Efficacy and safety of Lopinavir/Ritonavir in COVID-19: A Systematic Review
Creators: name: Patel, Tejas
name: Patel, Parvati
name: Barvaliya, Manish
name: Saurabh, Manoj
Publisher: name: Open Science Framework
Year: 2022
Subjects: subject: Medicine and Health Sciences
subject: COVID-19
subject: Lopinavir-Ritonavir
subject: Mortality
subject: Systematic review

description: Introduction Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the current pandemic of Corona Virus Disease 2019 (COVID-19). Few patients infected with SARS-CoV-2 develop acute respiratory distress syndrome, leading to a high rate of admission to intensive care units and ultimately death in severe cases [Chen et al., 2020; Huang et al., 2020]. No antiviral treatment has been proven to be effective in SARS-CoV-2 infection. Optimized supportive care remains the mainstay of therapy for it. The Lopinavir/ ritonavir combination is one of the repurposed drugs currently used in the treatment of COVID-19. They are protease inhibitors used for treating the HIV infection. The protease is considered key enzyme in coronavirus polyprotein processing [Sanders et al. 2020]. In-vitro study by Kang et al observed significant antiviral activity of combination of lopinavir/ritonavir against SARS-CoV-2 [Kang et al., 2020]. However, the current use of lopinavir/ritonavir is mainly based on the experience of use of lopinavir/ritonavir in SARS and MERS. The aim of this systematic review is to find out the efficacy and safety outcomes in COVID-19 patients treated with lopinavir/ ritonavir combination. Study identification Two investigators will independently searched the following databases: PubMed, medrxiv.org, biorxib.org, mediterranee-infection.com/pre-prints-ihu, Google Scholar and CNKI. The search terms will be: (Lopinavir AND Ritonavir) AND (COVID-19 OR coronavirus OR SARS-CoV-2). There will be no language and time restriction to include the published articles. Selection criteria All randomized clinical studies evaluating the efficacy and/or safety of Lopinavir/ritonavir on COVID-19 patients will be included. The studies will be considered irrespective dose and duration of lopinavir/ritonavir and its comparator interventions (placebo, supportive care or any other treatment modalities). Risk of bias assessment of included studies Two investigators will assess the methodological quality of the included studies as per “risk of bias assessment tool for the randomized controlled clinical trials (ROB-II)” [Sterne et al., 2019]. Data extraction The following data will be extracted in a Microsoft Excel sheet, 2016: first author, publication year, study design, study site, baseline data of study population in treatment arms, efficacy and safety data. Efficacy and safety outcomes The efficacy outcome variables will be virological cure, radiological improvement and mortality between patients who received lopinavir/ritonavir and comparator interventions at the end of the study period. The safety outcomes will be adverse events between lopinavir/ritonavir and comparator interventions at the end of the study period. The subgroup analyses of efficacy and safety outcomes will be performed based on the type of control interventions. Data synthesis All outcomes will be summarized as risk ratio (RR) with 95% CI and will be pooled using the Mantle-Hanzle method using the fixed effect or random model. The heterogeneity will be assessed using I2 test. The publication bias will be assessed visually through a ‘funnel plot’. The meta-analysis will be performed through ‘Review manager software version 5.3’. References: 1.Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet 2020;395(10223):507-13. 2. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020;395(10223):497-506. [Erratum in: Lancet. 2020 Jan 30;: PMID: 31986264; PMCID: PMC7159299]. 3.Kang CK, Seong MW, Choi SJ, Kim TS, ChoePG, Song SH, et al. In vitro activity of lopinavir/ritonavir and hydroxychloroquine against severe acute respiratory syndrome coronavirus 2 at concentrations achievable by usual doses. Korean J Intern Med 2020. doi: 10.3904/kjim.2020.157. 4.Sanders JM, MonogueML, Jodlowski TZ, Cutrell JB. Pharmacologic Treatments for Coronavirus Disease 2019 (COVID-19): A Review. JAMA 2020. doi: 10.1001/jama.2020.6019. Sterne JAC, Savović J, Page MJ, ElbersRG, BlencoweNS, Boutron I, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ 2019;366:l4898.