A randomized, open-label trial of combined nitazoxanide and atazanavir/ritonavir for mild to moderate COVID-19

Abstract

BackgroundThe nitazoxanide plus atazanavir/ritonavir for COVID-19 (NACOVID) trial investigated the efficacy and safety of repurposed nitazoxanide combined with atazanavir/ritonavir for COVID-19.MethodsThis is a pilot, randomized, open-label multicenter trial conducted in Nigeria. Mild to moderate COVID-19 patients were randomly assigned to receive standard of care (SoC) or SoC plus a 14-day course of nitazoxanide (1,000 mg b.i.d.) and atazanavir/ritonavir (300/100 mg od) and followed through day 28. Study endpoints included time to clinical improvement, SARS-CoV-2 viral load change, and time to complete symptom resolution. Safety and pharmacokinetics were also evaluated (ClinicalTrials.gov ID: NCT04459286).ResultsThere was no difference in time to clinical improvement between the SoC (n = 26) and SoC plus intervention arms (n = 31; Cox proportional hazards regression analysis adjusted hazard ratio, aHR = 0.898, 95% CI: 0.492–1.638, p = 0.725). No difference was observed in the pattern of saliva SARS-CoV-2 viral load changes from days 2–28 in the 35% of patients with detectable virus at baseline (20/57) (aHR = 0.948, 95% CI: 0.341–2.636, p = 0.919). There was no significant difference in time to complete symptom resolution (aHR = 0.535, 95% CI: 0.251–1.140, p = 0.105). Atazanavir/ritonavir increased tizoxanide plasma exposure by 68% and median trough plasma concentration was 1,546 ng/ml (95% CI: 797–2,557), above its putative EC90 in 54% of patients. Tizoxanide was undetectable in saliva.ConclusionNitazoxanide co-administered with atazanavir/ritonavir was safe but not better than standard of care in treating COVID-19. These findings should be interpreted in the context of incomplete enrollment (64%) and the limited number of patients with detectable SARS-CoV-2 in saliva at baseline in this trial.Clinical trial registration[https://clinicaltrials.gov/ct2/show/NCT04459286], identifier [NCT04459286].

The FDA-approved drug nitazoxanide is a potent inhibitor of human seasonal coronaviruses acting at postentry level: effect on the viral spike glycoprotein

“…More importantly several studies have recently shown an antiviral activity and clinical benefits of nitazoxanide in COVID-19 patients ( Blum et al, 2021 ; Rocco et al, 2021 , 2022 ; Silva et al, 2021 ; Rossignol et al, 2022a ). It should be mentioned that no significant effect of nitazoxanide in the prevention or outcome of SARS-CoV-2 infections was reported in some studies ( Fowotade et al, 2022 ; Sokhela et al, 2022 ). A recent study, while confirming the in vitro efficacy of nitazoxanide and tizoxanide against SARS-CoV-2, found that, in a SARS-CoV-2 virus challenge model in hamsters, oral and intranasal treatment with nitazoxanide failed to impair viral replication in affected organs, due to insufficient diffusion of the drug into the lungs and in the upper respiratory tract ( Driouich et al, 2022 ), suggesting that the different results reported could depend on the dosage used, and that optimization of the NTZ formulation may be required to improve clinical efficacy of the drug.…”

Eficácia Da Ivermectina E Atazanavir No Tempo De Recuperação Dos Sintomas De Covid-19: Uma Coorte Prospectiva

“…Desde o início da pandemia de COVID- (MAZAHERPOUR et al, 2022;KALANTARI et al, 2021;FOWOTADE et al, 2022;CHAVES et al, 2021).…”

“…A doença de coronavírus 2019 MEDINA et al, 2021;MSD, 2009) e Atazanavir (KALANTARI et al, 2021;FOWOTADE et al, 2022) no tratamento de pacientes sintomáticos da COVID-19.…”

COVID‐19: An Overview of SARS‐CoV‐2 Variants—The Current Vaccines and Drug Development

“…The effectiveness and safety of repurposed nitazoxanide in combination with atazanavir/ritonavir were assessed in a trial carried out in Nigeria among mild to moderate COVID-19 patients. In treating COVID-19, nitazoxanide coadministered with atazanavir/ritonavir was safe but ineffective compared to standard therapy [ 130 ]. In a study involving 62 patients with moderate-to-severe COVID-19, the patients were divided into two groups: KH (receiving lopinavir/ritonavir [Kaletra] plus hydroxychloroquine) and ADH (receiving atazanavir/ritonavir, dolutegravir, and hydroxychloroquine).…”