Today’s blog is about N4-(7-Chloro-4-quinolinyl)-N1,N1-diethyl-1,4-pentanediamine (say that five times really fast!), better known as hydroxychloroquine (HCQ), a drug to treat malaria, lupus and rheumatoid arthritis. And possibly COVID-19. There is conflicting pre-clinical and early clinical data, and it has been a hot topic of conversation since President Trump endorsed it.1-4
In our prior blog post, we talked about the virus entering the host cell via the Angiotensin-converting enzyme-2 (ACE2) receptor. HCQ may help inhibit Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2) entry through changing the glycosylation of ACE2 receptor and spike protein.5
Also, HCQ may have additional effects once the virus enters the cell.
Under normal circumstances the SARS-CoV2 virus enters the cell after binding of the spike protein to the ACE2 receptor. A little sphere, called an endosome, is formed by the host cell membrane folding over the virus and pulling it into the cell. HCQ is a weak base that is known to elevate the pH of acidic intracellular organelles, such as endosomes/lysosomes, essential for membrane fusion. Thus, HCQ may also prevent viral release into the host cell.
To date, only a few trials have been performed – with conflicting results. A French study of 42 patients (26 HCQ, 16 controls) showed improvement in viral clearance by Day 6.6
Figure 1: Percentage of patients with PCR-positive nasopharyngeal samples from inclusion to day6 post-inclusion in COVID-19 patients treated with hydroxychloroquine and in COVID-19 control patients. Philippe Gautret, Jean-Christophe Lagier, Philippe Parola, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial, International Journal of Antimicrobial Agents. 2020 https://doi.org/10.1016/j.ijantimicag.2020.105949.
A subsequent study in France expanded to 80 patients noted clinical improvement in 78 (97%) of patients with viral clearance by Day 5 when treated with a combination of HCQ and azithromycin (AZ).
A more recent report from the US Veterans Administration of 368 patients (HCQ, n=97; HC+AZ, n=113; no HC, n=158) found the following. Rates of death in the HC, HC+AZ, and no HC groups were 27.8%, 22.1%, 11.4%, respectively. Rates of ventilation in the HC, HC+AZ, and no HC groups were 13.3%, 6.9%, 14.1%, respectively. Compared to the no HC group, the risk of death from any cause was higher in the HC group (adjusted hazard ratio, 2.61; 95% CI, 1.10 to 6.17; P=0.03) but not in the HC+AZ group (adjusted hazard ratio, 1.14; 95% CI, 0.56 to 2.32; P=0.72). An association of increased overall mortality was identified in patients treated with hydroxychloroquine alone.7
At this point, I think it’s safe to say that the efficacy and safety of HCQ in COVID-19 is still an unknown and underscores the need for well-controlled clinical trials to answer these difficult questions. Early data can look very promising, but we need to be patient and wait for confirmation before altering clinical practice. First – do no harm! Certainly, if patients can be treated on trial (for HCQ and other treatments), that will accelerate getting these answers and ultimately help everyone, because we are all in this together.
(1)Yao X, Ye F, Zhang M, Cui C, Huang B, Niu P, et al. In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Clin Infect Dis. 2020 Mar 9.
(2) Liu J, Cao R, Xu M, Wang X, Zhang H, Hu H, et al. Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro. Cell Discov. 2020;6:16.
(3) Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020 Mar;30(3):269-71.
(4)Gao J, Tian Z, Yang X. Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. Biosci Trends. 2020 Feb 19.
(5) Savarino, A. et al. New insights into the antiviral effects of chloroquine. Lancet Infect. Dis. 6, 67–69 (2006).
(6) Philippe Gautret, Jean-Christophe Lagier, Philippe Parola, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial, International Journal of Antimicrobial Agents. 2020 https://doi.org/10.1016/j.ijantimicag.2020.105949.
(7) Joseph Magagnoli, Siddharth Narendran, Felipe Pereira, Tammy Cummings, James W Hardin, S Scott Sutton, Jayakrishna Ambati. Outcomes of hydroxychloroquine usage in the United States veterans hospitalized with COVID-19. medRxiv 2020.04.16.20065920; doi: https://doi.org/10.1101/2020.04.16.20065920