Catalysing the Containment of COVID-19

COVID-19 that is caused by SARS-CoV-2 infection is a rapidly escalating global pandemic(9). The pandemic is on an upward and escalating trajectory in most countries though some countries like China have shown a substantial decrease in the number of new cases being recorded. It is unclear if there will be a second wave of the epidemic.

Most cases of COVID-19 are either asymptomatic or have minimal symptoms (~80%) and act as carriers for disease transmission. Recent longitudinal studies indicate that the SARS-COV-2 viral load in the pharynx is highest during the prodromal phase of COVID-19. Thus, early therapeutic intervention, prior to respiratory tract dissemination and disease amplification, is likely to be a promising strategy. Although such persons are advised to be in self isolation, many, especially in resource-poor settings (due to several factors including poverty, overcrowding, environmental conditions, personal beliefs, stigma and human fallibility), continue to have contact with others thus fuelling the epidemic. Therefore, reducing the period of infectiousness in ambulatory patients will have major public health impact by shortening the epidemic, thereby reducing morbidity and mortality.

Retarding the progression of the 15 to 20% that will develop more severe disease will have benefits for the public health system, which is struggling to cope with a surge in cases and will thus have a likely impact on mortality. Thus, therapeutic agents that can reduce viral load, viral shedding, the duration of illness and progression to severe disease are urgently needed. It is important to note that HIV-infected persons and certain sub-groups (including those > 35 years of age, and with comorbidities like diabetes and hypertension etc.) may have 'enhanced risk' of disease progression. Collectively such persons would constitute an enhanced risk group and are at the highest risk of disease progression. The risk of disease progression in HIV-infected persons and whether they will respond to the NTZ intervention to the same extent as HIV uninfected persons remains unknown.

NTZ is licensed in the USA for treatment of diarrhoea caused by Cryptosporidium parvum and Giardia lamblia. NTZ is a pro-drug for tizoxanide, which also has broad spectrum antiviral properties, has many viral indications and shows promising pharmacodynamics against Coronaviridae. NTZ was identified as a first-in-class broad-spectrum antiviral drug and has been repurposed for the treatment of influenza. In vitro studies evaluating tizoxanide, the active circulating metabolite of NTZ, inhibits the replication of broad range of influenza A and B, HIN1, H3N2, H3N2V, H3N8, H5N9, H7N1 and oseltamivir resistant strain and coronaviruses. It has been shown to have anti-viral activity against several viruses including Ebola, hepatitis B and C, rotavirus and norovirus.

A Phase 2b/3 clinical trial recently published in The Lancet Infectious Diseases found that oral administration of NTZ slow release formulation 600 mg twice daily for five days reduced the duration of clinical symptoms and reduced viral shedding compared to placebo in persons with laboratory-confirmed influenza. These dosages are suitable for treating viral respiratory infections caused by influenza and other viruses as in vitro IC50s are typically between 0.1 and 1ug/mL. The same study also suggested a potential benefit for subjects with influenza-like illness who did not have influenza or other documented respiratory viral infection.

The broad-spectrum antiviral activity of tizoxanide is attributed to interference with host regulated pathways involved in viral replication. These pathways include IFN and mTOR1 (autophagy) signalling pathways. NTZ upregulates the innate anti-viral mechanisms by broadly amplifying cytoplasmic RNA sensing and type I IFN pathways. It is also a potent driver of autophagy, an antiviral and anti-bacterial mechanism. Thus, NTZ interferes with the viral infection by upregulating the precise host mechanisms that viruses target to bypass host cellular defences. Additionally, NTZ inhibits replication of a broad range of influenza viruses, including neuraminidase inhibitor-resistant strains by blocking the maturation of viral haemagglutinin at the post-translational level. NTZ impairs intracellular trafficking and insertion of viral haemagglutinin into the host plasma membrane. In cell culture studies, NTZ acts synergistically with neuraminidase inhibitors.

NTZ may inhibit the glycosylation of the SARS-CoV-2, similar to its action on the hemagglutinin antigen of the influenza virus. Additionally, NTZ also exhibits inhibitory activity against IL-6 production from murine macrophages both in vitro and in vivo. Moreover, there is a good possibility that diseases associated with IL-6 overproduction (cytokine storm) like SARS-CoV-2 could be ameliorated by NTZ.

NTZ may be useful for the early treatment of COVID-19 when viral load is at its highest in the pharynx; and could serve to limit viral shedding thus significantly reducing disease transmission. In the same group it may retard progression to severe disease. Although only 15 to 20% of patients with COVID-19 may develop severe disease, large numbers of such patients will totally overwhelm healthcare systems as currently being experienced in the USA and the Western Cape province of South Africa. Thus, whether NTZ is useful in patients with mild to moderate COVID-19 disease remains unclarified and urgently needs to be addressed. Unreliability with using duration of illness (pre-symptomatic period is variable and symptom onset is subject to substantial recall bias) and viral load (may be different in different anatomical locations and will depend on tolerance and host immunity) as proxy measures means that the investigators have to embark on a phase IIB/III study to determine whether NTZ effects a clinically meaningful outcome.

Study design: A single-stage, double-blinded, randomised, placebo-controlled trial.

Primary aim: To evaluate the effectiveness of nitazoxanide (NTZ) in reducing the progression from mild to severe COVID-19 in non-hospitalised patients.

Significance and impact: The investigators will perform a randomised placebo-controlled trial recruiting 440 mildly symptomatic non-hospitalised COVID-19 patients at multiple sites from 4 cities in South Africa. The primary outcome measure will be time-specific (30- and 60-day) disease severity based on the WHO clinical progression scale. This will have implications for disease transmission and amplification of the epidemic. The rate of progression to severe disease will determine hospitalisation rates, morbidity, and mortality. It will also have implications for reducing healthcare burden, costs and improving healthcare worker safety. The investigators predict that the progression to severe disease (need for presentation or admission to hospital) will be reduced with NTZ. As disease progression will more likely occur in those who are HIV-infected or with enhanced risk (older patients or those with immunosuppression), the investigators will stratify randomisation for HIV-infected and enhanced risk patients.