Study reveals that Nitazoxanide for mild to moderate COVID-19 is not effective in improving outcomes in HIV-infected and HIV-uninfected adults with enhanced risk
Cape Town | A study funded by the South African Medical Research Council (SAMRC) has revealed that nitazoxanide (NTZ), an oral antiparasitic agent with antiviral properties, was ineffective in improving outcomes in ambulatory patients with mild-to-moderate COVID-19.
Performed at four sites in South Africa, namely, Western Cape, Cape Town (UCT Lung Institute); North West, Klerksdorp, (Perinatal HIV Research Unit); Gauteng, Tembisa (the Aurum Institute) and KwaZulu-Natal (University of KwaZulu-Natal), the primary goal of the C3-RCT was to evaluate the effectiveness of nitazoxanide (given at a dose of 1g twice daily for 7 days) in reducing the progression from mild to severe COVID-19 in ambulatory patients. Progression to severe disease was defined as hospitalisation or death. The trial underwent an interim analysis at 67% of the recruitment target (290 participants), and the data was reviewed by an independent data and safety monitoring board (DSMB). Following the interim analysis, the DSMB made a recommendation to halt recruitment of the trial on the grounds of futility.
One of the key findings of the study was that there was no significant difference in serious adverse events, which included all cause of hospitalisation and death, between the nitazoxanide and the placebo groups [12/144 (8.3%) vs. 10/146 (6.8%); RR = 0.82 (0.37, 1.84) OR = 0.81 (0.34,1.94); p-value = 0.664)]. Rates of hospitalisation specifically due to COVID-19 showed the same pattern [7/144 (4.9%) vs. 8/146 (5.5%); RR = 1.13 (0.42, 3.03); OR = 1.13 (0.40, 3.21); p-value = 1)].
According to the study’s principal investigator (PI), Prof Keertan Dheda from the University of Cape Town (UCT) and the London School of Hygiene and Tropical Medicine, the results of the C3-RCT, although disappointing, contributes to the growing body of evidence, clarifying what works and what doesn’t for the treatment of COVID-19. Thus, clarifying what does not work is as important as finding effective therapies so that clinically useful management algorithms can be developed.
Nitazoxanide, a low-cost drug with an extensive safety record, showed very promising activity against SARS-CoV-2 in laboratory studies. However, this did not translate into tangible benefits when tested in a real-world setting. This highlights the importance of well-designed studies, such as the C3-RCT, in gauging the true benefits of potential therapies that show promise in laboratory studies. It is still possible that nitazoxanide may be of benefit at higher doses (greater than the dose used in the C3 RCT, which was already twice the normal dose), however this will undoubtedly be accompanied by an increase in likely intolerable gastrointestinal side effects. “The next step will be to focus on formally publishing the data in a peer reviewed journal and to evaluate secondary objectives of the study, including assessing the efficacy of nitazoxanide in reducing the duration of illness, reducing SARS-CoV-2 viral load, and its efficacy, if any, in preventing COVID-19 in close contacts”, said Prof Dheda who is also Director of the SAMRC/UCT Centre for the Study of Antimicrobial Resistance Research Unit.
Prof Dheda concluded that it is also possible that nitazoxanide could have a less than 30% benefit (the limit of the efficacy that the study was designed or powered to detect), and a larger study would have detected a lower level of benefit. However, it is questionable whether such an effect size is clinically relevant given the number needed to treat to prevent disease progression, adverse events, cost and that other therapies have emerged (e.g. paxlovid) with an efficacy benefit of great than 80%.
SAMRC President and CEO, Prof Glenda Gray said although the study did not meet its primary endpoint, the results are an important addition into the scientific repository. “COVID-19 and HIV in their very nature are unique and complex viruses which have posed unprecedented challenges for vaccine development, globally – however, the knowledge gained from this trial will help us advance our pursuit of effective therapies and vaccines for both COVID-19 and HIV alike, said Prof Gray.
Gray, who also has led numerous trials in search of effective HIV and COVID-19 vaccines, said COVID-19 poses substantial challenges for those living with HIV which evades the immune system. “Until an effective vaccine has been found, all people living with HIV should take all recommended preventive measures to minimize their exposure to COVID-19”, concluded Gray.
NOTE TO THE EDITOR
More About the study:
Trial title: Nitazoxanide for mild to moderate COVID-19 in HIV-infected and HIV-uninfected adults with enhanced risk: a double-blind, randomised, placebo-controlled trial in a resource-poor setting (Catalysing the Containment of COVID-19; the C3-RCT).
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Tendani Tsedu
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Email: tendani.tsedu@mrc.ac.za