Department of Pharmaceutical and Administrative Sciences, Drake University College of Pharmacy and Health Sciences, 2507 University Ave., Des Moines, IA, 50311, USA.
Chimerix, 2505 Meridian Parkway, Suite 100, Durham, NC, 27713, USA.
Antiviral Res. 2018 Oct;158:255-263. doi: 10.1016/j.antiviral.2018.08.015. Epub 2018 Aug 25.
Human cytomegalovirus (HCMV) can cause severe disease in patients with compromised or immature immune systems. Currently approved pharmacotherapies for the treatment of systemic HCMV infections [ganciclovir (GCV), cidofovir (CDV), foscarnet] are limited by a high incidence of adverse effects and/or the development of drug resistance. Given that many of these drugs have the same viral target (HCMV-encoded DNA polymerase), cross-resistance is relatively common. The primary means to combat drug resistance is combination pharmacotherapy using therapeutics with different molecular mechanisms of action with the expectation that those combinations result in an additive or synergistic enhancement of effect; combinations that result in antagonism can, in many cases, be detrimental to the outcome of the patient. We therefore tested select combinations of approved (GCV, CDV, letermovir (LMV)) and experimental (brincidofovir (BCV), cyclopropavir (CPV), maribavir (MBV), BDCRB) drugs with the hypothesis that combinations of drugs with different and distinct molecular mechanisms of action will produce an additive and/or synergistic enhancement of antiviral effect against HCMV in vitro. Using MacSynergy II (a statistical package that measures enhancement or lessening of effect relative to zero/additive), select drug combination studies demonstrated combination indices ranging from 160 to 372 with 95% confidence intervals greater than zero indicating that these combinations elicit a synergistic enhancement of effect against HCMV in vitro. These data suggest that administration of a viral DNA polymerase inhibitor, MBV, and/or a viral terminase inhibitor in combination has the potential to address the resistance/cross-resistance problems associated with currently available therapeutics.
人巨细胞病毒（HCMV）可导致免疫系统受损或不成熟的患者发生严重疾病。目前，批准用于治疗全身性 HCMV 感染的药物疗法[更昔洛韦（GCV）、西多福韦（CDV）、膦甲酸]存在不良反应发生率高和/或耐药性发展的局限性。鉴于许多此类药物具有相同的病毒靶标（HCMV 编码的 DNA 聚合酶），交叉耐药性相对常见。对抗耐药性的主要方法是使用具有不同作用机制的治疗药物进行联合药物治疗，以期这些组合产生增效或协同作用；那些产生拮抗作用的组合在许多情况下可能对患者的预后不利。因此，我们测试了选定的批准药物（GCV、CDV、来特莫韦（LMV））和实验药物（溴夫定（BCV）、环丙氧鸟苷（CPV）、马拉韦罗（MBV）、BDCRB）的组合，假设具有不同和独特作用机制的药物组合将在体外产生针对 HCMV 的抗病毒作用的增效和/或协同增强。使用 MacSynergy II（一种衡量相对于零/增效作用的增强或减弱的统计软件包），对选定的药物组合研究表明，组合指数范围为 160 至 372，95%置信区间大于零，表明这些组合在体外对 HCMV 产生协同增效作用。这些数据表明，联合使用病毒 DNA 聚合酶抑制剂 MBV 和/或病毒末端酶抑制剂有可能解决与现有治疗方法相关的耐药性/交叉耐药性问题。
