University of Virginiagrid.27755.32, Department of Cell Biology, Charlottesville, Virginia, USA.
University of Virginiagrid.27755.32, Department of Microbiology, Charlottesville, Virginia, USA.
mBio. 2021 Dec 21;12(6):e0334721. doi: 10.1128/mbio.03347-21.
The world was unprepared for coronavirus disease 2019 (COVID-19) and remains ill-equipped for future pandemics. While unprecedented strides have been made developing vaccines and treatments for COVID-19, there remains a need for highly effective and widely available regimens for ambulatory use for novel coronaviruses and other viral pathogens. We posit that a priority is to develop pan-family drug cocktails to enhance potency, limit toxicity, and avoid drug resistance. We urge cocktail development for all viruses with pandemic potential both in the short term (<1 to 2 years) and longer term with pairs of drugs in advanced clinical testing or repurposed agents approved for other indications. While significant efforts were launched against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and in the clinic, many studies employed solo drugs and had disappointing results. Here, we review drug combination studies against SARS-CoV-2 and other viruses and introduce a model-driven approach to assess drug pairs with the highest likelihood of clinical efficacy. Where component agents lack sufficient potency, we advocate for synergistic combinations to achieve therapeutic levels. We also discuss issues that stymied therapeutic progress against COVID-19, including testing of agents with low likelihood of efficacy late in clinical disease and lack of focus on developing virologic surrogate endpoints. There is a need to expedite efficient clinical trials testing drug combinations that could be taken at home by recently infected individuals and exposed contacts as early as possible during the next pandemic, whether caused by a coronavirus or another viral pathogen. The approach herein represents a proactive plan for global viral pandemic preparedness.
世界对 2019 年冠状病毒病（COVID-19）毫无准备，仍然没有为未来的大流行做好充分准备。虽然在开发 COVID-19 的疫苗和治疗方法方面取得了前所未有的进展，但仍然需要为新型冠状病毒和其他病毒病原体开发高度有效且广泛可用的门诊治疗方案。我们认为，当务之急是开发泛家族药物鸡尾酒，以提高效力、降低毒性和避免耐药性。我们敦促在短期内（<1 至 2 年）和长期内，为所有具有大流行潜力的病毒开发鸡尾酒，包括处于临床后期测试或已批准用于其他适应症的重新定位药物的配对药物。虽然针对严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）进行了重大努力，并且在临床上许多研究都使用了单一药物，但结果令人失望。在这里，我们回顾了针对 SARS-CoV-2 和其他病毒的药物联合研究，并介绍了一种基于模型的方法来评估具有最高临床疗效可能性的药物对。在缺乏足够效力的情况下，我们提倡使用协同组合来达到治疗水平。我们还讨论了阻碍 COVID-19 治疗进展的问题，包括在临床疾病晚期测试疗效较低的药物和缺乏关注开发病毒学替代终点。需要尽快开展有效的临床试验，测试那些在大流行期间可能由冠状病毒或其他病毒病原体引起的、新近感染个体和接触者在家中即可使用的药物组合。本文所提出的方法代表了全球病毒性大流行准备的积极计划。
