Protecting Frontline Health Care Workers From COVID-19 With Hydroxychloroquine Pre-exposure Prophylaxis: A Randomized, Placebo-controlled Multi-Site Trial in Toronto, Canada

On March 11th, 2020, the World Health Organization (WHO) declared coronavirus disease (COVID-19) caused by severe acute respiratory virus coronavirus 2 (SARS-CoV-2) a pandemic. As of March 22, 2020 there have been over 267,013 confirmed cases and 11,201 deaths in 185 different countries or regions; it is quickly overwhelming health care systems worldwide to detrimental effect. Even with current moderate interventions imposed, estimates predict that 10-18% of the Canadian population will be infected with the virus by its peak in July. Health care workers (HCWs) remain a critical line of defence in the fight against this pandemic and maintaining their health is not only an important social responsibility of the government, but it is also of vital national interest to treat and control others infected with this virus or sick with other disease.

Estimates from China indicate that HCWs make up 3.8% of cases, while in Italy it is reported to be much higher - 8.3%. Early numbers from front-line workers in Italy suggested up to 20% of HCWs become infected with COVID-19, and these rates are approximately 3 times higher than the general population. When HCWs become sick, not only do they risk dying, but they also must take weeks away from work limiting the ability of the health care system to function. The fear associated with becoming ill also causes higher rates of missed work and higher rates of burnout, as seen with previous outbreaks. It is also now clear that asymptomatic transmission of COVID-19 not only occurs, but may even be the most important factor in spread of the virus. HCWs may therefore become vectors of viral spread to those who are the most vulnerable in other areas of the hospital. Preventing HCWs from acquiring SARS-CoV-2 should therefore be of the utmost importance to national interests.

Repurposing drugs already known to be safe and tolerable in humans provides a major advantage in a pandemic where time is critical. Of candidate drugs, chloroquine (CQ) and its derivative hydroxychloroquine (HCQ), have shown some promise. Originally an anti-malarial medication, CQ exerts direct antiviral effects by inhibiting pH-dependent steps of the replication of several viruses, including coronaviruses. It also has immunomodulatory effects, suppressing the release of TNFα and IL-6, which are involved in the inflammatory complications of several viral diseases. In vitro data has shown that CQ potently blocks virus infection at low micromolar concentrations with a high selectivity index. CQ is also widely distributed throughout the body, including the lungs, after oral administration. An early clinical trial of more than 100 COVID-19 patients in China reported that CQ was superior to placebo in inhibiting pneumonia, improving lung imaging, promoting viral seroconversion, and shortening the disease course, although data was not released. Based on those results experts in China recommended CQ 500mg twice daily for ten days in all patients with COVID-19. HCQ has also been shown to also have anti-SARS-CoV-2 activity in vitro and may actually be more potent. It has a better safety profile than CQ (during long term use), and allows a higher daily dose, with fewer concerns of drug-drug interactions. Preliminary clinical data also suggests that HCQ may lead to significantly faster viral clearance in COVID-19 patients as assessed by nasopharyngeal swab (70% vs. 12.5%, p=0.001).

Pre-exposure prophylaxis (PrEP) offers the ability to protect front-line HCWs from illness, decrease nosocomial spread of SARS-CoV-2, and prevent loss of work force due to illness. Rigorous testing of HCQ for this purpose is critical at this time. The investigators therefore aim to conduct the first randomized placebo-controlled trial of HCQ to prevent COVID-19 infections in emergency departments (ED) as they prepare for escalating rates of COVID-19 in Toronto, Canada.