Comparing the effectiveness of Atazanavir/Ritonavir/Dolutegravir/Hydroxychloroquine and Lopinavir/Ritonavir/Hydroxychloroquine treatment regimens in COVID‐19 patients

Kalantari, Saeed; Fard, Soheil Rahmani; Maleki, Donya; Talebi-Taher, Mahshid; Yassin, Zeynab; Alimohamadi, Yousef; Minaeian, Sara

doi:10.1002/jmv.27195

Cited by 15 publications

(14 citation statements)

References 42 publications

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“…In the BAL infected and treated animals displayed lower levels of IL-6, TNF-a, KC and PF4, compared to untreated mice. The in vivo anti-inflammatory of ATV observed here is in line with the ability of this molecule to inhibit pyroptosis in human primary monocytes for both BAL and lung samples clearly showing that ATV protect both cell death and inflammation [23,32].…”

Section: Discussionsupporting

confidence: 82%

Atazanavir Is a Competitive Inhibitor of SARS-CoV-2 Mpro, Impairing Variants Replication In Vitro and In Vivo

et al. 2021

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Atazanavir (ATV) has already been considered as a potential repurposing drug to 2019 coronavirus disease (COVID-19); however, there are controversial reports on its mechanism of action and effectiveness as anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Through the pre-clinical chain of experiments: enzymatic, molecular docking, cell-based and in vivo assays, it is demonstrated here that both SARS-CoV-2 B.1 lineage and variant of concern gamma are susceptible to this antiretroviral. Enzymatic assays and molecular docking calculations showed that SARS-CoV-2 main protease (Mpro) was inhibited by ATV, with Morrison’s inhibitory constant (Ki) 1.5-fold higher than GC376 (a positive control) dependent of the catalytic water (H2Ocat) content. ATV was a competitive inhibitor, increasing the Mpro’s Michaelis–Menten (Km) more than sixfold. Cell-based assays indicated that different lineages of SARS-CoV-2 is susceptible to ATV. Using oral administration of ATV in mice to reach plasmatic exposure similar to humans, transgenic mice expression in human angiotensin converting enzyme 2 (K18-hACE2) were partially protected against lethal challenge with SARS-CoV-2 gamma. Moreover, less cell death and inflammation were observed in the lung from infected and treated mice. Our studies may contribute to a better comprehension of the Mpro/ATV interaction, which could pave the way to the development of specific inhibitors of this viral protease.

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Section: Discussionsupporting

confidence: 82%

Atazanavir Is a Competitive Inhibitor of SARS-CoV-2 Mpro, Impairing Variants Replication In Vitro and In Vivo

et al. 2021

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“…Similarly, the RECOVERY trial, a larger trial involving 176 hospitals from UK, did not find any differences in time until discharge alive from hospital or in the number of alive patients at discharge in 28 days [ 72 ]. Many other trials have reached the same outcomes; thus, the antiviral combination is not currently recommended for use in any of the clinical settings [ 73 , 74 , 75 , 76 ].…”

Section: First Evidence From Deploying Therapeutics: Sars-cov-2 Targe...mentioning

confidence: 99%

Molecular Insights of SARS-CoV-2 Antivirals Administration: A Balance between Safety Profiles and Impact on Cardiovascular Phenotypes

2022

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The COVID-19 pandemic has resulted in a complex clinical challenge, caused by a novel coronavirus, partially similar to previously known coronaviruses but with a different pattern of contagiousness, complications, and mortality. Since its global spread, several therapeutic agents have been developed to address the heterogeneous disease treatment, in terms of severity, hospital or outpatient management, and pre-existing clinical conditions. To better understand the rationale of new or old repurposed medications, the structure and host–virus interaction molecular bases are presented. The recommended agents by EDSA guidelines comprise of corticosteroids, JAK-targeting monoclonal antibodies, IL-6 inhibitors, and antivirals, some of them showing narrow indications due to the lack of large population trials and statistical power. The aim of this review is to present FDA-approved or authorized for emergency use antivirals, namely remdesivir, molnupinavir, and the combination nirmatrelvir-ritonavir and their impact on the cardiovascular system. We reviewed the literature for metanalyses, randomized clinical trials, and case reports and found positive associations between remdesivir and ritonavir administration at therapeutic doses and changes in cardiac conduction, relatable to their previously known pro-arrhythmogenic effects and important ritonavir interactions with cardioactive medications including antiplatelets, anti-arrhythmic agents, and lipid-lowering drugs, possibly interfering with pre-existing therapeutic regimens. Nonetheless, safety profiles of antivirals are largely questioned and addressed by health agencies, in consideration of COVID-19 cardiac and pro-thrombotic complications generally experienced by predisposed subjects. Our advice is to continuously adhere to the strict indications of FDA documents, monitor the possible side effects of antivirals, and increase physicians’ awareness on the co-administration of antivirals and cardiovascular-relevant medications. This review dissects the global and local tendency to structure patient-based treatment plans, for a glance towards practical application of precision medicine.

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“…However, in contrast to the current study, Atazanavir/Ritonavir was better tolerated with lower rates of nausea and vomiting in the aforementioned study on moderately-ill COVID-19 patients. (14).…”

Section: Discussionmentioning

confidence: 99%

Efficacy and Safety of Atazanavir/Ritonavir versus Lopinavir/Ritonavir in Hospitalized COVID-19 Patients: A Randomized Clinical Trial

2022

ircmj

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While several antivirals have been considered among the candidate repurposed drugs against SARS-CoV-2 infection, limited evidence exists on Atazanavir/Ritonavir. Objectives This trial was designed to assess the efficacy of Atazanavir/Ritonavir compared to Lopinavir/Ritonavir, another antiretroviral drug investigated in the previous studies. Methods This randomized, double-blind clinical trial was conducted on hospitalized patients with laboratory or confirmed SARS CoV-2 infection. Patients were randomly assigned (1:1) to receive either Lopinavir/Ritonavir (200mg Lopinavir+50mg Ritonavir, twice a day) or Atazanavir/Ritonavir (300mg Atazanavir+100 mg Ritonavir, once a day) for up to 14 days during their admission along with the standard care. The primary endpoint was total all-cause death in all patients during the hospitalization period. Secondary outcomes included length of hospitalization. Results Out of 103 adults included in the analysis 54 and 49 were assigned to Atazanavir/Ritonavir and Lopinavir/Ritonavir groups, respectively. The occurrence of adverse effects, defined as symptoms attributed to the drugs which no longer appear upon the cessation of the drug, was higher for cardiac side effects in Atazanavir/Ritonavir group. No statistically significant difference was observed between the two groups in terms of the length of hospitalization. After adjustment for other covariates in the study, treatment with Atazanavir/ritonavir did not result in a significant reduction in mortality compared to treatment with Lopinavir/Ritonavir. Conclusion The efficacy of Atazanavir/Ritonavir in this preliminary study was not superior to Lopinavir/Ritonavir in reducing mortality and length of hospitalization in COVID-19 patients. However, the limited efficacy of both compounds does not support their use in primary care for COVID-19 patients.

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Comparing the effectiveness of Atazanavir/Ritonavir/Dolutegravir/Hydroxychloroquine and Lopinavir/Ritonavir/Hydroxychloroquine treatment regimens in COVID‐19 patients

Cited by 15 publications

References 42 publications

Atazanavir Is a Competitive Inhibitor of SARS-CoV-2 Mpro, Impairing Variants Replication In Vitro and In Vivo

Atazanavir Is a Competitive Inhibitor of SARS-CoV-2 Mpro, Impairing Variants Replication In Vitro and In Vivo

Molecular Insights of SARS-CoV-2 Antivirals Administration: A Balance between Safety Profiles and Impact on Cardiovascular Phenotypes

Efficacy and Safety of Atazanavir/Ritonavir versus Lopinavir/Ritonavir in Hospitalized COVID-19 Patients: A Randomized Clinical Trial

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