COVID-19: Hydroxychloroquine Reviewed (15 August 2020)
One of the hot button topics being discussed nowadays is the utility of hydroxychloroquine in the treatment of patients infected with SARS-CoV-2, the virus that causes Coronavirus Disease 2019 (COVID-19); and accusations abound on social media that the drug is being inappropriately withheld from prescribers and their patients. In this post, I briefly review the timeline of the drug vis-à-vis the COVID-19 pandemic and also the data regarding its efficacy in treating COVID-19 patients.
Hydroxychloroquine (HCQ) belongs to a class of drugs called the aminoquinolines and is a derivative of chloroquine, which is itself a derivative of quinine. It was first synthesized in 1950 and was approved for medical use in the United States in 1955; and HCQ remains a commonly prescribed medication, with more than 53.5 million prescriptions being written between 2007–2017 [1]. Historically, HCQ has been used for the treatment of patients with malaria and certain other infections (e.g. Q fever), as well as a number of rheumatologic diseases including rheumatoid arthritis, systemic lupus erythematosus, antiphospholipid syndrome, dermatomyositis, and Sjögren syndrome [2], and also porphyria cutanea tarda and post-Lyme arthritis [3,4]. Interestingly, the mechanism by which HCQ exhibits activity against Plasmodium, the genus of protozoa that causes malaria, is unknown. It is a weak base and may work by concentrating in the acidic lysosomes of the parasite, inhibiting the polymerization of heme and other functions [5]. Hydroxychloroquine also has immunomodulatory properties, to include the inhibition of immune activation by reducing Toll-like receptor signaling and cytokine production and, in T cells, reducing CD154 expression, making it a potent Disease Modifying Anti-Rheumatic Drug (DMARD) [2].
The use of HCQ in the treatment of patients with COVID-19 was first reported by physicians in Wuhan, China, the pandemic’s origin. The report, which was an interim analysis of more than one hundred COVID-19 patients treated with chloroquine, claimed that treated patients had less severe disease, a shorter course, and had stopped shedding virus sooner than did non-treated patients [6]. These findings led to an expert consensus recommendation in China for the use of chloroquine (500 mg BID for ten days) for patients with COVID-19 [7]. A role for HCQ was subsequently endorsed by French physician Didier Raoult of l’Institut Hospitalo-Universitaire Méditerranée Infection (IHU-MI) in Marseille in an online video on 17 March 2020 (Dr. Raoult is widely known in the infectious diseases community as a subject matter expert on rickettsial diseases and Q fever, which is caused by the Rickettsia-like bacterium Coxiella burnetii). In this video, Dr. Raoult described a trial at IHU-MI of HCQ (plus azithromycin for some patients) for the treatment of 24 patients with COVID-19 and claimed that patients who received HCQ 600 mcg daily recovered faster and became noncontagious sooner than did patients who had not received HCQ, an effect that was enhanced by the addition of azithromycin [8]. This was followed by an online report of the study in the International Journal of Antimicrobial Agents [9]. However, Dr. Raoult’s paper was met with widespread criticism for its “methodological shortcomings which make it almost, if not completely, uninformative” [10]. Moreover, given the association between HCQ and QT prolongation (an arrhythmia characterized by an increase in the interval between ventricular contraction and subsequent relaxation), critics warned against touting it as “a wonder drug”, and lambasted the study as “irresponsible”[10]. Nonetheless, based on Raoult’s paper, along with an endorsement by the Italian Medicines Agency of the off-label use of chloroquine and hydroxychloroquine for the treatment of patients with COVID-19 [11], President Trump promoted the use of both drugs in a 19 March press briefing, and claimed that chloroquine and hydroxychloroquine had been “approved very, very quickly” by the Food and Drug Administration (FDA) for both COVID-19 prophylaxis and treatment [12]. In fact, the FDA had not approved COVID-19 as an indication per se but was permitting the use of the drugs, as well as the antiviral remdesivir, to be administered under compassionate use [13]; and on 28 March, the FDA issued an emergency use authorization (EUA) allowing the drugs to be released from the Strategic National Stockpile for the treatment of critically ill COVID-19 patients [14]. However, on 24 April, the EUA was tempered with a caution by the FDA about the use of HCQ outside of a hospital or clinical trial, due to “reports of serious heart rhythm problems and other safety issues”; and on 15 June the FDA revoked the EUA [15]. This was driven, in part, by a study published online on 29 April that urged that HCQ “should only be used with caution and in the context of carefully thought out clinical trials, or on a case‐by‐case basis after rigorous consideration of the risks and benefits of this therapeutic approach” [16]. This study, a meta-analysis of ten other studies, concluded that 1) there is “no high‐quality clinical data showing a clear benefit of (chloroquine or hydroxychloroquine) for this disease”; 2) there is “the potential to cause harm, including a broad range of adverse events (such as) serious cardiac side effects when combined with other agents”; and 3) “the impact of HCQ on cytokine production and suppression of antigen presentation may have immunologic consequences that hamper innate and adaptive antiviral immune responses for patients with COVID‐19”. The study authors summarized that despite widespread initial enthusiasm based on the Chinese reports for the use of chloroquine and hydroxychloroquine, there was a paucity of significant data, making “well designed, large randomized controlled trials” necessary. The authors also pointed out that in prior studies, HCQ had demonstrated in vitro activity against influenza virus that did not translate to clinical efficacy (In other words, although HCQ inhibited the replication of influenza virus in cell cultures, it had no apparent clinical benefit), a phenomenon that might be similar with respect to the SARS coronaviruses.
Of note, chloroquine and hydroxychloroquine were also studied in the World Health Organization-sponsored “Solidarity Trial”, that was designed to evaluate the efficacy of repurposed medications approved for other conditions to treat COVID-19 patients. The medications (indications) studied included remdesivir (HCV, SARS-CoV-1, MERS-CoV), lopinavir/ritonavir (HIV)+/- interferon-beta, and chloroquine/hydroxychloroquine [17]. However, the hydroxychloroquine arm was interrupted in May 2020 due to safety concerns and evidence of arrhythmias and was suspended in June 2020 for lack of benefit [18].
Similar to the Solidarity Trial, the University of Oxford’s RECOVERY (Randomized Evaluation of COVID-19 therapy) Trial was a large randomized controlled study of repurposed drugs (lopinavir-ritonavir, dexamethasone, azithromycin, tocilizumab, and hydroxychloroquine) as well as convalescent plasma for the treatment of patients with severe COVID-19 [19]. (For a discussion of convalescent plasma for the treatment of patients with COVID-19, please see my 6 April 2020 post at: https://medium.com/@michaelzapor/covid-19-convalescent-plasma-and-masks-6-april-2020-6515b69685f5) As with the Solidarity Trial, the RECOVERY trial showed that there was no clinical benefit from the use of hydroxychloroquine in people hospitalized with COVID-19 and that the use of HCQ was associated with longer hospital stays and higher mortality rates.
More recently, the results of a randomized, controlled trial involving 667 suspected or confirmed COVID-19 patients at 55 hospitals in Brazil were published in the New England Journal of Medicine [20]. In this trial, patients were randomized to receive either the standard of care, the standard of care plus HCQ, or the standard of care plus HCQ plus azithromycin. As with other trials, this study failed to show any clinical benefit of hydroxychloroquine, alone or in combination with azithromycin; and as with other studies, the use of HCQ was associated with a higher incidence of QT prolongation.
Despite the results of the Solidarity, RECOVERY, and other trials, a number of physicians’ groups have been very vocal nonetheless in their support of HCQ for the treatment of patients with COVID-19. One such group is the American Association of Physicians and Surgeons (AAPS), which despite appearing to have the imprimatur of science, has a track record of promoting unconventional and unsubstantiated claims, to include questioning whether HIV causes AIDS (It does) and alleging that vaccines cause autism (They do not). The AAPS also opposes the requirement for face coverings and social distancing as mitigants in the spread of COVID-19 [21]. Perhaps the most curious among the proponents of HCQ is a group that has dubbed itself American Frontline Doctors (AFL), which recently assembled on the steps of the Supreme Court arguing among other things, that neither masking nor shutdowns are necessary for curbing the COVID-19 pandemic. Some of the most eyebrow-raising comments during this assembly were made by Cameroonian-born, Nigerian-educated physician and minister, Stella Immanuel. These comments, which attributed various medical conditions to demons, witchcraft, space aliens, and the Illuminati, did little to substantiate her claim that HCQ is a “cure” for COVID [22]. Nonetheless, Dr. Immanuel has her adherents, to include Tennessee State Representative Terri Lynn Weaver [23].
People are understandably frustrated by the early consensus position on HCQ, which flicked back and forth between enthusiastic support and vehement disapproval. So, what conclusions can be drawn regarding the use of hydroxychloroquine for the treatment of patients with COVID-19? Unfortunately, the most reputable studies to date have consistently demonstrated a lack of benefit and have shown instead, an increased risk of adverse effects such as arrhythmia. Certainly, these results are disappointing; but the path to any preventative or therapeutic is rarely navigated without encountering obstacles, detours, and dead ends. Consider, for example, that it was four years into the AIDS pandemic before the first HIV drug (zidovudine or AZT) was approved and twelve years until the discovery of potent Highly Active Antiretroviral Therapy (i.e. HAART or “AIDS cocktails”). Similarly, reliably effective drugs against hepatitis C virus, which was identified in 1989 (Previously, it was called non-A, non-B hepatitis), were discovered less than six years ago [24]. Although it may seem as if the COVID-19 pandemic is interminable, it is less than eight months since the first case was reported in Wuhan, China, and the reality is that Nature does not readily give up her secrets. Hypotheses must be formulated and tested; results must be interpreted and reconciled; and conclusions must withstand the tincture of time. As for the hydroxychloroquine saga, perhaps there is consolation in the words of Jules Verne: “Science, my boy, is made up of mistakes, but they are mistakes which it is useful to make, because they lead little by little to the truth [25].”
As with my prior COVID-19-themed posts, my intention here is not to politicize, sensationalize, or trivialize the pandemic, but only to provide information and thoughtful commentary.
Until my next update — regards.
Michael Zapor, MD, PhD, CTropMed, FACP, FIDSA
(15 August 2020)
To read this and my other COVID-19 posts on Medium.com, please see: https://medium.com/@michaelzapor
References
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