Canducci Filippo, Sampaolo Michela, Marinozzi Maria Chiara, Boeri Enzo, Spagnuolo Vincenzo, Galli Andrea, Castagna Antonella, Lazzarin Adriano, Clementi Massimo, Gianotti Nicola
Università Vita-Salute San Raffaele, Italy.
AIDS. 2009 Feb 20;23(4):455-60. doi: 10.1097/QAD.0b013e328323da60.
: Evaluate HIV-1 subtype B integrase gene evolution in patients failing raltegravir (RAL)-based savage regimens by clonal analysis of the replicating viral quasispecies.
: Seven triple class failure HIV-1 (subtype B)-infected patients, followed at San Raffaele Hospital and enrolled in the RAL Expanded Access Program (MK0518-023), were evaluated. Patients were followed up for 24-48 weeks and due to the absence of other active drugs, RAL was maintained in their regimens even if resistance mutations were detected.
: Immunologic and virologic parameters were recorded every 4 weeks, and amplification and clonal analysis of viral populations were performed at baseline and every 4-12 weeks in all patients.
: Resistance to RAL appeared initially associated with selection of single variants (Y143R, Q148R N155H) in the majority of patients; however, in three patients, complex patterns of viral mutations were observed. The clonal analysis of viral quasispecies allowed to describe the evolution of each viral population and the progressive accumulation of RAL resistance-associated mutations and polymorphisms associated with therapy failure.
: The complex patterns of resistance mutations observed, including novel variants evolved under continuous RAL pressure, suggesting that they are the result of the equilibrium between drug resistance and enzyme function. Despite the efficacy of this compound, our data discourage its use in a functional monotherapy and maintaining RAL even in presence of RAL resistance-associated mutations may lead to the progressive formation of viral reservoirs with multiple integrase inhibitor-resistant variants that may limit the future efficacy of other integrase inhibitors due to cross-resistance.
通过对复制性病毒准种进行克隆分析，评估基于雷特格韦（RAL）的挽救方案治疗失败的患者中HIV-1 B亚型整合酶基因的进化情况。
对在圣拉斐尔医院接受随访并参加RAL扩大准入项目（MK0518-023）的7例HIV-1（B亚型）三重治疗失败感染患者进行评估。对患者随访24至48周，由于没有其他活性药物，即使检测到耐药突变，他们的治疗方案中仍保留RAL。
每4周记录免疫和病毒学参数，所有患者在基线时以及每4至12周进行病毒群体的扩增和克隆分析。
在大多数患者中，对RAL的耐药性最初与单个变异体（Y143R、Q148R、N155H）的选择有关；然而，在3例患者中观察到了复杂的病毒突变模式。病毒准种的克隆分析有助于描述每个病毒群体的进化以及与治疗失败相关的RAL耐药相关突变和多态性的逐步积累。
观察到的耐药突变复杂模式，包括在持续RAL压力下进化出的新变异体，表明它们是耐药性与酶功能之间平衡的结果。尽管该化合物有效，但我们的数据不支持将其用于功能性单一疗法，并且即使存在与RAL耐药相关的突变仍维持RAL治疗可能会导致具有多种整合酶抑制剂耐药变异体的病毒库逐步形成，这可能会因交叉耐药而限制其他整合酶抑制剂未来的疗效。
