COVID-19 Therapeutics for Low- and Middle-Income Countries: A Review of Candidate Agents with Potential for Near-Term Use and Impact

Abstract

Low- and middle-income countries (LMICs) face significant challenges in the control of COVID-19, given limited resources, especially for inpatient care. In a parallel effort to that for vaccines, the identification of therapeutics that have near-term potential to be available and easily administered is critical. Using the United States (US), European Union (EU), and World Health Organization (WHO) clinical trial registries, we reviewed COVID-19 therapeutic agents currently under investigation. The search was limited to oral or potentially oral agents, with at least a putative anti-SARS-CoV-2 virus mechanism and with at least five registered trials. The search yielded 1,001, 203, and 1,128 trials, in the US, EU, and WHO trial registers, respectively. These trials covered 13 oral or potentially oral repurposed agents that are currently used as antimicrobials and immunomodulatory therapeutics with established safety profiles. The available evidence regarding proposed mechanisms of action, potential limitations, and trial status is summarized. The results of the search demonstrate few published studies of high quality, a low proportion of trials completed, and the vast majority with negative results. These findings reflect limited investment in COVID-19 therapeutics development compared with vaccines. We also identified the need for better coordination of trials of accessible agents and their combinations in LMICs. To prevent COVID-19 from becoming a neglected tropical disease, there is a critical need for rapid and coordinated efforts in the evaluation and deployment of those agents found to be efficacious.

Figure 1.

Flow diagram for drug selection based on results of trial search in World Health Organization International Clinical Trials Registry Platform (WHO ICTRP). *Drugs without putative antiviral mechanism (N = 14): anakinra, cholecalciferol, clazakizumab, dexamethasone, mavrilimumab, melatonin, methylprednisolone, nitric oxide, povidone-iodine (as no appreciable intracellular antiviral activity anticipated for studied intervention), prednisone, rivaroxaban, sargramostim, sarilumab, tocilizumab. †No oral or intranasal options for administration (N = 6): convalescent plasma, enoxaparin, LY3819253, nafamostat, REGN10933, remdesivir. ‡This search included all interventional trials and was not limited to trials where the intervention was listed as “Drug” or “randomized”. This figure appears in color at www.ajtmh.org.

Figure 2.

Proposed workflow for identifying effective COVID-19 therapeutics. This figure appears in color at www.ajtmh.org.