毒治疗，国际抗逆转录病毒方案正在开发用于治疗艾滋病毒-2感染的算法。为了应对这些严峻的挑战，并使公共卫生部门了解西非艾滋病毒-2感染者的治疗和护理方法，我们将在拟议的赠款中实现以下目标。目的1：为S抗逆转录病毒计划(ISAARV)中的HIV-2感染者二线抗逆转录病毒疗法(ART)开发、实施和评估新的HIV-2病毒载量和抗逆转录病毒耐药性通知算法的结果。目的2：测定HIV-2对新型和流行性抗逆转录病毒药物的基因和表型敏感性、耐药机制和耐药途径。目的3：建立一种新的HIV-2和HIV-1总核酸检测方法，并用于临床诊断。我们为塞内加尔感染艾滋病毒-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结局的巨大潜力。

 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.