Chloroquine and Hydroxychloroquine in the Era of COVID-19: A Mini-Review

Coronavirus disease of 2019 (COVID-19) has severely affected global health, and caused a significant health burden worldwide in all, the patients, and healthy people. Globally, 17 August 2021, there have been 207,784,507 confirmed cases of COVID-19, including 4,370,424 deaths reported to WHO. As of 16 August 2021, a total of 4,462,336,040 vaccine doses have been administered. Many risk factors, such as older adults, people with medical conditions and pregnant people and recently pregnant people are at an increased risk for severe illness from COVID-19 when compared to non-pregnant people. CQ and HCQ also used in the management of rheumatism, joint inflammation, systemic lupus and showed positive and promising results in the primary research for COVID-19 management but, it’s still confusing whether to use them in patients infected with COVID-19 or it is better to avoid them. Although these drugs, chloroquine (CQ) and hydroxychloroquine (HCQ), which have been tried for the treatment of this disease, COVID-19 vaccines can help end the pandemic. In this review we aim to evaluate the evidence regarding the efficacy and safety of CQ and HCQ used against viral infection caused by COVID-19. Our hope is to shed light on CQ and HCQ as a management modality in the era of COVID-19. We can’t do without drug therapy as a mainstream till antiviral agents and effective vaccines would be available.


INTRODUCTION
A novel coronavirus (nCoV), also named "SARS-CoV-2", was declared by the World Health Organization (WHO) in December 2019 to be responsible for the outbreak of COVID-19. There have been 207,784,507 confirmed cases of COVID-19, comprising 4,370,424 deaths, reported to WHO 16 August 2021 [1]. Coronaviridae is the main family to which Coronaviruses belong. Coronavirinae and Torovirinae are two subfamilies divided from the main family. Coronavirinae is also subdivided into four genera: Alpha, Beta, Gamma and Deltacoronavirus [2].SARS-CoV-2 is closely related to the beta-coronaviruses. Like other coronaviruses, SARS-CoV-2 genome is positive, single-stranded RNA with a 5′-cap, 3'-UTR poly(A) tail [3]. At the beginning, case fatality rate of the virus was measured to be 2%, but in some countries, ranged from 4 to 9 %. Meanwhile, the actual fatality rate was 1% after adjustment for asymptomatic cases. Now, the major fears of COVID-19 are the rapid transmission and the substantial proportion of asymptomatic people who responsible for about 40-50% of transmission [4].
Many efforts, including both pharmacological and non-pharmacological interventions, are being done to fight against this virus. In a trial to find a potential pharmacologic substance that may be useful to protect against that virus and/or treat COVID-19 patients. Clinicians have considered chloroquine (CQ) and hydroxychloroquine (HCQ) as a treatment regimen [4]. Many rationales supported the selection of this regimen. Since this time, the world has divided into one with while the others against this regimen. Currently more than one billion people are in lockdown in their homes, flights have been cancelled, and the global transportation system has become paralyzed worldwide in response to the highly contagious nature of the COVID-19. Till now, there is no effective, proved pharmacological treatment for it. In-vitro studies have suggested that chloroquine and hydroxychloroquine, an immunomodulant drugs traditionally used to treat malaria, are effective in reducing viral replication in other infections, including the SARS-associated coronavirus (CoV) and MERS-CoV [5,6]. In this review, we aim to investigate indirect epidemiologic evidence of the antiviral characteristics of hydroxychloroquine and chloroquine in the treatment of COVID-19 infection.

STRUCTURE OF THE SARS-COV-2 VIRUS
SARS-CoV-2 is round or elliptic in shape with pleomorphic structure and has small size, ranging from 60 to 140 nm in diameter. The outer morphology of SARSCoV-2 has multiple nucleoproteins, membranous proteins and polyproteins-like spike glycoproteins S [7]. The latter has homo-trimers that project from the outer surface of the virus's, resulting in a halolike shape.

CHEMICAL COMPOSITIONS AND SOURCES OF CQ AND HCQ
Hydroxychloroquine is a disease-modifying antirheumatic drug (DMARD) with a chemical structure very similar to that of chloroquine [14][15][16]. Both are absorbed from the upper intestinal tract [17]. Systemic modifications are added to quinine, which is a plant alkaloid and quinoline containing compound, to produce CQ. HCQ is a derivative of CQ and synthesized from it by adding a hydroxyl group to CQ [4]. The toxicity of CQ in animals is believed to be three times more than HCQ [18]. Also, HCQ is used widely to treat auto-immune diseases such as, rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) [19].

MECHANISM OF ACTION
Chloroquine (CQ) and hydroxychloroquine (HCG) were originally used to cure patients with rheumatoid arthritis (RA) and those diseased with lupus (SLE) [20]. Both drugs have the same mechanism of action and adverse effect. And all of which are well known and reported [21-23]. A short time ago, CQ and it's derivative HCQ were discovered to treat many viral infections, e.g. hepatitis A, AIDS and Borna disease [5]. Many studies say CQ and HCQ may have an impact on COOVID-19 by two diverse mechanisms; increasing the pH of endosomes, regulating lysosomes and improving immunity [24,25]. For COVID-19, The modulation of pH could be the commonest process, when in the unprotonated form, CQ/HCQ can diffuse passively across cellular membranes, where it is protonated and trapped in endosomes/lysosomes, resulting in alkalinization of the acidic compartments. Due to this alkaline media, the virus cannot enter the host cell. This entry was originally facilitated by spike proteins in the host cell (ACE2). For spike protein priming, this procedure involves the serine protease TMPRSS2, whereas TMPRSS2 priming uses endosomal cysteine proteases cathepsin B/L, which requires a low pH environment [26].
HCQ/CQ also inhibit glycosylation of angiotensin converting enzyme-2, to which the SARS-Cov-2

ADVERSE EFFECTS
Indeed, both CQ and HCQ cause severe adverse effects when prescribed in a high dose. This is mediated mainly by modulation of cellular excitability and action potential of excitable cells such as, neurons and cardiac myocytes [19].

Ocular Manifestations
Ocular manifestations like diplopia, decreased visual acuity, retinopathy, retinal detachment, and bilateral visual loss were found to be the most dangerous adverse effects caused by high doses of CQ [34]. Also, it can lead to maculopathies and macular degeneration which may be irreversible.

Psychiatric Manifestation
High dosage CQ causes major psychiatric issues as paranoia, hallucinations, and suicidal attempts [35]. Intramuscular CQ has proved to cause lifethreatening hypotension [36].

Cardiac Manifestation
On the heart, both proved to cause a decrease of myocardial activity and lead to manifest cardiac electrical conduction and QT interval elongation [36]. Clinical trials found that the mean prolongation of QT interval was about 35 [28-43] ms and QT interval exceed 500 ms during treatment with chloroquine in more than 20% percent of COVID-19 patients [37]. So, it should be taken in consideration when managing COVID-19, as in severe cases of this disease, there is increased cardiac mortality due to ARDS, and direct cardiac injury [38]. There are other adverse effects experienced such as metabolic abnormalities (hypokalemia, magnesemia and calcemia), pruritus, photosensitivity, seizures, paranoia, hallucinations, vomiting, diarrhea, and retinopathy [39-41].

THE CQ/HCQ EFFICACY IN LINE WITH THE PATHOGENESIS OF COVID-19
Indeed   [56][57][58]. Furthermore, the SARS-CoV spike protein has been shown to cause extracellular Ca2influx +, which causes the Ca2+-dependent protein kinase C alpha to be activated [59]. The downstream ERK/NF-kappa B pathway, which is necessary for COX-2 protein expression in SARS-associated coronavirus triggered cyclooxygenase-2, is regulated by PKC alpha (COX-2). As a result, by reducing Ca2+ influx into host cells, CQ/HCQ may lessen inflammation. CQ/HCQ may also directly control virulence by modulating coronavirus envelope (E) protein Ca2+ transport. The SARS-CoV virus's E protein is a viroporin, which allows Ca2+ and other cations to pass through. This is a crucial step in the production of pro-inflammatory cytokines such as IL-1. SARS E protein can even form a protein-lipid channel in the Golgi membrane, through which Ca2+ mediates pH and E protein pore selectivity. As a result, CQ/HCQ may alter immune response by limiting Ca2+ influx through viroporin and reducing SARS-CoV-2-induced, exacerbated proinflammation [60,61]. CQ/HCQ may also operate as an immunomodulator by inhibiting Ca2+dependent calcineurin activity [62]. The suppression of calcineurin limits nuclear factor translocation in activated T cells, which prevents cytokine transcription. These findings imply that cytosolic Ca2+ modification is a fundamental mechanism through which CQ/HCQ works as a broad-spectrum antiviral [52, 63,64]. Given the foregoing facts, as well as the tight phylogenic relationship between SARS-CoV and SARS-CoV-2, calcium targeting is likely to be a portion of COVID-19's CQ/HCQ effects.

EVIDENCE OF USING CQ AND HCQ TO MANAGE COVID-19 PATIENTS AND RECOMMENDATIONS
Till now, there are very limited data proving the use of CQ and HCQ for the management or prevention of COVID-19. A pilot study in China [65] on 30 confirmed patients with COVID-19 was done by dividing the patients into two groups, group a and group b. Group a received the standard treatment and group b received standard treatment plus hydroxychloroquine (400 mg for 5 days). The results were noted to be identical in both groups. By day 7, more patients in the group on standard treatment alone (93.3%) had a negative throat swab compared to those taking the HCQ (86.7%). Also, it was notable that patient on HCQ showed marked reduction in pneumonia (on CT scan). One patient in the HCQ group developed severe disease [65]. There were some limitations in this study such as small sample size.
On April 21, 2020, a reasonably large US study (n=368) of veterans hospitalized with COVID-19 revealed no evidence that using HCQ, with or without azithromycin, lowered the incidence of mechanical ventilation in COVID-19 patients. In patients treated alone with HCQ, there was a link to higher overall mortality [66]. This was a retrospective, non-randomized study that has not yet been peer reviewed. A small population of mostly African American males over the age of 65 was also a constraint. The authors could not rule out the possibility of selection bias or residual confounders after adjusting for variables such as comorbidities and concomitant drugs [66]. Many guidelines support the usage of CQ or HCQ for the management of COVID19 patients. Belgian guidelines support HCQ for severe disease and recommend it for mild to moderate disease; Chinese guidelines recommend CQ for hospitalized patients, while later revisions have voiced concern about dosing and special patient categories [67,68]; Italian guidelines recommend early usage of CQ or HCQ [69]. The WHO, and Public Health England are yet to recommend CQ or HCQ for treatment.

RECENT UPDATES REGARDING MANAGEMENT OF COVID-19
It is well known that understanding the interactions between the target and the ligand of the COVID-19 is the most crucial and difficult step in discovering drug for COVID-19. CoViTris2020 and ChloViD2020 were discovered to have proteins-inhibiting characteristics on SARS-CoV-2. The molecules CoViTris2020 and ChloViD2020 have been successfully reevaluated, repurposed, and reported as very promising hit molecules (they could also be considered the first extremely potent anticoronaviral-2 inhibitors). "Coronavirus-2 Killers" are polyphenolic 1,3,4-oxadiazole compounds having broad antiviral activity. SARS-CoV-2 enzymes are successfully inhibited by a multitarget and extremely powerful inhibitor. As a result, both compounds are two of the earliest recognized promising compounds. potential medicines under study for the effective and comprehensive treatment of COVID-19 [70,71].

CONCLUSION
Hydroxychloroquine and chloroquine don't lower the incidence of SARS-CoV-2 transmission than normal regimens. Adverse events are high; some of the most typically documented adverse effects of CQ/HCQ are likely to obstruct successful treatment of COVID-19 patients. Thought, no treatment-related serious adverse events were reported. As a result, until sufficiently powered randomized controlled trials (RCTs) give more evidence on the efficacy and safety of CQ/HCQ use in the treatment of COVID-19 patients, it is critical to balance the possible advantages of these drugs against the potential hazards. Furthermore, long-term, e.g., 3-6 months posttherapy, side effects of CQ/HCQ use in COVID-19, such as cardiomyopathy, muscle weakness, anxiety, insomnia, and gastrointestinal issues, should be evaluated in clinical trials. Off-label usage of CQ/HCQ should preferably be reserved only for COVID-19 patients treated in the context of clinical studies until evidence from RCTs becomes available, to improve our knowledge of safety and efficacy.

CONSENT
It is not applicable.

ETHICAL APPROVAL
It is not applicable.