A paper published online, Hydroxychloroquine and azithromycin plus zinc vs hydroxychloroquine and azithromycin alone: outcomes in hospitalized COVID-19 patients, shows that “zinc sulfate added to hydroxychloroquine and azithromycin may improve outcomes among hospitalized patients”.
Hydroxychloroquine has been a controversial treatment for COVID-19, at least since President Trump mentioned it as a potential treatment, along with Zinc, at a daily briefing. Various attempts to show the efficacy of Hydroxychloroquine have shown mixed results. Those who believe Hydroxychloroquine is harmful point to studies showing apparent side effects with no benefits. Those who believe Hydroxychloroquine could be helpful, claim that in order to be effective, it must be administered early and with Zinc. This paper attempts to address the question of whether the addition of Zinc makes a difference. The results shown in the paper indicate that Zinc is helpful. From the Results section:
The addition of zinc sulfate did not impact the length of hospitalization, duration of ventilation, or ICU duration. In univariate analyses, zinc sulfate
increased the frequency of patients being discharged home, and decreased the need for ventilation, admission to the ICU, and mortality or transfer to hospice for patients who were never admitted to the ICU. After adjusting for the time at which zinc sulfate was added to our protocol, an increased frequency of being discharged home (OR 1.53, 95% CI 1.12-2.09) reduction in mortality or transfer to hospice remained significant (OR 0.449, 95% CI 0.271-0.744).
The conclusion of the paper:
This study provides the first in vivo evidence that zinc sulfate in combination with hydroxychloroquine may play a role in therapeutic management for COVID-19.
Here are some quotes that I found of interest from the paper, along with some of my thoughts:
The U.S. Food and Drug Administration authorized the emergency use of hydroxychloroquine for the treatment of COVID-19 with or without azithromycin.
I’m curious where Zinc fit into the authorization – and if dosage levels were mentioned.
Chloroquine analogues are weak bases that concentrate within acidic endosomes and lysosomes. Once intracellular, chloroquine analogues become protonated and increase pH resulting in prevention of endosomal trafficking, dysfunctional cellular enzymes, and impaired protein synthesis .
This inhibits viral replication through interference with endosome-mediated viral entry or late transport of the enveloped virus. Further, this results in interference with the terminal glycosylation of ACE2 receptor expression which prevents SARS-CoV-2 receptor binding and spread of infection .
 is a 2003 paper written (in The Lancet Infectious Diseases) during the initial SARS epidemic by Savarino et. al. entitled Effects of chloroquine on viral infections: an old drug against today’s diseases.
 is a 2005 paper written (in Virology Journal) just after the initial SARS epidemic by Vincent et al. entitled Chloroquine is a potent inhibitor of SARS coronavirus infection and spread.
For COVID-19, hydroxychloroquine (a hydroxy-derivative of chloroquine) has been proposed to be used instead of chloroquine. Recently, it has been shown to have 3x higher cytotoxic potential in vitro against SARS-CoV-2 compared to chloroquine .
 is a 2020 paper (written in Clinical Infectious Diseases) by Yao et. al. entitled The Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2).
A 2010 paper (written in PLOS Pathogens) by the Velthuis et. al. entitled Zn2+Inhibits Coronavirus and Arterivirus RNA Polymerase Activity in Vitro and Zinc Ionophores Block the Replication of These Viruses in Cell Culture. The title pretty much says it all.
The idea behind combining Hydroxychloroquine with Zinc is based on the difficulty of achieving a high enough intracellular concentration of Zinc without a zinc ionophore, such as chloroquine. (Reference: Xue et. al. 2014 paper in PLoS one entitled Chloroquine is a zinc ionophore)
Regarding the main finding of this paper:
The main finding of this study is that after adjusting for the timing of zinc therapy, we found that the addition of zinc sulfate to hydroxychloroquine and azithromycin was found to associate with a decrease in mortality or transition to hospice among patients who did not require ICU level of care, but this association was not significant in patients who were treated in the ICU.
Our findings suggest a potential therapeutic synergistic mechanism of zinc sulfate with hydroxychloroquine, if used early on in presentation with COVID-19.
The authors identified a number of limitations of their study and ended with:
In light of these limitations, this study should not be used to guide clinical practice. Rather, our observations support the initiation of future randomized clinical trials investigating zinc sulfate against COVID-19.