In vitro activity of lopinavir/ritonavir and hydroxychloroquine against severe acute respiratory syndrome coronavirus 2 at concentrations achievable by usual doses
2
조회
0
다운로드
5
인용
0
참고문헌
키워드
초록
Background/Aims: As the coronavirus disease-2019 global pandemic progresses, screening of antiviral agents effective against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is urgently needed. In addition, considering the viral load kinetics of SARS-CoV-2, which peaks early in the illness, and the massive burden of the disease, which may increase in the near future, identifying well-tolerated oral antivirals becomes increasingly important. We examined the in vitro activity of lopinavir/ritonavir and hydroxychloroquine on SARSCoV- 2, at concentrations which can be used to treat coronavirus-19 patients with little concern of toxicity. Methods: Lopinavir/ritonavir (7/1.75 μg/mL), hydroxychloroquine base (1 or 2 μg/ mL), or a combination thereof were administered 1 hour after the inoculation of SARS-CoV-2 to Vero cells at a multiplicity of infection of 0.05. We examined cytopathic effects of virus 48 hours after administration of the respective treatments and measured viral loads at three time points (0, 24, and 48 hours posttreatment) by quantitative real-time reverse-transcription polymerase chain reaction, and compared the results obtained from the different antiviral regimens tested. Results: The severity of cytopathic effects was lower in lopinavir/ritonavir-treated cells, and viral load was significantly reduced in this group compared with the control group (p < 0.001). However, hydroxychloroquine did not show significant inhibitory effects on anti-SARS-CoV-2-mediated cytotoxicity or on viral load at either concentration. Conclusions: Lopinavir/ritonavir showed signif icant inhibitory effects on SARS-CoV-2 in vitro at its usual plasma concentration. However, the in vitro antiviral activity of hydroxychloroquine at concentrations commonly used in humans was minimal, whether used alone or in combination with lopinavir/ ritonavir.
Abstract
Background/Aims: As the coronavirus disease-2019 global pandemic progresses, screening of antiviral agents effective against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is urgently needed. In addition, considering the viral load kinetics of SARS-CoV-2, which peaks early in the illness, and the massive burden of the disease, which may increase in the near future, identifying well-tolerated oral antivirals becomes increasingly important. We examined the in vitro activity of lopinavir/ritonavir and hydroxychloroquine on SARSCoV- 2, at concentrations which can be used to treat coronavirus-19 patients with little concern of toxicity. Methods: Lopinavir/ritonavir (7/1.75 μg/mL), hydroxychloroquine base (1 or 2 μg/ mL), or a combination thereof were administered 1 hour after the inoculation of SARS-CoV-2 to Vero cells at a multiplicity of infection of 0.05. We examined cytopathic effects of virus 48 hours after administration of the respective treatments and measured viral loads at three time points (0, 24, and 48 hours posttreatment) by quantitative real-time reverse-transcription polymerase chain reaction, and compared the results obtained from the different antiviral regimens tested. Results: The severity of cytopathic effects was lower in lopinavir/ritonavir-treated cells, and viral load was significantly reduced in this group compared with the control group (p < 0.001). However, hydroxychloroquine did not show significant inhibitory effects on anti-SARS-CoV-2-mediated cytotoxicity or on viral load at either concentration. Conclusions: Lopinavir/ritonavir showed signif icant inhibitory effects on SARS-CoV-2 in vitro at its usual plasma concentration. However, the in vitro antiviral activity of hydroxychloroquine at concentrations commonly used in humans was minimal, whether used alone or in combination with lopinavir/ ritonavir.
참고문헌 (22)
- "Novel coronavirus (2019-nCoV) situation reports" (2020)[URL]
- Chan JF, "Treatment with lopinavir", ritonavir or interferon-β1b improves outcome of MERSCoV infection in a nonhuman primate model of common marmoset, 2015, pp.212, 1904~1913
- Chu CM, "Role of lopinavir", ritonavir in the treatment of SARS : initial virological and clinical findings, 2004, pp.59, 252~256
- Choy KT, "Remdesivir, lopinavir, emetine, and homoharringtonine inhibit SARSCoV-2 replication in vitro", Antiviral Res, 178, pp.104786~ (2020)
- Vincent MJ, "Chloroquine is a potent inhibitor of SARS coronavirus infection and spread", Virol J, 2, pp.69~ (2005)
- Yao X, "In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)", Clin Infect Dis (2020)[DOI]
- Liu J, "Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARSCoV-2 infection in vitro", Cell Discov, 6, pp.16~ (2020)
- Wan Beom Park, "Virus Isolation from the First Patient with SARS-CoV-2 in Korea", Journal of Korean Medical Science, 35(7), pp.1~5 (2020), 대한의학회[DOI]
- "Kaletra" (2017)[URL]
- "Plaquenil" (2017)[URL]
- Jallouli M, "Determinants of hydroxychloroquine blood concentration variations in systemic lupus erythematosus", Arthritis Rheumatol, 67, pp.2176~2184 (2015)
- Kumar M, "Inactivation and safety testing of Middle East respiratory syndrome coronavirus", J Virol Methods, 223, pp.13~18 (2015)
- Pan Y, "Viral load of SARS-CoV-2 in clinical samples", Lancet Infect Dis, 20, pp.411~412 (2020)
- Zou L, "SARS-CoV-2 viral load in upper respiratory specimens of infected patients", N Engl J Med, 382, pp.1177~1179 (2020)
- Cao B, "A trial of lopinavir-ritonavir in adults hospitalized with severe COVID-19", N Engl J Med, 382, pp.1787~1799 (2020)
- Hicks C, "Long-term safety and durable antiretroviral activity of lopinavir", ritonavir in treatment-naive patients : 4 year follow-up study, 2004, pp.18, 775~779
- Gautret P, "Clinical and microbiological effect of a combination of hydroxychloroquine and azithromycin in 80 COVID-19 patients with at least a six-day follow up : a pilot observational study", Travel Med Infect Dis, 34, pp.101663~ (2020)
- Gautret P, "Hydroxychloroquine and azithromycin as a treatment of COVID-19 : results of an open-label non-randomized clinical trial", Int J Antimicrob Agents (2020)[DOI]
- Chen J, "A pilot study of hydroxychloroquine in treatment of patients with moderate COVID-19", Zhejiang Da Xue Xue Bao Yi Xue Ban, 49, pp.215~219 (2020)
- Chatre C, "Cardiac complications attributed to chloroquine and hydroxychloroquine : a systematic review of the literature", Drug Saf, 41, pp.919~931 (2018)
- Juurlink DN, "Safety considerations with chloroquine, hydroxychloroquine and azithromycin in the management of SARS-CoV-2 infection", CMAJ, 192, pp.E450~E453 (2020)
- Arnold SLM, "Hydroxychloroquine for treatment of SARS-CoV-2 infection? Improving our confidence in a model-based approach to dose selection", Clin Transl Sci (2020)[DOI]