Efficacy and safety of nitazoxanide combined with ritonavir-boosted atazanavir for the treatment of mild to moderate COVID-19

Abstract

SummaryBackgroundFinding effective therapeutics for COVID-19 continues to be an urgent need, especially considering use context limitations and high cost of currently approved agents. The NACOVID trial investigated the efficacy and safety of repurposed antiprotozoal and antiretroviral drugs, nitazoxanide and atazanavir/ritonavir, used in combination for COVID-19.MethodsIn this pilot, randomized, open-label trial conducted in Nigeria, patients diagnosed with mild to moderate COVID-19 were randomly assigned to receive standard of care (SoC) or SoC plus a 14-day course of nitazoxanide (1000 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 of nitazoxanide active metabolite, tizoxanide, were also evaluated. This trial was registered withClinicalTrials.gov(NCT04459286).FindingsThere 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 to 28 in the 35% of patients with detectable virus at baseline (20/57) between the two arms (aHR = 0.948, 95% CI: 0.341-2.636, p = 0.919). There was no significant difference in time from enrolment 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 1546 ng/ml (95% CI: 797-2557), above its putative EC90in 54% of patients. Tizoxanide was not detectable in saliva.InterpretationThese findings should be interpreted in the context of incomplete enrolment (64%) and the limited number of patients with detectable SARS-CoV-2 in saliva at baseline in this trial.FundingThe University of Liverpool.Research in contextEvidence before this studyThe potential efficacy of nitazoxanide as a repurposed drug for COVID-19 is being investigated in a number of studies due to confirmedin vitroactivity against SARS-CoV-2. Available data from completed randomised controlled trials in which clinical improvement, effect on viral load, and symptom resolution were evaluated as outcomes do not offer conclusive evidence.Added value of this studyIn the NACOVID trial, we sought to take advantage of a model-informed strategy and known interaction between nitazoxanide and atazanavir/ritonavir to achieve optimal concentration of tizoxanide in plasma, and possibly in respiratory tracts of patients with mild to moderate COVID-19. While this strategy significantly enhanced tizoxanide exposure in the plasma of patients, our data indicated poor penetration into the respiratory tracts. Specifically, there were no differences in time to clinical improvement, viral load changes, and symptom resolutions between patients who were given standard of care alone and those who combined it with study intervention.Implications of all the available evidenceThe clinical benefit of nitazoxanide remains uncertain. The present study highlights the need for early insight into target site biodistribution of potential COVID-19 therapeutics to better inform candidate selection for clinical trials.