SARS-CoV-2 and the Use of Chloroquine as an Antiviral Treatment

Abstract

In December 2019, a newly discovered SARS-CoV-2 virus emerged from China and propagated worldwide as a pandemic, becoming a major global public health issue. Different publications have discussed the possible efficacy of the antimalarial drug chloroquine (CQ) and its derivatives as a possible treatment against the disease, and, as the drug has often been recommended, we would like to shed a light on the previous experiments and trials conducted with CQ and its derivatives on several viruses, the outcomes being based on in vitro and in vivo results, and call for a well-designed clinical evaluation. As a semisynthetic derivative of quinine, CQ has for decades been the drug of choice to treat malaria because of its relative safety, good efficacy, and for being relatively inexpensive. CQ is a lysosome-penetrating antimalarial drug that neutralizes lysosomal acidification and prevents autophagosomal degradation. Hydroxychloroquine (HCQ) is a 4-aminoquinoline that differs by the addition of a hydroxyl group, decreasing its toxicity while conserving its efficacy. Nevertheless, CQ has a narrow therapeutic window and can cause life-threating cardiovascular issues, documented since the early 80s, especially for patients with underlying cardiac diseases (1). Cardiomyopathies, fatal arrhythmia, or even complete heart block have been described for 40 years, for chronic as well as acute treatment, even in patients with normal underlying cardiac function (2, 3). Another issue is represented by the possibility of vision-threatening toxic retinopathy (4). Thus, major contraindications are related to ocular (pre-existing maculopathy and retinopathy) and cardiac abnormalities [recent myocardial infarction and heart failure, corrected QT interval (QTc) >500 ms] but also include hypersensitivity to the active ingredient, porphyria, or glucose-6-phosphate dehydrogenase (G6PD) deficiency. It is also not recommended to combine these drugs with macrolides such as Azithromycin, which are known to have a synergistic effect on QTc prolongation, as QTc prolongation is associated with an increased risk of life-threatening arrhythmia (5). For the same reason, CQ and HCQ should not be used concomitantly with lopinavir/ritonavir and remdesivir. However, these drugs are not contraindicated during pregnancy (6). In December 2019, COVID19, a novel pneumonia caused by a previously unknown pathogen, emerged in Wuhan, China. The pathogen was soon identified as a novel coronavirus (2019-nCoV, later called SARS-CoV-2), closely related to the one responsible for severe acute respiratory syndrome SARS (SARS-CoV). SARS-CoV-2 infection is triggered by the binding of the spike protein of the virus to angiotensin converting enzyme 2 (ACE2), which is highly expressed in the heart, gut, oral cavity, and lungs (7–9). SARS-CoV-2 mainly invades alveolar epithelial cells, resulting in respiratory symptoms. Briefly, in the cases where it is required, the median duration of hospitalization is 12 days (mean, 12.8) (10). Whereas, many people infected by SARS-CoV-2 develop mild, inconsequential respiratory symptoms, some individuals may develop more severe forms. During hospital stay, pneumonia is the most frequent diagnosis (91.1%), followed by acute respiratory distress syndrome (ARDS) (3.4%), but other organ dysfunctions can occur, leading to shock, multiple organ failure, and eventually death. Despite a lower case fatality rate than either SARS-CoV or Middle East respiratory syndrome-related coronavirus (MERS-CoV) (11, 12), the high number of infected patients can lead to a critical healthcare crisis, as depicted recently in China, Italy, France, and other countries. Currently, there is no specific treatment against the new virus other than supportive care. Therefore, identifying effective agents is urgently needed, either to combat the acute and severe forms of the disease, or to reduce infectiousness in less severe forms in order to reduce the burden for healthcare systems. CQ efficacy has been tested in vitro since the late 60s in different animal cells and viruses (13, 14). Thirty years ago, when comparing in vitro and in vivo trials and experiments, Hellgren et al. (15) already raised doubts concerning extrapolation drawn between the two systems and bench to bedside reproducibility. The sensitivity and therapeutic range of CQ, even in antimalarial treatment, cannot be easily derived from in vitro to in vivo. Hellgren et al. studied the in vivo response to a standard (25 mg/kg) dosage of chloroquine in a group of semi-immunized children from Tanzania. The EC99 (99% inhibition of schizont maturation) in vitro was 2.7 μg/L, and in vivo minimum inhibitory concentrations (MIC) median values were 44.29 (13–202; n = 22) μg/l, for a clearance of parasites, but recrudescence 1–4 weeks later and 237 (range 133–261; n = 7) μg/L for a response when parasitemia failed to clear after 1 week of treatment. CQ, by inhibiting pH-dependent steps of the replication of several viruses, has already been quite extensively tested in vitro and in vivo on different virus strains: African swine fever virus (16), HIV (17), SARS-CoV (18, 19), Influenza A (20), Chikungunya (21), Ebola (22, 23), Zika (24), and, recently, on SARS-CoV-2 (25–27). Treatment with CQ has showed interesting results but also strong differences of application between live animals and cell lines. The major conclusion of these studies was that, if CQ exhibited promising results on virus and cells, the in vivo application is not that straightforward. In the case of Influenza A, the effectiveness of CQ in vitro on limiting the replication of viruses does not extend to in vivo models of influenza. For Ebola virus, the replication was inhibited by chloroquine in vitro but failed to protect Guinea pigs, mice, and hamsters. The...