Chloroquine and hydroxychloroquine: Clutching at straws in the time of COVID-19?

Abstract

INTRODUCTION The world has changed drastically in the past 100 days. It started in December 2019 when a mysterious illness (severe acute respiratory infection) was first reported in Wuhan, China. The cause of the disease was soon confirmed to be a new kind of coronavirus related to the virus that caused the SARS outbreak of 2003. The International Committee on Taxonomy of Viruses called it the “severe acute respiratory syndrome coronavirus 2” or SARS-CoV-2. With the infection spreading across the world, the WHO declared it a pandemic in February 2020.[1] The virus is highly infectious, and at present, 1,734,913 people worldwide have been infected with 108,192 deaths as of the April 12, 2020.[2] This is arguably the greatest global crisis to hit the world since World War II. The presentation and clinical course of the infection has a varied spectrum, with mild (81%), severe (14%) and critical cases (5%), and a 2% fatality rate, as per initial data from China.[3] The statistics seem to vary from country to country; with fatalities being higher in countries like Italy, and older people with comorbidities, including those with cancer, seem to be at a higher risk of developing severe complications.[234] This tiny virus has brought the world down to its knees and the onus is upon researchers to find a cure/vaccine as soon as possible. Drug repurposing has taken the forefront in this race against time, and a broad range of antibiotics, antivirals, and immune modulatory therapies have been tested in the preclinical as well as the clinical scenario. However, there is no standard of care treatment option yet. It is under these exceptional desperate circumstances that the focus has shifted to chloroquine (CQ) in the fight against SARS-CoV-2. RATIONALE BEHIND CHLOROQUINE USE Chloroquine and hydroxychloroquine (HCQ), commonly used for malaria and autoimmune disorders, possess anti-inflammatory and immune-modulatory effects.[5] The drugs have been shown to have antiviral activity in multiple preclinical studies, and multiple mechanisms of actions have been postulated [Figure 1].[6789] Figure 1: The postulated antiviral mechanism of action of chloroquine/hydroxychloroquine. ACRONYMS: CQ: Chloroquine, HCQ: Hydroxychloroquine, SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2, MAPK: Microtubule-associated protein kinase, ACE2: Angiotensin-converting enzyme 2, M protein: Membrane proteinThe drugs, however, have not been proven to successfully treat any acute viral infection in humans till date.[10] In vitro studies have suggested an antiviral effect in SARS-CoV-2. Wang et al. studied the efficacy of CQ against a Vero E6 cell line infected with SARS-CoV-2 and demonstrated that CQ inhibited virus yield and cytotoxicity at both the entry, as well as the post-entry stages of the viral infection.[11] The authors concluded that “CQ (is) highly effective in the control of 2019-nCoV in vitro” and that, “its safety track record suggests that it should be assessed in human patients suffering from the novel coronavirus disease.”[11] Yao et al. also used a Vero E6 cell line infected by SARS-CoV-2 to study the effect of HCQ and CQ on the virus. They found that although both drugs had antiviral activity, HCQ was more potent than CQ.[12] The attempt to translate these data from the lab to the clinics has yielded a gamut of results and information regarding the therapeutic efficacy is at present conflicting. The first data came from a commentary mentioning clinical studies of over 100 COVID-19 patients conducted in China. Compared to the control drug, patients who received CQ had a shorter disease duration, less exacerbation of pneumonia, better radiological response, and higher chances of virus-negative seroconversion.[13] Detailed results of these studies have not yet been published. Gautret et al. conducted a non-randomized trial in Marseille, France, and demonstrated the efficacy of HCQ in decreasing the viral load in 36 COVID-19 infected patients.[14] Twenty-two patients received HCQ alone (600 mg once daily for 3 days) or HCQ with azithromycin compared with 16 patients as control. The control group consisted of untreated patients from other centers, patients not fulfilling the inclusion criteria for the study and patients refusing study drugs. The primary endpoint was virological clearance on nasal swabs on day 6; about 70% of HCQ-treated patients achieved this endpoint, as compared to 12.5% of the control patients. 100% of patients treated with HCQ and azithromycin combination were virologically cured. A better response was observed in patients with symptoms of upper and lower respiratory tract infections, as compared to asymptomatic patients, and all these findings were statistically significant. Notably, neither did the researchers look at look at other clinical parameters nor did they study the impact of the drug on eventual clinical outcomes. Another very small, randomized study from China looked at a similar primary endpoint of the negative conversion rate of COVID-19 nucleic acid in the respiratory pharyngeal swabs of 31 patients. The patients were randomized to the standard of care alone versus the addition of HCQ. The study found no difference in nasal swab negativity rates on day 7 of randomization between the two arms.[15] Other clinical parameters, like median time to body temperature normalization, were also similar. In another Chinese study, 62 patients with documented COVID-19 infection with mild illness and findings of pneumonia on chest CT scan were randomized to receive either standard treatment alone or with the addition of HCQ 200 mg orally twice daily for 5 days. The 31 patients who received HCQ had a significantly shorter body temperature recovery time (2.2 vs. 3.2 days, P = 0.0008), cough remission time (2.0 vs. 3.1 days, P = 0.0016) and better radiological response (80.6% vs. 54.8%).[16] No patient in the HCQ group progressed to severe illness as compared to four patients in the control group. The trial has not yet been published in a peer-reviewed journal. Coupled with all these enticing results, a controversial tweet by President Trump on March 21, 2020, claiming that “HCQ and azithromycin, taken together, have a real chance to be one of the biggest game-changers in the history of medicine” has put the spotlight firmly on these drugs. While these data are encouraging, they are at best hypothesis-generating, and caution must be exercised before they are labeled practice-changing. Patient numbers were quite small in the above studies, and not all of these trials were randomized controlled trials. It must also be remembered that while these drugs have some in vitro activity against several viruses, including coronavirus and influenza, previous randomized trials in patients with influenza have been negative.[1718] CURRENT STATUS AND FUTURE DIRECTIONS On March 28, 2020, the Food and Drug Administration (FDA) approved Emergency use Authorization of HCQ for COVID-19.[19] According to The Centers for Disease Control and Prevention, CQ and HCQ may be considered for use as part of an investigational protocol for pre-or post-exposure prophylaxis and for the treatment.[20] The European Medicines Agency has till now not approved these drugs for the management of this pandemic.[21] At present, the National taskforce of India for COVID-19 recommends the use of HCQ as prophylaxis in: Asymptomatic health-care workers involved in the care of suspected or confirmed cases of COVID-19: 400 mg orally twice a day on day 1, followed by 400 mg orally once a week for the next 7 weeks Asymptomatic household contacts of laboratory-confirmed cases: 400 mg orally twice a day on day 1, followed by 400 mg orally once a week for the next 3 weeks.[22] There is no recommendation presently regarding the treatment of established cases with CQ/HCQ in India. Several interventional trials are currently underway evaluating the role of HCQ prophylaxis for COVID-19 in high-risk groups. As per The ClinicalTrials.gov database dated April 5, 2020, currently, there are 17 randomized and non-randomized ongoing trials on HCQ as chemoprophylaxis.[23] CHLOROQUINE AND ITS POTENTIAL IMPACT IN ONCOLOGY The ongoing pandemic has special implications for both oncologists and their patients. Liang et al. analyzed the data of cancer patients who developed SARS-CoV-2 infections and concluded that patients with cancer had a higher risk of getting infected with COVID-19 and had a poorer prognosis than those without cancer.[4] Similarly, Zhang et al. looked at 28 cancer patients infected with COVID-19 and noted severe manifestations in 53.6% as well as a 28.6% mortality rate. The risk of developing severe events was increased significantly if the antitumor therapy had been given in the preceding 14 days, and if the patients had patchy consolidation on their admission computed tomography scans.[24] These findings could be attributed to the immunosuppressive state of cancer due to the malignancy itself or anticancer therapies. Another important aspect of COVID-19 infection in cancer patients is that presenting symptoms may be different from immunocompetent patients with atypical manifestations.[25] In addition, oncologists frequently care for patients with fever and febrile neutropenia, commonly with respiratory system symptoms and signs. These confounding manifestations could predispose unsuspecting oncologists to get easily infected with SARS-CoV-2. This has led to a call for defining the indications for CQ prophylaxis for patients receiving chemotherapy, their family/caregivers as well as for health-care providers. However, it must again be emphasized that there is no large randomized trial that has established the therapeutic or prophylactic efficacy of CQ and HCQ in general as well as the oncology setting. It is important to understand that these drugs are not magic pills and while the side effects are tolerable, they do have the propensity to cause serious complications like cardiomyopathy and QT prolongation, which can lead to the development of conduction blockade, ventricular arrhythmias, and cardiovascular collapse.[2627] The drugs have also been reported to cause retinopathy, hypoglycemia, myopathy, extrapyramidal side effects, lower the seizure threshold, and cause suicidal tendencies.[2627] Patients with cancer and COVID-19 are frequently older and may have multiple comorbidities and organ dysfunctions; the risk of increased toxicity due to the above factors, as well as drug-drug interactions, represents a challenging clinical scenario that must be kept in mind while taking a decision to prescribe these drugs. Drug interactions become especially important in oncology as a number of medications increase the QT interval, for example: osimertinib, ribociclib, aprepitant, and ondansetron. Concomitant use of tamoxifen citrate increases the risk of developing retinopathy.[2627] Notwithstanding the points mentioned above, FDA approval has resulted in large scale hoarding of the drugs, off label usage by physicians, and self-medication by patients. This has led to a scarcity of the drug for patients suffering from various rheumatological disorders. This may have grave consequences for these patients, as withdrawal of HCQ can cause flare-ups of disease, including life-threatening manifestations, such as lupus nephritis.[28] CONCLUSION While we await the results of adequately powered, randomized trials to assess the benefit of CQ/HCQ as prophylaxis and/or treatment of COVID-19, the knee-jerk reaction of prescribing these drugs (especially for prophylaxis) for one and all must be avoided. Simple, effective measures such as social distancing and frequent hand washing are of paramount importance. Physicians should adhere to the medical council advisories regarding drug usage, and if the drugs do get approval for the treatment of established cases in India, clinicians should follow the advisories and guidelines regarding dosing and duration. Pending clarity on this subject, we recommend constant vigilance regarding preventive measures to minimize the medical community's as well as our patients' risk of getting infected. However, there seems to be some light shining at the end of the tunnel, with recently publicized non-randomized data showing good clinical outcomes of 1061 patients with the combination of HCQ and azithromycin and a mortality rate of only 0.5% in the subgroup of older patients.[29] We sincerely hope that this straw of hope turns into a raft and takes the human population safely ashore in these troubling times.

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