Authors: Nardos Makkonen, MD and Amita Sudhir, MD
University of Virginia, USA
In The Great Influenza, The story of the Deadliest Pandemic in History, the author John Barry states, “Life does not choose the logically best design to meet a new situation. It adapts what already exists…The result, unlike the clean straight lines of logic, is often irregular, messy.” This has never been more evident than now as the way we practice medicine changes fundamentally in the face of a new pandemic. While the news of a novel coronavirus spread, many in the scientific community found themselves struggling to find answers. In the wake of the pandemic, multiple studies were published aiming to identify risk factors, disease progression, and most importantly, therapeutic options.
As the number of positive cases grew exponentially, so did the urgency to find an effective therapy. Scientists and medical professionals were tasked with finding a swift solution. In addition to vaccine development, trials looking at the effectiveness of previously existing antiviral medications against SARS-CoV-2 were underway. A number of in-vitro models showed promising results – existing antiviral and antimalarial medications, including Hydroxychloroquine and Remdesivir, were noted to have cytotoxic properties against the novel coronavirus (1, 2). At first, it was difficult to tell how this could shape the management of affected patients. Then came a study that would change the global conversation on COVID therapies.
An article published on March 20th in the International Journal of Antimicrobial Agents looked at the effect of hydroxychloroquine and azithromycin on COVID positive patients. The study was an open-label, non-randomized clinical trial of thirty-six patients; twenty patients were treated with hydroxychloroquine, while sixteen were in the control group. The article looked at SARS–CoV-2 clearance from the nasopharynx after six days. Higher frequency of viral clearance was reported in the treatment group, hydroxychloroquine (plus azithromycin if deemed necessary) versus an untreated control group [14 out of 20 (70%) vs. 2 out of 16 (13%); P < 0.001]. The authors concluded that the addition of azithromycin to hydroxychloroquine was significantly more efficient for virus elimination (3). Multiple articles were published that questioned various aspects of the original article. Nonetheless, the original excitement surrounding the medication led to its widespread use for treatment of COVID positive patients in various hospitals across the world. However, in the ensuing months, multiple additional studies have been published that have informed our understanding of hydroxychloroquine as a treatment option for SARS–CoV-2, suggesting that it may not be the panacea that the initial study suggested it is.
One of the first randomized control trials on the topic was a multicenter, open-label, randomized control trial looking at 150 patients. Seventy-five patients were assigned to hydroxychloroquine plus standard of care, while the other 75 were assigned to standard of care alone. The primary endpoint of this study was looking at viral clearance by 28 days. The results suggested hydroxychloroquine was not associated with a significantly higher probability of negative conversion than the standard of care alone (4). In another retrospective cohort study of 1438 patients hospitalized in metropolitan New York, treatment with hydroxychloroquine, azithromycin, or both did not result in a significantly lower in-hospital mortality (5). A meta-analysis looked at eleven studies, including three randomized controlled trials and eight observational studies. Here, 2354 patients received hydroxychloroquine alone or in combination, while 1952 did not. The study found no significant difference in clinical progression, mortality, or viral clearance by RT-PCR among patients with COVID-19 infection who are treated with hydroxychloroquine compared with control groups (6). In addition, a significantly higher incidence of adverse events associated with hydroxychloroquine use across a number of studies was noted.
Adverse effects were also noted in a multinational registry analysis of the use of hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19. The registry comprised data from 671 hospitals in six continents. The findings show no confirmed benefit of hydroxychloroquine or chloroquine when used alone or with a macrolide on in-hospital outcomes for COVID-19. Notably, each of these drugs was found to be associated with decreased in-hospital survival and increased frequency of ventricular arrhythmias (7). Importantly, the Lancet has since released a letter of concern on 6/2/20 regarding its publication of this multinational registry analysis (8).
Beyond its potential therapeutic use for known COVID positive patients, hydroxychloroquine was touted as beneficial for prophylactic use. Prior to the publication of significant studies on the prophylactic efficacy of the medication, the Indian Council of Medical Research, under the Ministry of Health and Family Welfare, recommended chemoprophylaxis with hydroxychloroquine for asymptomatic health-care workers treating patients with suspected or confirmed COVID-19, and for asymptomatic household contacts of confirmed cases. The announcement led some in the scientific community to express concern, stating “the drug is untested, the benefits unknown, and the risks not negligible” (9). This concern was substantiated in subsequent studies. A recent randomized, double-blind, placebo-controlled trial analyzed the effect of hydroxychloroquine in postexposure prophylaxis. The study included 821 asymptomatic participants. 87.6% of the participants (719 of 821) had a high-risk exposure to a confirmed COVID contact. The primary outcome was symptomatic illness confirmed by a positive molecular assay or, if testing is not available, COVID-related symptoms. The results noted no significant difference in the primary outcome between participants receiving hydroxychloroquine (49 out of 414 [11.8%]) and those receiving placebo (58 out of 407 [14.3%]) (10). Additionally, side effects were noted to be more common with hydroxychloroquine than with placebo (40.1% vs. 16.8%).
On May 27th, Dr. Anthony Fauci, the director of National Institute of Allergy and Infectious Diseases, when asked about hydroxychloroquine, stated that “The scientific data is really quite evident now about the lack of efficacy.” As of now, the World Health Organization is planning on resuming Hydroxychloroquine clinical trials after previously halting studies due to safety concerns (11). One adage often repeated in medicine is that what we learn now may not apply in 10 years. In the age of COVID, what we learn now may not apply in the next few months or even weeks. Seeing images of ventilated patients, and at times dead bodies across hospital hallways have filled us all with a deep desire for a quick fix. As physicians, we are likely to grasp at any straws that might help us fight this disease; we have to be careful to look critically at the evidence. Hope springs for a cure with each new study, but we should apply the same rigorous scientific methodology to COVID that we have developed for other diseases. As we move towards alleviating the suffering of this pandemic, it is essential to avoid falling into pitfalls and causing more harm along the way.
References and Further Reading
- Wang M, Cao R, Zhang L, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020;30(3):269-271.
- 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.
- 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;:105949.
- 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.
- 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;
- Chacko J, Brar G, Premkumar R. Hydroxychloroquine in COVID-19: A systematic review and meta-analysis. 2020. doi:10.1101/2020.05.14.20101774
- Mehra MR, Desai SS, Ruschitzka F, Patel AN. Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis. The Lancet. 2020. doi:10.1016/s0140-6736(20)31180-6.
- Editors TL. Expression of concern: Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis. The Lancet. 2020. doi:10.1016/s0140-6736(20)31290-3.
- Rathi S, Ish P, Kalantri A, Kalantri S. Hydroxychloroquine prophylaxis for COVID-19 contacts in India. Lancet Infect Dis. 2020;
- Boulware DR, Pullen MF, Bangdiwala AS, et al. A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19. N Engl J Med. 2020;
- BerkeleyJr. World Health Organization resumes coronavirus trial on malaria drug hydroxychloroquine after examining safety concerns. CNBC. https://www.cnbc.com/2020/06/03/world-health-organization-resumes-coronavirus-trial-on-malaria-drug-hydroxychloroquine-after-safety-concerns.html. Published