In vitro testing of combined hydroxychloroquine and azithromycin on SARS-CoV-2 shows synergistic effect

Andréani, Julien; Bideau, Marion Le; Duflot, Isabelle; Jardot, Priscilla; Rolland, Clara; Boxberger, Manon; Wurtz, Nathalie; Rolain, Jean‐Marc; Colson, Philippe; Scola, Bernard La; Raoult, Didier

doi:10.1016/j.micpath.2020.104228

Cited by 285 publications

(290 citation statements)

References 39 publications

(47 reference statements)

Supporting

Mentioning

274

Contrasting

Unclassified

Order By: Relevance

“…We found that combinations of virus-directed nelfinavir with host directed salinomycin, amodiaquine, obatoclax, emetine and homoharringtonine were synergistic. This finding and previous studies suggest that synergy is achieved when virus-directed and host-directed antivirals target the same stage of virus replication cycle, whereas combinations of host-directed antivirals are usually toxic for the cells (Andersen et al, 2019;Andreani et al, 2020;Fu et al, 2016;Kuivanen et al, 2017) (https://doi.org/10.1101/2020.04.14.039925).…”

Section: Discussionsupporting

confidence: 64%

Potential antiviral options against SARS-CoV-2 infection

Ianevski

Yao

Fenstad

et al. 2020

Preprint

View full text Add to dashboard Cite

As of May 2020, the number of people infected with SARS-CoV-2 continues to skyrocket, with more than 4,5 million cases worldwide. Both the World Health Organization (WHO) and United Nations (UN) has highlighted the need for better control of SARS-CoV-2 infections. Developing novel virus-specific vaccines, monoclonal antibodies and antiviral drugs against SARS-CoV-2 can be time-consuming and costly. Convalescent plasma and safe-in-man broad-spectrum antivirals (BSAAs) are readily available treatment options. Here we developed a neutralization assay using SARS-CoV-2 virus and monkey Vero-E6 cells. We identified most potent sera from recovered patients for treatment of SARS-CoV-2-infected patients. We also screened 136 safe-in-man broad-spectrum antivirals against SARS-CoV-2 infection in Vero-E6 cells and identified antiviral activity of nelfinavir, salinomycin, amodiaquine, obatoclax, emetine and homoharringtonine. We found that combinations of virus-directed drug nelfinavir with host-directed drugs, such as salinomycin, amodiaquine, obatoclax, emetine and homoharringtonine exhibit synergistic effect against SARS-CoV-2 in vitro. Finally, we developed a website to disseminate the knowledge on available and emerging treatments of COVID-19.

show abstract

Section: Discussionsupporting

confidence: 64%

Potential antiviral options against SARS-CoV-2 infection

Ianevski

Yao

Fenstad

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…6 In a separate study (preprint), following a 60-hour incubation period, a synergistic effect with the combination HCQ 2 µM + AZ 10 µM was observed in vitro on SARS-CoV-2 at concentrations expected in human lung, leading to total inhibition of viral replication. 7 Caution should be exercised in comparing the EC 50 values across these studies due to the differences in experimental conditions (e.g., different cell lines, MOI, time of drug addition to culture, incubation times, and analytical methods).…”

Section: Reviewmentioning

confidence: 99%

“…In a companion in vitro study by investigators in Marseilles, France, when AZ was dosed in combination with HCQ, 2,3 a synergistic effect was observed in vitro against SARS-CoV-2; however, no EC 50 was determined. 7 The determination of in vitro EC 50 for agents administered alone and in combination against SARS-CoV-2 under similar experimental conditions is needed to further understand the putative antiviral effect of this combination. Other possible mechanisms including the amplification of the host's IFN pathway-mediated antiviral responses as well as AZ's potential to interfere with viral entry requires further experimental work.…”

Section: A0661154: a Phase IImentioning

confidence: 99%

Clinical Pharmacology Perspectives on the Antiviral Activity of Azithromycin and Use in COVID‐19

Damle

Vourvahis

Wang

et al. 2020

Clin Pharma and Therapeutics

154

View full text Add to dashboard Cite

Azithromycin (AZ) is a broad-spectrum macrolide antibiotic with a long half-life and a large volume of distribution. It is primarily used for the treatment of respiratory, enteric, and genitourinary bacterial infections. AZ is not approved for the treatment of viral infections, and there is no well-controlled, prospective, randomized clinical evidence to support AZ therapy in coronavirus disease 2019 . Nevertheless, there are anecdotal reports that some hospitals have begun to include AZ in combination with hydroxychloroquine or chloroquine (CQ) for treatment of COVID-19. It is essential that the clinical pharmacology (CP) characteristics of AZ be considered in planning and conducting clinical trials of AZ alone or in combination with other agents, to ensure safe study conduct and to increase the probability of achieving definitive answers regarding efficacy of AZ in the treatment of COVID-19. The safety profile of AZ used as an antibacterial agent is well established. 1 This work assesses published in vitro and clinical evidence for AZ as an agent with antiviral properties. It also provides basic CP information relevant for planning and initiating COVID-19 clinical studies with AZ, summarizes safety data from healthy volunteer studies, and safety and efficacy data from phase II and phase II/III studies in patients with uncomplicated malaria, including a phase II/III study in pediatric patients following administration of AZ and CQ in combination. This paper may also serve to facilitate the consideration and use of a priori-defined control groups for future research.

show abstract

“…Moreover, most trials are testing the efficacy of antimalarial drugs, particularly hydroxychloroquine (alone or in combination with azithromycin or lopinavir/ritonavir) and chloroquine, followed by the antiviral drugs lopinavir/ritonavir, favipiravir and remdesivir. Indeed, substantial interest has been placed in demonstrating the effectiveness of these specific drugs or drugs combinations [13][14][15].…”

Section: Discussionmentioning

confidence: 99%

The race to find a SARS-CoV-2 drug can only be won by a few chosen drugs: a systematic review of registers of clinical trials of drugs aimed at preventing or treating COVID-19

Martínez‐Vizcaíno

Mesas

Cavero‐Redondo

et al. 2020

Preprint

View full text Add to dashboard Cite

Considering the massive amount of clinical trial registers aimed to find effective drugs for the prevention and treatment of COVID-19, it is challenging to have a comprehensive view of which drugs are being studied more extensively and when is expected that we will have consistent results regarding their effectiveness. This systematic review included all clinical trials on pharmacological therapy related to COVID-19 and SARS-CoV-2 registered at the International Clinical Trials Registry Platform (WHO-ICTRP) up to April 22, 2020. Clinical trials characteristics (country, design, sample size, main outcomes, expected completion data, type of participants, length of the interventions, main outcomes). How many trials and the accumulated sample size by drug or combination of drugs, and by month in 2020 was depicted. We identified 412 clinical trials registers addressing the effect of pharmacological treatments on COVID-19, predominantly from Asia and Europe (42.2% and 31.1% of clinical trials registers, respectively). The most main outcomes studied were clinical recovery (54.4% of the clinical trials registers, respiratory recovery (28.2%) mortality (27.4%), viral load/negativity (20.4%). During 2020, a huge amount of clinical trials are expected to be completed: 41 trials (60,366 participants) using hydroxychloroquine, 20 trials (1,588 participants) using convalescent's plasma, 18 trials (6,830 participants) using chloroquine, 12 trials (9,938 participants using lopinavir/ritonavir, 11 trials(1,250 participants) using favipiravir, 10 trials ( 2,175 participants) using tocilizumab and 6 trials (13,540 participants) using Remdesivir. The distribution of the number of registered clinical trials among the different therapeutic options leads to an excess of sample size for some and a lack for others. Our data allow us to conclude that by the end of June we will have results of almost 20 trials involving 40000 patients for hydroxychloroquine and 5 trials with 4500 patients for remdesivir; however, low statistical power is expected from the 9 clinical trials testing the efficacy of favipiravir or the 5 testing tocilizumab, since they will recruit less than 1000 patients each one.

show abstract

In vitro testing of combined hydroxychloroquine and azithromycin on SARS-CoV-2 shows synergistic effect

Cited by 285 publications

References 39 publications

Potential antiviral options against SARS-CoV-2 infection

Potential antiviral options against SARS-CoV-2 infection

Clinical Pharmacology Perspectives on the Antiviral Activity of Azithromycin and Use in COVID‐19

The race to find a SARS-CoV-2 drug can only be won by a few chosen drugs: a systematic review of registers of clinical trials of drugs aimed at preventing or treating COVID-19

Contact Info

Product

Resources

About