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Revisión sistemática
Medwave 2020;20(6):e7966 doi: 10.5867/medwave.2020.06.7966
Lopinavir/ritonavir para COVID-19: una revisión sistemática viva
Lopinavir/ritonavir for COVID-19: A living systematic review
Francisca Verdugo-Paiva, Ariel Izcovich, Martín Ragusa, Gabriel Rada, COVID-19 L·OVE Working Group
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Palabras clave: COVID-19, Severe acute respiratory syndrome coronavirus 2, Coronavirus Infections, Systematic review, Lopinavir, Lopinavir/ritonavir, Antivirals

Resumen

Objetivo
Esta revisión sistemática viva tiene como objetivo entregar un resumen oportuno, riguroso y constantemente actualizado de la evidencia disponible sobre los efectos de lopinavir/ritonavir en pacientes con COVID-19.

Métodos
Se realizó una búsqueda en la plataforma L·OVE COVID-19 (Living OVerview of Evidence), un sistema que mantiene búsquedas regulares en PubMed/Medline, Embase, Cochrane Central Register of Controlled Trials (CENTRAL) y otras 33 fuentes. Se buscaron ensayos aleatorios y estudios no aleatorios que evaluaran el uso de lopinavir/ritonavir versus placebo o ningún tratamiento en pacientes con COVID-19. Dos revisores evaluaron de forma independiente los artículos potencialmente elegibles, de acuerdo con criterios de selección predefinidos, y extrajeron los datos mediante un formulario estandarizado. Los resultados fueron combinados mediante un metanálisis utilizando modelos de efectos aleatorios y evaluamos la certeza de la evidencia utilizando el método GRADE. Una versión viva de esta revisión estará disponible durante la pandemia de COVID-19.

Resultados
La búsqueda inicial arrojó 862 referencias. Finalmente, identificamos 12 estudios incluyendo 2 ensayos aleatorios, que evaluaban lopinavir/ritonavir adicionado al tratamiento estándar versus tratamiento estándar en 250 pacientes adultos hospitalizados con COVID-19. Los resultados provenientes de los ensayos aleatorios muestran que el uso de lopinavir/ritonavir puede reducir la mortalidad (riesgo relativo: 0,77; intervalo de confianza 95%: 0,45 a 1,3; certeza de evidencia baja), pero la magnitud de la reducción absoluta de la mortalidad varía según los diferentes grupos de riesgo. El uso de lopinavir/ritonavir mostró además una ligera reducción en el riesgo de requerir ventilación mecánica invasiva, desarrollar insuficiencia respiratoria o síndrome de dificultad respiratoria aguda. No se observó diferencias en la duración de la hospitalización y su uso puede producir un aumento en el número de efectos adversos totales. La certeza global de la evidencia fue baja o muy baja.

Conclusiones
Para pacientes graves y críticos con COVID-19, el uso de lopinavir/ritonavir podría desempeñar un papel en la mejora de los resultados, pero la evidencia disponible aún es limitada. La gran cantidad de estudios en curso deberían proporcionar evidencia valiosa para informar a los investigadores y los tomadores de decisiones en el futuro cercano.


 

Solo disponible la versión en inglés.

Licencia Creative Commons Esta obra de Medwave está bajo una licencia Creative Commons Atribución-NoComercial 3.0 Unported. Esta licencia permite el uso, distribución y reproducción del artículo en cualquier medio, siempre y cuando se otorgue el crédito correspondiente al autor del artículo y al medio en que se publica, en este caso, Medwave.

 

Objective
Provide a timely, rigorous, and continuously updated summary of the evidence on the role of lopinavir/ritonavir in the treatment of patients with COVID-19.

Methods
We conducted searches in the special L·OVE (Living OVerview of Evidence) platform for COVID-19, a system that performs regular searches in PubMed, Embase, CENTRAL, and other 33 sources. We searched for randomized trials and non-randomized studies evaluating the effect of lopinavir/ritonavir versus placebo or no treatment in patients with COVID-19. Two reviewers independently evaluated potentially eligible studies, according to predefined selection criteria, and extracted data using a predesigned standardized form. We performed meta-analyses using random-effect models and assessed overall certainty in evidence using the GRADE approach. A living, web-based version of this review will be openly available during the COVID-19 pandemic.

Results
Our search strategy yielded 862 references. Finally, we identified 12 studies, including two randomized trials, evaluating lopinavir/ritonavir, in addition to standard care versus standard care alone in 250 adult inpatients with COVID-19. The evidence from randomized trials shows lopinavir/ritonavir may reduce mortality (relative risk: 0.77; 95% confidence interval: 0.45 to 1.3; low certainty evidence), but the anticipated magnitude of the absolute reduction in mortality, varies across different risk groups. Lopinavir/ritonavir also had a slight reduction in the risk of requiring invasive mechanical ventilation, developing respiratory failure, or acute respiratory distress syndrome. However, it did not lead to any difference in the duration of hospitalization and may lead to an increase in the number of total adverse effects. The overall certainty of the evidence was low or very low.

Conclusions
For severe and critical patients with COVID-19, lopinavir/ritonavir might play a role in improving outcomes, but the available evidence is still limited. A substantial number of ongoing studies should provide valuable evidence to inform researchers and decision-makers soon.

Autores: Francisca Verdugo-Paiva[1,2], Ariel Izcovich[3], Martín Ragusa[3,4], Gabriel Rada[1,2,5], COVID-19 L·OVE Working Group []

Filiación:
[1] Epistemonikos Foundation, Santiago, Chile
[2] UC Evidence Center, Cochrane Chile Associated Center, Pontificia Universidad Católica de Chile, Santiago, Chile
[3] Internal Medicine Service, German Hospital, Buenos Aires, Argentina
[4] Internal Medicine Service, Fernandez Hospital, Buenos Aires, Argentina
[5] Internal Medicine Department, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile

E-mail: fverdugo@epistemonikos.org

Correspondencia a:
[1] Holanda 895
Providencia, Santiago
Chile

Citación: Verdugo-Paiva F, Izcovich A, Ragusa M, Rada G, . Lopinavir/ritonavir for COVID-19: A living systematic review . Medwave 2020;20(6):e7966 doi: 10.5867/medwave.2020.06.7966

Fecha de envío: 25/5/2020

Fecha de aceptación: 25/6/2020

Fecha de publicación: 15/7/2020

Origen: No solicitado.

Tipo de revisión: Con revisión externa por tres pares revisores a doble ciego

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World Health Organization. Director-General's remarks at the media briefing on 2019-nCoV on 11 February 2020. World Health Organization; 2020 [Accessed 2020 April 12]. [Internet] | Link |

Hui DS, I Azhar E, Madani TA, Ntoumi F, Kock R, Dar O, et al. The continuing 2019-nCoV epidemic threat of novel coronaviruses to global health - The latest 2019 novel coronavirus outbreak in Wuhan, China. Int J Infect Dis. 2020 Feb;91:264-266. | CrossRef | PubMed |

Dong E, Du H, Gardner L. An interactive web-based dashboard to track COVID-19 in real time. Lancet Infect Dis. 2020 May;20(5):533-534. | CrossRef | PubMed |

Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, et al. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med. 2020 Apr 30;382(18):1708-1720. | CrossRef | PubMed |

Tavakoli A, Vahdat K, Keshavarz M. Novel Coronavirus Disease 2019 (COVID-19): An Emerging Infectious Disease in the 21st Century. BPUMS. 2020;22(6):432-450. | CrossRef |

Li LQ, Huang T, Wang YQ, Wang ZP, Liang Y, Huang TB, et al. COVID-19 patients' clinical characteristics, discharge rate, and fatality rate of meta-analysis. J Med Virol. 2020 Jun;92(6):577-583. | CrossRef | PubMed |

Centre for Evidence-Based Medicine. Global Covid-19 Case Fatality Rates UK [Accessed 2020 April 12]. [Internet] | Link |

Rodriguez-Morales AJ, Cardona-Ospina JA, Gutiérrez-Ocampo E, Villamizar-Peña R, Holguin-Rivera Y, Escalera-Antezana JP, et al. Clinical, laboratory and imaging features of COVID-19: A systematic review and meta-analysis. Travel Med Infect Dis. 2020 Mar-Apr;34:101623. | CrossRef | PubMed |

Chu CM, Cheng VC, Hung IF, Wong MM, Chan KH, Chan KS, et al. Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings. Thorax. 2004 Mar;59(3):252-6. | CrossRef | PubMed |

Chan KS, Lai ST, Chu CM, Tsui E, Tam CY, Wong MM, et al. Treatment of severe acute respiratory syndrome with lopinavir/ritonavir: a multicentre retrospective matched cohort study. Hong Kong Med J. 2003 Dec;9(6):399-406. | PubMed |

Momattin H, Mohammed K, Zumla A, Memish ZA, Al-Tawfiq JA. Therapeutic options for Middle East respiratory syndrome coronavirus (MERS-CoV)--possible lessons from a systematic review of SARS-CoV therapy. Int J Infect Dis. 2013 Oct;17(10):e792-8. | CrossRef | PubMed |

Al-Tawfiq JA, Memish ZA. Update on therapeutic options for Middle East Respiratory Syndrome Coronavirus (MERS-CoV). Expert Rev Anti Infect Ther. 2017 Mar;15(3):269-275. | CrossRef | PubMed |

Yao TT, Qian JD, Zhu WY, Wang Y, Wang GQ. A systematic review of lopinavir therapy for SARS coronavirus and MERS coronavirus-A possible reference for coronavirus disease-19 treatment option. J Med Virol. 2020 Jun;92(6):556-563. | CrossRef | PubMed |

Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. J Clin Epidemiol. 2009 Oct;62(10):1006-12. | CrossRef | PubMed |

Rada G, Verdugo-Paiva F, Ávila C, Morel-Marambio M, Bravo-Jeria R, Pesce F, et al. Evidence synthesis relevant to COVID-19: a protocol for multiple systematic reviews and overviews of systematic reviews. Medwave. 2020 Apr 1;20(3):e7868. | CrossRef | PubMed |

Verdugo-Paiva F, Izcovich A, Ragusa M, Rada G, COVID-19 L-OVE Working Group. Lopinavir/ritonavir for the treatment of COVID-19: A living systematic review protocol. medRxiv 2020.04.11.20062109. | CrossRef |

Github repository [Accessed 2020 May 24]. [Internet] | Link |

Epistemonikos Foundation. Epistemonikos Database Methods. Santiago. [Accessed 2020 May 24]. [Internet] | Link |

Epistemonikos Foundation. Methods for the special L·OVE of Coronavirus infection. Santiago. [Accessed 2020 May 24]. [Internet] | Link |

Schünemann HJ, Cuello C, Akl EA, Mustafa RA, Meerpohl JJ, Thayer K, et al. GRADE guidelines: 18. How ROBINS-I and other tools to assess risk of bias in nonrandomized studies should be used to rate the certainty of a body of evidence. J Clin Epidemiol. 2019 Jul;111:105-114. | CrossRef | PubMed |

Jin X, Pang B, Zhang J, Liu Q, Yang Z, Feng J, et al. Core Outcome Set for Clinical Trials on Coronavirus Disease 2019 (COS-COVID). Engineering (Beijing). 2020 Mar 18. | CrossRef | PubMed |

COVID-19 Core Outcomes. [Accessed 2020 May 24]. [Internet] | Link |

Guyatt GH, Oxman AD, Santesso N, Helfand M, Vist G, Kunz R, et al. GRADE guidelines: 12. Preparing summary of findings tables-binary outcomes. J Clin Epidemiol. 2013 Feb;66(2):158-72. | CrossRef | PubMed |

Epistemonikos Foundation. Collaboratron [Software]. Santiago, 2017.

Sterne JAC, Savović J, Page MJ, Elbers RG, Blencowe NS, Boutron I, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019 Aug 28;366:l4898. | CrossRef | PubMed |

Sterne JA, Hernán MA, Reeves BC, Savović J, Berkman ND, Viswanathan M, et al. ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. BMJ. 2016 Oct 12;355:i4919. | CrossRef | PubMed |

Guyatt GH, Thorlund K, Oxman AD, Walter SD, Patrick D, Furukawa TA, et al. GRADE guidelines: 13. Preparing summary of findings tables and evidence profiles-continuous outcomes. J Clin Epidemiol. 2013 Feb;66(2):173-83. | CrossRef | PubMed |

Guyatt GH, Oxman AD, Santesso N, Helfand M, Vist G, Kunz R, et al. GRADE guidelines: 12. Preparing summary of findings tables-binary outcomes. J Clin Epidemiol. 2013 Feb;66(2):158-72. | CrossRef | PubMed |

Review Manager (RevMan) [Software]. Version 5.3.5 Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014.

Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ. 2008 Apr 26;336(7650):924-6. | CrossRef | PubMed |

Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G, et al. A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19. N Engl J Med. 2020 May 7;382(19):1787-1799. | CrossRef | PubMed |

Li Y, Xie Z, Lin W, Cai W, Wen C, Guan Y, et al. An exploratory randomized controlled study on the efficacy and safety of lopinavir/ritonavir or arbidol treating adult patients hospitalized with mild/moderate COVID-19 (ELACOI). medRxiv. 2020:2020.03.19.20038984. | CrossRef |

Hurst M, Faulds D. Lopinavir. Drugs. 2000 Dec 1;60(6):1371-9. | CrossRef | PubMed |

Bai X, Fang C, Zhou Y, Bai S, Liu Z, Chen Q, et al. Predicting COVID-19 Malignant Progression with AI Techniques. Preprint. Infectious Diseases (except HIV/AIDS), March 23, 2020. | CrossRef |

Yan L, Zhang HT, Goncalves J, Xiao Y, Wang M, Guo Y, et al. A Machine Learning-Based Model for Survival Prediction in Patients with Severe COVID-19 Infection. Preprint. Epidemiology, March 1, 2020. | CrossRef |

Ji D, Zhang D, Xu J, Chen Z, Yang T, Zhao P, et al. Prediction for Progression Risk in Patients with COVID-19 Pneumonia: the CALL Score. Clin Infect Dis. 2020 Apr 9:ciaa414. | CrossRef | PubMed |

Bi Q, Hong C, Meng J, Wu Z, Zhou P, Ye C, et al. Characterization of Clinical Progression of COVID-19 Patients in Shenzhen, China. Preprint. Epidemiology, April 27, 2020. | CrossRef |

Li X, Xu S, Yu M, Wang K, Tao Y, Zhou Y, et al. Risk factors for severity and mortality in adult COVID-19 inpatients in Wuhan. J Allergy Clin Immunol. 2020 Jul;146(1):110-118. | CrossRef | PubMed |

Wang X, Fang J, Zhu Y, Chen L, Ding F, Zhou R, et al. Clinical characteristics of non-critically ill patients with novel coronavirus infection (COVID-19) in a Fangcang Hospital. Clin Microbiol Infect. 2020 Apr 3:S1198-743X(20)30177-4. | CrossRef | PubMed |

Gong J, Ou J, Qiu X, Jie Y, Chen Y, Yuan L, et al. A Tool to Early Predict Severe Corona Virus Disease 2019 (COVID-19) : A Multicenter Study using the Risk Nomogram in Wuhan and Guangdong, China. Clin Infect Dis. 2020 Apr 16:ciaa443. | CrossRef | PubMed |

Hu L, Chen S, Fu Y, Gao Z, Long H, Wang JM, et al. Risk Factors Associated with Clinical Outcomes in 323 COVID-19 Hospitalized Patients in Wuhan, China. Clin Infect Dis. 2020 May 3:ciaa539. | CrossRef | PubMed |

Pang J, Wang MX, Ang IYH, Tan SHX, Lewis RF, Chen JI, et al. Potential Rapid Diagnostics, Vaccine and Therapeutics for 2019 Novel Coronavirus (2019-nCoV): A Systematic Review. J Clin Med. 2020 Feb 26;9(3):623. | CrossRef | PubMed |

Rios P, Radhakrishnan A, Antony J, Thomas SM, Muller M, Straus SE, et al. Effectiveness and safety of antiviral or antibody treatments for coronavirus: A rapid review. medRxiv. 2020:2020.03.19.20039008. | CrossRef |

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