Efficacy and safety of nitazoxanide combined with ritonavir-boosted atazanavir for the treatment of mild to moderate COVID-19
Adeola Fowotade, Folasade Bamidele, Boluwatife Egbetola, Adeniyi Francis Fagbamigbe, Babatunde Ayodeji Adeagbo, Bolanle Olufunlola Adefuye, Ajibola Olagunoye, Temitope Olumuyiwa Ojo, Akindele Olupelumi Adebiyi, Omobolanle Ibitayo Olagunju, Olabode Taiwo Ladipo, Abdulafeez Akinloye, Adedeji Onayade, Oluseye Oladotun Bolaji, Steve Rannard, Christian Happi, Andrew Owen, PhD Adeniyi Olagunju
doi:10.1101/2022.02.03.22270152
Background Finding 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.
Methods In 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 with ClinicalTrials.gov
(NCT04459286). Findings There 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 EC90 in 54% of patients. Tizoxanide was not detectable in saliva. Interpretation These 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. Funding The University of Liverpool. 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 evidence The 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.
Declaration of interests We declare no competing interests.
Contributors AdO, AnO and SR conceived the initial study. AdO designed the study and developed the protocol with input from all authors. AF, FB, BE, and BOA were responsible for study enrolment and data acquisition. CH was responsible for SARS-CoV-2 viral load determination using RT-PCR. AdO, AA, BA and OOB were responsible for database management and pharmacokinetic analyses. AdO, AA, AF and BE verified the underlying data. AFF and AdO were responsible for analysis and interpretation of data. AdO drafted the manuscript. AnO and OOB critically revised the manuscript. All authors contributed to conducting the trial. All authors revised the report and read and approved the final version before submission. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication.
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