key: cord-0963432-5yvjbr5q
authors: Hashem, Anwar M.; Alghamdi, Badrah S.; Algaissi, Abdullah A.; Alshehri, Fahad S.; Bukhari, Abdullah; Alfaleh, Mohamed A.; Memish, Ziad A.
title: Therapeutic use of chloroquine and hydroxychloroquine in COVID-19 and other viral infections: A narrative review
date: 2020-05-06
journal: Travel Med Infect Dis
DOI: 10.1016/j.tmaid.2020.101735
sha: a104d0245d5300da286463398a1bacecd71a174e
doc_id: 963432
cord_uid: 5yvjbr5q

Abstract The rapidly spreading Coronavirus Disease (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus (SARS-CoV-2), represents an unprecedented serious challenge to the global public health community. The extremely rapid international spread of the disease with significant morbidity and mortality made finding possible therapeutic interventions a global priority. While approved specific antiviral drugs against SARS-CoV-2 are still lacking, a large number of existing drugs are being explored as a possible treatment for COVID-19 infected patients. Recent publications have re-examined the use of Chloroquine (CQ) and/or Hydroxychloroquine (HCQ) as a potential therapeutic option for these patients. In an attempt to explore the evidence that supports their use in COVID-19 patients, we comprehensively reviewed the previous studies which used CQ or HCQ as an antiviral treatment. Both CQ and HCQ demonstrated promising in vitro results, however, such data have not yet been translated into meaningful in vivo studies. While few clinical trials have suggested some beneficial effects of CQ and HCQ in COVID-19 patients, most of the reported data are still preliminary. Given the current uncertainty, it is worth being mindful of the potential risks and strictly rational the use of these drugs in COVID-19 patients until further high quality randomized clinical trials are available to clarify their role in the treatment or prevention of COVID-19.

6 a receptor for cell entry, suggesting a possible similar effect of CQ on SARS-CoV-2 at this step of virus replication [40] . CQ can also affect early stage of virus replication by inhibiting virus-endosome fusion, likely via increasing endosomal pH [41] . CoVs such as SARS-CoV were shown to be able to enter target cells via pH-dependent mechanism in which the acidic pH of the lysosome triggers fusion of the viral and endosomal membranes resulting in viral particle uncoating and subsequent release of viral nucleic acid into the cytoplasm [42] . CQ can also impair posttranslational modifications of viral proteins through interfering with proteolytic processes [43] and inhibition of glycosylation via specific interactions with sugarmodifying enzymes or glycosyltransferases [28] . CQ can also hamper lysosomal protein degradation and lysosomal fusion with autophagosomes [44] [45] [46] . Moreover, it has been suggested that CQ has the ability to affect the cytotoxic mechanisms and works as antiautophagy agent in vitro [47] . CQ works as anti-inflammatory agent through reducing tumor necrosis factor (TNFα) release and suppressing TNF receptors on monocytes [26, 28] .

On the other hand, HCQ has a similar effect to CQ in interfering with the glycosylation of ACE2, blocking virus/cell fusion and inhibiting lysosomal activity by increasing pH [22] . HCQ can also impede major histocompatibility complex (MCH) class II expression which inhibits T cell activation, expression of CD145 and cytokines release [48] [49] [50] . Furthermore, HCQ has been shown to impair Toll-like receptors (TLRs) signaling through increasing endosomal pH and interfering with TLR7 and TLR9 binding to their DNA/RNA ligands thereby inhibiting transcription of pro-inflammatory genes [51] [52] [53] . The aforementioned immunomodulatory properties of CQ and HCQ have raised the interest in using these drugs in COVID-19 patients at risk of cytokines release syndrome (CRS) [22] . 7 

The fact that both CQ and HCQ are considered for the management of COVID-19 patients clearly highlights the need to better understand their pharmacokinetics (PK) parameters.

However, a full understanding of these parameters has been challenging despite the numerous reported studies. Generally, PK parameters for CQ and HCQ are comparable (Table 1) [54, 55] . Following oral administration of CQ and HCQ, their bioavailability can reach up to 80% with plasma peak time around 2-4 hours [56] [57] [58] . Thus, parenteral administration, if available, might be a better route especially that oral administration has shown huge interpatient variability [56, 59, 60] . The long half-life of both CQ and HCQ which could range from 30 to 60 days is likely attributed to their large volume of distribution (200 to 800 L/kg) and extensive tissue uptake [61] [62] [63] [64] [65] [66] [67] [68] . CQ and HCQ are metabolized via CYP-450 enzymes to other active compounds, which are responsible for the extended pharmacological actions and increased toxicity [61, 69] . Up to 60% of CQ and HCQ is primarily excreted renally as unchanged or metabolized forms, and the remaining (40%) is usually cleared through the liver, feces and skin or stored in other lean body tissues [54, [69] [70] [71] [72] [73] [74] . It's important to note that CQ and HCQ have a chiral center, which produces two enantiomers R(−) or S(+) forms or isomers [75] , in which little is known about the differences in their pharmacological activity and their corresponding metabolites. Most clinically used CQ and HCQ exist as a racemic mixture (50:50) of both isomers which complicates the understanding of their PK and associated toxicity as they could behave differently inside the body [57, [75] [76] [77] .

The most common CQ and HCQ adverse effects are gastrointestinal symptoms such as nausea, vomiting and abdominal discomfort [78] , and uncommonly worrisome fulminant hepatic failure [79] , toxic epidermal necrolysis (TEN) [80] and cardiotoxicity that could 8 manifest with QT abnormality [81] [82] [83] . Nevertheless, over the years CQ and HCQ have maintained a good safety profile when used in several chronic diseases such as RA and SLE.

Despite some animal experiments suggesting that HCQ is probably less toxic than CQ, there is a lack of high quality evidence from clinical trials supporting this claim [74, [84] [85] [86] [87] . These toxicities could be related to the very long half-life and the large volume of distribution of both drugs. One of the significant toxic effects of CQ and HCQ is the possible ocular pigmentation due to their binding to melanin, which could lead to damage in different parts of the eye including the cornea, ciliary body and retina [88] . Notably, the incidence of such ocular toxicity is usually rare. For instance, it was shown that only 0.5% out of ~400 patients treated with HCQ (≤6.5 mg/kg/day) for 6 years due to RA or SLE had developed ocular related complications [89] . Most studies have shown that such complications might only occur with long term treatment of chronic diseases which extends for more than 5 years with doses above or equal to 6.5 mg/kg/day [90, 91] . However, ocular toxicity and changes could still occur with shorter treatments. Other complications such as development of proximal myopathy associated with respiratory failure have also been reported in patients treated with either CQ or HCQ [92] [93] [94] [95] . Nonetheless, most of these complications were seen in elderly patients with an average age of 70 years suffering from chronic RA or autoimmune diseases.

Both CQ and HCQ were also shown to be associated with rare but life-threatening cardiomyopathy [96] [97] [98] . Other less reported CQ and HCQ toxicities include urticaria [99] , ototoxicity [100, 101] and some neurological effects [102, 103] .

The antiviral effects of CQ were suggested at least 50 years ago [23, 25] . Since then, several studies have tested the ability of CQ and HCQ to inhibit the replication of a wide range of CoVs and non-CoV viruses in vitro as shown in Tables 2 and 3 , respectively. The majority of 9 these studies have revealed a substantial ability of CQ and HCQ as well as some of their derivatives to inhibit viral replication with no to low toxicity. Specifically, CQ has been shown to inhibit the replication of different CoVs including SARS-CoV, MERS-CoV and SARS-CoV-2 among others in several studies (Table 2) [37, [104] [105] [106] [107] [108] [109] [110] [111] [112] [113] [114] [115] . Only two studies showed no significant inhibitory effects of CQ on MERS-CoV and mouse hepatitis virus (MHV4) [116, 117] . Other CQ derivatives such as amodiaquine (AMD), Ferroquine (FQ), Hydroxy ferroquine (HFQ) have been also shown to exerts some antiviral activity [105, 106] .

Interestingly enough, while HCQ does not seem to have a significant effect in reducing SARS-CoV and Feline CoV replication [106] , it was recently shown to have a potent in vitro inhibitory effect against SARS-CoV-2 replication [112, 116] .

Similarly, these compounds have shown excellent in vitro antiviral activity against several non CoV (mostly RNA viruses) with low toxicity in most cases (Table 3) . For instance, HIV was shown to be inhibited by CQ alone or in combination with HCQ, hydroxyurea (HU1), didanosine (ddI), zidovudine (ZDV), indinavir (IDV), saquinavir (SQV) or ritonavir (RTV) [106, [118] [119] [120] [121] [122] . While other derivatives such as HCQ and HFQ have been also shown to inhibit HIV replication [106, 123, 124] , one study showed no effect of HCQ and FQ on HIV [106] . Similarly, it was found that CQ could enhance Epstein-Barr virus replication [125] .

Furthermore, another study has suggested possible enhanced HIV replication with CQ treatment through protection of tat protein from proteolytic degradation [126] . Influenza A and B viruses have also been shown to be inhibited by CQ [27, [127] [128] [129] [130] [131] although contradicting results have been seen for some subtypes and strains such as avian H7N3 strains (A/Mallard/It/43/01 and A/Ty/It/220158/02) [106, 130] . Several other studies have also reported in vitro inhibitory effect of CQ on multiple viruses such as chikungunya virus (CHIKV) [41, 132, 133] , zika virus (ZIKV) [134] [135] [136] , Ebola virus (EBOV) [137] [138] [139] , dengue viruses (DENV) in mammalian cells [43, 140, 141] but not insect cells [141] as well 10 as several others [43, 139, [142] [143] [144] [145] [146] [147] [148] [149] [150] . Nonetheless, some reports failed to observe antiviral activity of CQ, HCQ and FQ on several other viruses including polio virus, reovirus, respiratory syncytial virus (RSV), herpes simplex viruses, coxsackie virus, vesicular stomatitis virus (VSV), vaccinia virus, sindbis virus, parainfluenza-3 virus and Punta Toro virus [106, 151] .

There are limited studies established to investigate the possible antiviral effect of CQ or HCQ in animal models (Table 4 ). In general, studies showed no significant effect of CQ on CoVs including SARS-CoV and feline infectious peritonitis virus (FIPV) replication or clinical scores in mice and cats, respectively [105, 110] . However, it has been found that CQ significantly reduced HCoV-OC43 dissemination and replication in mice central nervous system (CNS) after CQ administration [152] and increased the survival rate of HCoV-OC43 infected newborn mice when their mothers treated by CQ most probably through placental and maternal milk transfer [108] .

On the other hand, CQ administration has shown contradicting outcomes when used against non-CoVs RNA viruses in different animal models. Some studies have demonstrated antiviral efficacy of CQ in influenza A virus H5N1, ZIKV and EBOV infected mice [29, 134, 139] .

Interestingly, CQ was effective against ZIKV in both wild type and IFNAR deficient mice, and protected infected suckling pups from infection and microcephaly when given to their mothers [29, 134, 136] . However, several other studies showed no significant antiviral effect of CQ against influenza A H1N1 and H3N2 viruses in mice and Ferrets, respectively [129] .

Similarly, CQ was ineffective against EBOV in guinea pigs, mice and hamsters [137, 138] , Nipah virus (NiV) in Ferrets and hamsters [148, 153] , Hendra virus (HeV) in hamsters [148] , 11 CHIKV in cynomolgus macaques [133] , Lassa virus (LASV) in mice [139] and Semliki Forest Virus (SIV) in mice [154] . Importantly, most of these previous in vivo studies showed toxicity in animals [129, 133, 137, 138, 154] . Furthermore, it was shown that CQ could lead to disease exacerbation correlating with increased type I IFN response and delayed immune responses in CHIKV infected macaques [133] , increased mortality rate of SFV-infected mice [154] and NiV or HeV infected hamsters [148] .

There are very limited published clinical trials that studied the possible antiviral effect of CQ or HCQ in CoV and non-CoV infected patients (Table 5 ). These published clinical trials have clearly shown no significant benefit of using CQ in the prevention or treatment against influenza, DENV or CHIKV infections in patients [133, [155] [156] [157] [158] . In fact, in one study, patients treated with CQ were more likely to develop adverse effects such as arthralgia at day 200 post-treatment [157] . On the other hand, few studies have reported that HCQ could decease HIV-1 viremia, stabilize CD4 T cell count and reduce IL-6 and IgG levels in infected patients [159] , although others showed contradicting finding of increased HIV RNAemia in HCQ treated patients [160, 161] . Interestingly, while few clinical studies have suggested that the use of HCQ alone or with azithromycin (AZT) could be beneficial for COVID-19 patients as it reduces viral shedding and time to clinical recovery [162] [163] [164] , others have reported no effect in infected patients [165, 166] . However, it is important to note that most of these studies have several limitations in study designs with small sample sizes. Nonetheless, around 104 clinical trials are ongoing in different countries to asses and evaluate the therapeutic and prophylactic effects of both CQ and/or HCQ in COVID-19 patients (Table 6 ).

The COVID-19 pandemic has spread out of control and has caused considerable morbidity and mortality in several countries. In this unprecedented situation, clinicians have tried all kinds of treatments in an effort to stem the progression of this disease. One treatment that has received huge attention was the empirical use of anti-malarial CQ/HCQ. While there is no strong and enough scientific and clinical data to support their use, several countries have already included CQ/HCQ in COVID-19 treatment protocols [167, 168] , not only as a treatment option for severely ill patients but also as a prophylactic measure.

In this comprehensive review of the antiviral effects of CQ and HCQ on SARS-CoV-2 as well as other viruses, we show a broad variation in the research outcomes. Both CQ and HCQ demonstrated promising in vitro results, however, such data have not yet been translated into meaningful in vivo studies. While few clinical trials have suggested some beneficial effects of CQ and HCQ in COVID-19 patients, most of the reported data are still preliminary [20, 162] , [163] . Furthermore, at least 7 of the ongoing trials were canceled or stopped and it is not yet clear if this was due to possible adverse effects, ineffectiveness or other reasons.

There are several toxicities associated with these drugs [78] [79] [80] , the one that is foremost concerning is the possibility of QT prolongation and the risk of Torsades de pointes, which is a potentially life-threatening arrhythmia [81] [82] [83] . Nevertheless, while our literature review showed that this is quite rare, it is not yet evident whether there would be any additive or possible synergistic risk when these drugs are combined with other medications such as AZT [83] . In fact, it is challenging to base a treatment decision in the absence of a complete research cycle and a clear vision of drug efficacy and safety. Given the current uncertainty, it is worth being mindful of the potential risks and strictly rational the use of these drugs in 13 COVID-19 patients until further high quality randomized clinical trials are available to clarify their role in the treatment or prevention of COVID-19.

This work was funded by King Abdulaziz City for Science and Technology (KACST) grant number 09-1, which is a part of the Targeted Research Program (TRP). 

AZT: Azithromycin; Vit C: Vitamin C; Vit D: Vitamin D; LST: Losartan; RDV: Remdesivir; IFß-1a: Interferon ß-1a; NIVO: Nivolumab; TCZ: Tocilizumab; LEV: Levamisole; BUD: Budesonide; FORM: Formoterol; SOF: Sofosbuvir; LDV: Ledipasvir; OTV: Oseltamivir; ATV: Atazanavir; COBI: Cobicistat; TDF: Tenofovir disoproxil fumarate

HRCT: Pulmonary inflammation resolution time, IMV: invasive mechanical ventilation; HCW: Healthcare workers; ; ARS: Acute respiratory syndrome

SpO2/FiO2: oxygen saturation/fraction of inspired oxygen ratio

ICU: Intensive Care Unit; CRP: C-reactive protein

* The same study was registered in ISRCTN registry (registration no. ISRCTN50189673) with a total number of 5000 patients

); the European Union

ISRCTN registry

/) and the Australian New Zealand Clinical trial Registry (ANZCTR)

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