Hydroxychloroquine and COVID-19 – What is true, Who to believe?
I am being asked by many people about Hydroxychloroquine (HCQ) and COVID-19 so I felt the need to do a deep dive into this subject. I am also going to admit right away that I, like everyone else, have high hopes we identify a medication that works for this disease.
This subject continues to be controversial. Recently an opinion piece by a respected Yale epidemiologist in favor of HCQ use published in Newsweek brought it back to public discussion.1 A controversial video of several doctors, rapidly removed from social media, raised additional questions as to why there are contested opinions on this matter.
Proposed Mechanism of Action for HCQ with COVID-19
Within our cells, we have small intracellular transporters called endosomes that aid in transporting materials. For example, LDL cholesterol binds to a receptor on the outside of a cell membrane, enters the cell, reaches an endosome, is released from the LDL receptor on the cell surface, and then transported to the appropriate processing part of the cell by the endosome.
HCQ changes the acidity of the endosomes which inhibits the fusion of the COVID virus with the host cell membranes. In vitro (in laboratory testing), HCQ may block the transport of the COVID virus within the cell. This is why people argue for its use early in the disease course and why it would make less or no difference late in the disease course.2 The hope is this observed in vitro behavior would also occur in vivo (in the body).
Is it safe?
HCQ, brand name Plaquenil, was developed in 1946 and has been approved for use in other conditions (lupus, rheumatoid arthritis, malaria prophylaxis, etc) for many years. We have many years of data to learn its adverse effects.
I have heard many people say this drug is safe. They argue its safety is evidenced by that the fact it has been out for so long and used so much.
Our long term use of HCQ has demonstrated that people taking HCQ can develop serious adverse effects including irreversible vision loss, bone marrow failure, aplastic anemia, severe cardiac disease, fatigue, suicidal behavior, nightmares, and life threatening skin rashes.
With every medication, doctors try to weigh the potential benefit of using the medication with the potential risks from taking the medicine. Many people might not experience these adverse effects, but if more people take the medication, that number will rise.
If we were to conclude HCQ is helpful in early treatment for COVID-19, each patient and their doctor will need to consider if they think the potential for adverse effects (such as permanent vision loss or early heart disease) is an acceptable risk to treat a disease like COVID, where the majority of infected patients recover without the need for hospitalization.
Does it work?
The current treatment guidelines for COVID-19 recommend against using HCQ for treatment of COVID-19 except in clinical trials.3
Let’s go through and analyze the evidence as objectively as we can:
Positive Studies for use of HCQ in COVID-19 Patients
A Case Series of Hydroxychloroquine Versus Control
This study followed 26 adults who received HCQ compared with 16 who did not. They removed 6 patients from the HCQ group for different reasons (death, ICU transfer, patients withdrew), 6 patients also received azithromycin, and clinical outcomes were not reported for all patients. This study reported 70% recovery in HCQ group compared with 12.5% in the no HCQ group. Their methods are so inconsistent, number of subjects so low, and the fact that they selectively excluded patients makes me not even want to rate the level of evidence of any conclusions they came up with. Level of evidence: Extremely low
Gautret P, Lagier JC, Parola P, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32205204.
Case Series of Hydroxychloroquine Plus Azithromycin
This study looked at 80 hospitalized patients with HCQ and azithromycin. This study suffers from poor trial design and no control group to compare to. The results, while favorable, thus lack usefulness in determining recommendations and the study is clinically unhelpful. Level of evidence: Low
Gautret P, Lagier JC, Parola P, et al. Clinical and microbiological effect of a combination of hydroxychloroquine and azithromycin in 80 COVID-19 patients with at least a six-day follow up: a pilot observational study. Travel Med Infect Dis. 2020;34:101663. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32289548.
Vadodara Municipal Corporation Analysis
This is an analysis by a health department from India where they provided HCQ to close contacts of people with COVID. They found a dose-dependent improvement in the COVID infection rate and mortality. From this analysis, this region in India concludes that, “The benefits seem to far outweigh the debate around its risks and it has certainly helped in implementing the preventive strategies planned for the city.” Level of evidence: Low (due to lack of transparency in methods and publication)
https://indianexpress.com/article/india/vadodara-administration-drive-hcq-helping-in-containing-covid-19-cases-say-docs-as-analysis-begins-6486049/ (I can only find a news article about it and not the actual study)
Retrospective Analysis of Hydroxychloroquine and Azithromycin
This study reviewed the management of 3,119 patients (mean age=45yo) treated with HCQ and azithromycin. They found treatment was associated with lower ICU transfer and death rates. Level of evidence: Low
Lagier JC, Million M, Gautret P, et al. Outcomes of 3,737 COVID-19 patients treated with hydroxychloroquine/azithromycin and other regimens in Marseille, France: A retrospective analysis [published online ahead of print, 2020 Jun 25]. Travel Med Infect Dis. 2020;36:101791. 10.1016/j.tmaid.2020.101791
Empirical Treatment with Hydroxychloroquine and Azithromycin in Brazil
This study offered 636 symptomatic outpatients HCQ and azithromycin and compared those who used the treatment to those who refused. They state those who received the treatment had a much lower hospitalization rate compared with those who refused. There are numerous limitations to this study. Level of evidence: Low
Treatment with hydroxychloroquine, azithromycin, and combination in patients hospitalized with COVID-19
This study looked at 2,541 patients and HCQ with and without azithromycin. They conclude that there is a reduction in mortality. Level of evidence: Low
Arshad S, Kilgore P, Chaudhry ZS, et al. Treatment with hydroxychloroquine, azithromycin, and combination in patients hospitalized with COVID-19. Int J Infect Dis. 2020;97:396-403. 10.1016/j.ijid.2020.06.099
Negative Studies for use of HCQ in COVID-19 Patients
Observational Study of Hydroxychloroquine at a Large Medical Center in New York City
This observational study of 1,376 patients and looked at length of time from ER to intubation or death based on receiving HCQ. This study found no association between HCQ use for COVID and harm or benefit. Level of evidence: Low
Geleris J, Sun Y, Platt J, et al. Observational study of hydroxychloroquine in hospitalized patients with COVID-19. N Engl J Med. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32379955
Retrospective Observational Cohort from the United States Veterans Health Administration (NOT peer reviewed)
This study compared HCQ, HCQ with azithromycin, and no HCQ. Endpoints were mechanical ventilation or death. This study showed no beneficial effect of hydroxychloroquine plus azithromycin and a possible association between hydroxychloroquine and increased mortality. Level of evidence: Low
Magagnoli J, Narendran S, Pereira F, et al. Outcomes of hydroxychloroquine usage in United States veterans hospitalized with COVID-19. medRxiv. 2020;[Preprint]. Available at: https://www.medrxiv.org/content/10.1101/2020.04.16.20065920v2.
Randomized Controlled Trial of Hydroxychloroquine Versus Standard of Care for Mild/Moderate COVID-19
This study of 150 people compared 2 different doses of HCQ and standard of care for patients with mild and moderate COVID disease evaluating the outcome of negative COVID test at 28 days. This study demonstrated no difference in viral clearance between HCQ and not using HCQ. Level of evidence: Low
Tang W, Cao Z, Han M, et al. Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial. BMJ. 2020;369:m1849. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32409561.
Observational Cohort of Hydroxychloroquine Versus No Hydroxychloroquine
This study of hospitalized patients compared HCQ to no HCQ. They found no difference in clinically important outcomes between patients who received HCQ early on in their hospitalization and those who did not. Level of evidence: Low
Mahevas M, Tran VT, Roumier M, et al. Clinical efficacy of hydroxychloroquine in patients with COVID-19 pneumonia who require oxygen: observational comparative study using routine care data. BMJ. 2020;369:m1844. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32409486
New York Department of Health Study on Hydroxychloroquine With or Without Azithromycin
This study evaluated HCQ with and without azithromycin in 1,438 hospitalized patients looking at mortality. They found that HCQ and azithromycin together are not associated with increased risk of in-hospital death but may be associated with increased risk of cardiac arrest. Level of evidence: Low
Rosenberg ES, Dufort EM, Udo T, et al. Association of treatment with hydroxychloroquine or azithromycin with in-hospital mortality in patients with COVID-19 in New York State. JAMA. 2020;323(24):2493-2502. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32392282.
Small Prospective Case Series of Hydroxychloroquine Plus Azithromycin
This study looked at 11 hospitalized patients who received HCQ and azithromycin. They did not find these patients to have rapid viral clearance. Level of evidence: Low
Molina JM, Delaugerre C, Le Goff J, et al. No evidence of rapid antiviral clearance or clinical benefit with the combination of hydroxychloroquine and azithromycin in patients with severe COVID-19 infection. Med Mal Infect. 2020;50(4):384. Available at: https://pubmed.ncbi.nlm.nih.gov/32240719.
As it turns out, studies of HCQ use to treat COVID-19 mostly come from patients with mild or moderate disease. These patients usually recover without hospitalization or additional complications. The overall data is simply limited, of low quality, and difficult to make a definitive conclusion one way or another. Prospective and larger studies are required to provide a valid answer to these questions.
A recent study (An Updated Systematic Review of the Therapeutic Role of Hydroxychloroquine in Coronavirus Disease-19) that reviewed all the current evidence on COVID and HCQ — much more thoroughly than I just did — concluded with, “The results of efficacy and safety of HCQ in COVID-19, as obtained from the clinical studies, are not satisfactory, although many of these studies had major methodological limitations. Stronger evidence from well-designed robust randomized clinical trials is required before conclusively determining the role of HCQ in the treatment of COVID-19. Clinical prudence is required in advocating HCQ as a therapeutic armamentarium in COVID-19.”4 Another in-depth review (A systematic review of the prophylactic role of chloroquine and hydroxychloroquine in coronavirus disease-19) came to similar conclusions.5
Do I recommend using HCQ to my patients?
This is the real crux of the issue. It makes sense to me why HCQ should work early on in COVID patients given the in vitro studies. I read all the studies listed here, thought through their methods and their limitations, and critically appraised their conclusions. I read the opinion piece by the respected Yale epidemiologist and the transcript of the controversial video removed from social media.
After doing my best to honestly weigh both sides of the HCQ question, I am not convinced HCQ sufficiently works in vivo to treat COVID-19 to outweigh the known risks of the medication for most patients.
The FDA has issued a warning of using HCQ outside of a clinical trial due to the increased risk for heart rhythm (cardiac arrest and death).6 I was able to identify 201 active clinical trial studies regarding HCQ for treatment of COVID-19. I am happy to work to enroll patients who want HCQ for COVID into a study that they qualify for. I am encouraged there are so many studies as more evidence will be forthcoming soon!
What about other related treatments?
Remdesivir is used in hospitalized patients. We know HCQ should not be co-administered with remdesivir (an antiviral we know works for those with more severe disease) as it decreases the antiviral activity of remdesivir.7
Azithromycin is helpful in those with COVID who develop pneumonia.
Zinc is helpful in all patients with COVID and I encourage its use.
2 Liu J, Cao R, Xu M, et al. Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro. Cell Discov. 2020;6:16. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32194981
4 Das S, Bhowmick S, Tiwari S, Sen S. An Updated Systematic Review of the Therapeutic Role of Hydroxychloroquine in Coronavirus Disease-19 (COVID-19). Clin Drug Investig. 2020;40(7):591-601. 10.1007/s40261-020-00927-1
5 Shah S, Das S, Jain A, Misra DP, Negi VS. A systematic review of the prophylactic role of chloroquine and hydroxychloroquine in coronavirus disease-19 (COVID-19). Int J Rheum Dis. 2020;23(5):613-619. 10.1111/1756-185X.13842
7 Food and Drug Administration. Remdesivir by Gilead Sciences: FDA warns of newly discovered potential drug interaction that may reduce effectiveness of treatment. 2020. Available at: https://www.fda.gov/safety/medical-product-safety-information/remdesivir-gilead-sciences-fda-warns-newly-discovered-potential-drug-interaction-may-reduce.