Lack of antiviral activity of darunavir against SARS-CoV-2

Meyer, Sandra De; Bojkova, Denisa; Cinatl, Jindrich; Damme, Ellen Van; Buyck, Christophe; Loock, Marnix Van; Woodfall, Brian; Ciesek, Sandra

doi:10.1016/j.ijid.2020.05.085

Cited by 122 publications

(93 citation statements)

References 19 publications

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“…Overall, 15 in vitro published studies were included in the systematic review, which comprised majorly of treatments done on Vero E6 cells for viral titration, drug inhibition and cytotoxicity analyses. Nine studies were included from China, 4,5,[18][19][20][21][22][23][24] three from United States of America (USA), [25][26][27] one each from Germany, 28 Netherlands 29 and Australia. 30 There were two studies 5,20 involving the antimalarial drug on hydroxychloroquine, which had chloroquine as a positive control in both the studies.…”

Section: Results From the Systematic Review Of In Vitro Studiesmentioning

confidence: 99%

“…One study each involving 47D11 H2L2 antibody, 29 arbidol, 18 auranofin, 27 beta-d-N4-hydroxycytidine, 25 darunavir, 28 antibodies n3086/n3113, 24 interferon-α/interferon -β, 26 ivermectin, 30 lianhuaqingwen, 21 chloroquine, 4 lopinavir, 23 ementine hydrochloride, 23 homoharringtonine 23 and Pudilan Xiaoyan oral liquid 22 All the studies had an incubation time (hours postinfection) of treatment ranging from 24 to 72 hours on average with a median of 48 hours. Table 1 depicts the baseline characteristics of in vitro studies included in our systematic review.…”

Section: Results From the Systematic Review Of In Vitro Studiesmentioning

confidence: 99%

See 1 more Smart Citation

Efficacy of various treatment modalities for nCOV‐2019: A systematic review and meta‐analysis

Misra

Nath

Hadda

et al. 2020

Eur J Clin Investigation

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Background: Several therapeutic agents have been investigated for treatment of novel coronavirus 2019 (nCOV-2019). We conducted a systematic review and metaanalysis to assess the efficacy of various treatment modalities in nCOV-2019 patients. Methods: A literature search was conducted before 29 June 2020 in PubMed, Google Scholar and Cochrane library databases. A fixed-effect model was applied if I 2 < 50%, else results were combined using random-effect model. Risk ratio (RR) or standardized mean difference (SMD) along with 95% confidence interval (95% CI) was used to pool the results. Between-study heterogeneity was explored using influence and sensitivity analyses, and publication bias was assessed using funnel plots. Entire statistical analysis was conducted in R version 3.6.2. Results: Fifty studies involving 15 in vitro and 35 clinical studies including 9170 nCOV-2019 patients were included. Lopinavir-ritonavir was significantly associated with shorter mean time to clinical recovery (SMD −0.32; 95% CI −0.57 to −0.06), remdesivir was significantly associated with better overall clinical recovery (RR 1.17; 95% CI 1.07 to 1.29), and tocilizumab was associated with less all-cause mortality (RR 0.38; 95% CI 0.16 to 0.93). Hydroxychloroquine was associated with longer time to clinical recovery and less overall clinical recovery. It additionally had higher all-cause mortality and more total adverse events. Conclusion: Our meta-analysis suggests that except in vitro studies, no treatment has shown overall favourable outcomes in nCOV-2019 patients. Lopinavir-ritonavir, remdesivir and tocilizumab may have some benefits, while hydroxychloroquine administration may cause harm in nCOV-2019 patients. Results from upcoming large clinical trials may further clarify role of these drugs. K E Y W O R D S humans, interventions, nCOV-2019, novel coronavirus 2019, treatments 2 of 21 | MISRA et Al. 2 | METHODS 2.1 | Electronic search Electronic databases including, PubMed, EMBASE, Medline, Google Scholar, Cochrane library and clinicaltrials.gov were searched till 29 June 2020. The following MeSH terms or free text terms were used: '2019 novel coronavirus', '2019 nCOV', 'COVID19', 'SARS-CoV-2', 'drug therapy', 'antiviral therapy', 'symptomatic treatment', 'immunotherapy'. The detailed search criteria are given in the Appendix S1. Furthermore, the reference list of all the relevant identified articles was thoroughly searched. Only those articles were included whose full texts were available in English language. Studies published on human subjects after 31 December 2019 since the nCOV-2019 outbreak initiated, were only searched. The protocol for this systematic review and meta-analysis was registered in PROSPERO (ID: CRD42020175792), and there were no major deviations from the published protocol in PROSPERO. 2.2 | Population Subjects diagnosed with pneumonia caused by new coronavirus 2019 infection (nCOV-2019) confirmed positive on highthroughput sequencing or real-time reverse-transcription polymerase chain reaction analysis of thro...

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Section: Results From the Systematic Review Of In Vitro Studiesmentioning

confidence: 99%

Section: Results From the Systematic Review Of In Vitro Studiesmentioning

confidence: 99%

Efficacy of various treatment modalities for nCOV‐2019: A systematic review and meta‐analysis

Misra

Nath

Hadda

et al. 2020

Eur J Clin Investigation

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“…There are several ongoing clinical trials evaluating safety and efficacy of favilavir against other antivirals in China, Japan, Canada and avifavir in Russia. Darunavir/Cobicistat and Darunavir/Ritonavir [ 44 ] have also been tested in a randomized controlled trial of 30 patients in China which showed that darunavir/cobicistat was not effective in the treatment of COVID-19. There are no data from clinical trials that support the use of other HIV protease inhibitors to treat COVID-19, such as Atazanavir.…”

Section: Introductionmentioning

confidence: 99%

Emerging treatment strategies for COVID-19 infection

Gavriatopoulou

Ntanasis‐Stathopoulos

et al. 2020

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The new type of coronavirus (COVID-19), SARS-CoV-2 originated from Wuhan, China and has led to a worldwide pandemic. COVID-19 is a novel emerging infectious disease caused by SARS-CoV-2 characterized as atypical pneumonia. As of July 1, 2020, more than 10 million people worldwide had been infected with SARS-CoV-2. The typical manifestations of COVID-19 include fever, sore throat, fatigue, cough, and dyspnoea combined with recent exposure. Most of the patients with COVID-19 have mild or moderate disease, however up to 5–10% present with severe and even life-threatening disease course. The mortality rates are approximately 2%. Therefore, there is an urgent need for effective and specific antiviral treatment. Currently, supportive care measures such as ventilation oxygenation and fluid management remain the standard of care. Several clinical trials are currently trying to identify the most potent drug or combination against the disease, and it is strongly recommended to enroll patients into ongoing trials. Antivirals can be proven as safe and effective only in the context of randomized clinical trials. Currently several agents such as chloroquine, hydroxychloroquine, favipiravir, monoclonal antibodies, antisense RNA, corticosteroids, convalescent plasma and vaccines are being evaluated. The large numbers of therapeutic interventions aim to define the most efficacious regimen. The aim of this article is to describe the treatment strategies that have been used for COVID-19 patients and review all the available literature.

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“…To date, a number of old drugs have been clinically tested for potential e cacy against SARS-CoV-2, such as lopinavir/ritonavir, hydroxychloroquine, darunavir and cobicistat 20,21,24,25 . Although some of these molecules are effective in cellular models, clinical trials showed no signi cant improvement in symptoms and length of hospitalization 21,26 ; thus, the e cacy of these drugs remains controversial. Since the targets of these drugs on SARS-CoV-2 are unclear, the mechanism is ambiguous, which suggests that it is essential and reliable to start from a de ned target to identify candidate drugs.…”

Section: Discussionmentioning

confidence: 99%

High-throughput Screening and Experimental Identification of Potent Drugs Targeting SARS-CoV-2 Main Protease

Zhang

Wang

et al. 2020

Preprint

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The main protease (Mpro) is one of the best-characterized drug targets among coronaviruses. In the current study, we adopted a multiple cross-docking strategy against different crystal structures of SARS-CoV-2 Mpro to perform computer-based high-throughput virtual screening of possible inhibitors from a drug database using Autodock Vina and SeeSAR software, combined with our in-house automatic processing scripts. The KDs between screened candidates and Mpro were determined using Biacore. Seven drugs were found to fit the substrate-binding pocket of Mpro with a stable conformation, showing high KDs that ranged from 6.79E-7 M to 5.20E-5 M. Finally, mutagenesis studies confirmed that these drugs interact with Mpro specifically, suggesting that our method was reliable and convincing. Given the safety of these old drugs, they may serve as promising candidates to treat the infection of SARS-CoV-2. Our results also provide rational explanations for the behaviour of five drugs evaluated in clinical trials.

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Lack of antiviral activity of darunavir against SARS-CoV-2

Cited by 122 publications

References 19 publications

Efficacy of various treatment modalities for nCOV‐2019: A systematic review and meta‐analysis

Efficacy of various treatment modalities for nCOV‐2019: A systematic review and meta‐analysis

Emerging treatment strategies for COVID-19 infection

High-throughput Screening and Experimental Identification of Potent Drugs Targeting SARS-CoV-2 Main Protease

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